Search

Purpose: To assess the effect of axial length (AL) on the prevalence of pathologic myopia (PM) and associated myopic features in a Singaporean hospital-based cohort of patient with high myopia (HM).Methods: In total, 923 HM eyes from 495 individuals were recruited from the Myopic and Pathologic Eyes in Singapore (MyoPES) cohort and underwent ocular biometry, fundus photography, fundus autofluorescence, and swept-source optical coherence tomography (SS-OCT). Images were analyzed for the presence of myopic macular degeneration (MMD), myopic choroidal neovascularization (mCNV), myopic traction maculopathy (MTM), peripapillary atrophy (PPA), myopic tilted disc, posterior staphyloma (PS), dome-shaped macula (DSM), vitremacular adhesions (VMA), and the epiretinal membrane (ERM). Eyes were stratified into quartiles based on ALs to determine cut-off values to perform comparisons between shorter-length and longer-length groups. A χ2-test was done to determine the difference in the prevalence of pathologies between groups.Results: Overall, mean AL was 29.2 ± 2.2 mm (range 25.0–36.7 mm). Myopic macular degeneration, PPA, myopic tilted disc, and ERM have AL threshold of ≥27.5 mm, whereas MTM has an AL threshold of ≥29.0 mm. We found that there was a significantly higher prevalence of MMD (88.2 vs. 49.4%; p < 0.001), PPA (98.1 vs. 80.1%; p < 0.001), myopic tilted disc (72.7 vs. 50.2%; p < 0.001), and ERM (81.4 vs. 17.3%; p = 0.003) in eyes with AL ≥ 27.5 mm vs. eyes without AL

The purpose of this study is to determine the prevalence of asymptomatic male patients with urethral infections attending a government sexually transmitted infection clinic in Hong Kong and their microbiological profile. A total of 274 consecutive male patients without any symptoms for urethral infections were recruited. A questionnaire was used to record the symptoms, sexual history and demographics. Further assessment, including urethral smear for Gram stain, gonococcal culture and polymerase chain reaction (PCR) for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG) and Ureaplasma urealyticum (UU) were performed. In 274 asymptomatic patients, 36 patients had non-gonococcal urethritis (NGU) and two patients had positive gonococcal culture. Among the asymptomatic patients with NGU, there were 6 (16.6%), 10 (22.8%) and five (13.9%) patients with positive PCR for CT, UU and MG, respectively. In addition, there were 14 asymptomatic patients with positive PCR for CT but without evidence of NGU. In conclusion, urethral infections were identified in a significant number of asymptomatic male patients and therefore, routine screening for this group is warranted. [ABSTRACT FROM AUTHOR]

Background: The escalating rates of gonococcal resistance to quinolone in Hong Kong have prompted a search for an alternative first-line antimicrobial agent for use in treating uncomplicated gonococcal urethritis. Ceftibuten is an orally active third-generation cephalosporin with potent in vitro activity against Neisseria gonorrhoeae. Its pharmacokinetic properties allow single-dose administration.Objective: To evaluate the efficacy, safety, and tolerability of ceftibuten in the treatment of uncomplicated gonorrhea in men.Study Design: Ceftibuten was evaluated in an open-label, noncomparative, multicenter study. Eligible men with uncomplicated gonococcal urethritis were treated with a single 400-mg oral dose of ceftibuten and reassessed 1 week and 3 weeks after treatment. The main outcome measures were the isolation of N. gonorrhoeae, patient-reported side effects, and other safety parameters (e.g., blood counts and renal and hepatic function tests).Results: One hundred twenty-five men were enrolled in the study. The overall cure rate was 98.2% (110 of 112 evaluable patients). Adverse events, which occurred in 4.5% of patients, were all mild, well tolerated, and of short duration. No significant changes in laboratory test results were noted. Of the 125 isolates, 4.8% were -lactamase positive. Susceptibility to ofloxacin was found to be low in 59.2% of isolates (MIC 0.1 to < 1g/mL) and 25.6% of isolates were resistant (MIC1g/mL) to ofloxacin.Conclusions: A single 400-mg oral dose of ceftibuten is highly effective and well tolerated in the treatment of uncomplicated gonococcal urethritis in men. [ABSTRACT FROM AUTHOR]

Objective: Inappropriate use of short-acting beta2-agonists (SABA) in asthma has been associated with undesired outcomes. This national expert consensus was developed to increase awareness of SABA overuse and provide recommendations on the ways to eliminate SABA overprescription and overreliance in Malaysia., Data Sources: This expert consensus was developed by searching the PubMed database, using index terms to identify SABA overuse-related burden and recommendations made in asthma guidelines. Consensus recommendations were made via the Delphi method, involving a Malaysian expert committee comprising 13 healthcare professionals (five pulmonologists, four family medicine specialists, two emergency medicine physicians and two pharmacists)., Study Selections: The articles reviewed include randomized controlled trials, systematic reviews, meta-analyses, observational studies, guidelines, and surveys, with abstracts in English and published up until June 2023. Relevant recommendations were also sourced from verified websites of medical organizations and societies., Results: Eleven consensus statements were developed, each statement achieving a priori agreement level of at least 70%. The statements reflect SABA overreliance in asthma care, as well as recommendations to eliminate SABA overprescription and overreliance in Malaysia. Supporting evidence in the literature as well as expert committee discussions leading to the development of the finalized statements were elaborated., Conclusion: This national expert consensus discussed the burden of SABA overreliance and made specific recommendations to eliminate SABA overprescription and overreliance in the Malaysian context. This consensus document is anticipated to impart better awareness among Malaysian healthcare providers and contribute to the continuous improvement of asthma care in the country.

Background: The SARS-CoV-2 pandemic drove global vaccination. However, breakthrough infections raised concerns about vaccine performance, leading the World Health Organization (WHO) to recommend investigations thereof. This study aimed to evaluate the clinical outcomes (time to breakthrough infection, intensive care unit [ICU] admission, and in-hospital mortality) of hospitalised patients with SARS-CoV-2 breakthrough infection. This was the primary outcome and the risk factors associated with its severity were the secondary outcomes., Methods: This retrospective cohort study at a multispecialty tertiary hospital in Selangor, Malaysia included 200 fully adult vaccinated patients, with confirmed SARS-CoV-2 infection, admitted from September 2021 to February 2022. Participants were selected by simple random sampling. Infection severity was categorised as CAT 2-3 (mild-moderate) and 4-5 (severe-critical)., Results: The time to breakthrough infection was significantly longer for BNT162B2 recipients (128.47 ± 46.21 days) compared to CoronaVac (94.09 ± 48.71 days; P = 0.001) and ChAdOx1-S recipients (90.80 ± 37.59 days; P = 0.019). No significant associations were found between SARS-CoV-2-related ICU admission, mortality, and the vaccines. Multivariable analysis identified vaccine type, variant of concern, ethnicity, and hypertension as significant predictors of severity. BNT162b2 and ChAdOx1-S recipients had significantly (81 % and 74 %, respectively) lower odds of CAT 4-5 infection compared to CoronaVac recipients. Indian patients had a significantly (83 %) lower chance of CAT 4-5 infection compared to Malay patients. Patients with breakthrough infections during the Omicron period had a significantly (58 %) lower risk of CAT 4-5 compared to those in the Delta period. The CAT 4-5 risk was significantly (nearly threefold) higher in hypertensive patients., Conclusion: The results support the Malaysian Ministry of Health's recommended booster three months after primary vaccination and the WHO's recommended heterologous booster following CoronaVac. Certain ethnic groups, hypertensive patients, and viral variants may require attention in future pandemics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Introduction: The recent global pandemic of Covid-19 caused various disruptions. Among them were face-to-face teaching and learning activities being switched to virtual sessions in accordance with health authorities recommendations. The impact of these changes on work readiness of pharmacy graduates is unknown., Aim: This study aims to determine the impact of pharmacy graduate's work readiness, particularly those that had their studies disrupted from the pandemic., Methods: Practicing pharmacists with supervisory experience were interviewed on their opinions on work readiness of early career and intern pharmacists. Specifically, they were asked to comment on work readiness of pharmacy graduates who had their later stage of pharmacy education impacted by the pandemic. Data was transcribed verbatim and thematically analysed. This was also supplemented with quantitative data from graduating students in 2020 and 2021 using the Work Readiness Scale., Results: Qualitative feedback showed four themes related to workforce readiness: work competence, social intelligence, personal characteristics, and organizational acumen. Preceptors interviewed noted differences in communication abilities when interacting with patients. However, this improved with time. Quantitative data collected from graduates via the validated Work-Readiness Scale also showed a more positive agreement towards perceived work readiness. These graduates were comfortable with using technology as they had used these extensively in their learning during the pandemic and thus was comfortable in adopting digital health tools in their practice., Conclusion: Although graduates reported to be work ready, there were gaps in communication skills and confidence levels when interacting with patients, as reported by supervising preceptors. Graduates also described this sense of 'missing out' from not having the opportunity to attend face-to-face activities like their originally planned hospital placements and how it impacted their choice of career. As pharmacists continue to play vital roles as members of the broader healthcare workforce, both in clinical and nonclinical settings, learnings from this study should be considered in designing educational activities to train and develop the workforce of the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Background: Self-management interventions often employ behaviour change techniques in order to produce desired target behaviours that are necessary for day-to-day living with a chronic disease. Despite the large number of self-management interventions for patients with chronic obstructive pulmonary disease (COPD), previously reported interventions have been typically delivered by healthcare providers other than the pharmacist., Objective: This systematic review examined the components of pharmacists-delivered COPD self-management interventions according to an established taxonomy of behaviour change techniques (BCTs)., Methods: A systematic search was conducted on PubMed, ScienceDirect, OVID, and Google Scholar from January 2011 to December 2021 for studies of pharmacist-delivered self-management interventions in COPD patients., Results: A total of seventeen studies of intervention were eligible for inclusion in the narrative review. Interventions were educational and were delivered individually and face-to-face for the first session. Across studies, pharmacists spent an average of 35 min on the first meeting and had an average of 6 follow-up sessions. Recurrent BCTs in pharmacist interventions were "Information on the health consequence", "Feedback on behaviour", "Instruction on how to perform a behaviour", "Demonstration of the behaviour" and "Behavioural practice/rehearsal"., Conclusions: Pharmacists have provided interventions towards improving health behaviours, especially on adherence and usage of inhaler devices for patients with COPD. Future self-management interventions should be designed using the identified BCTs for the improvement of COPD self-management and disease outcomes., Competing Interests: Declaration of competing interest The authors declare that there was absence of any financial relationships that could be construed as a potential conflict of interest during the conduct of the study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ischemic heart disease, which is often associated with irreversibly damaged heart muscle, is a major global health burden. Here, we report the potential of stem cell-derived committed cardiac progenitors (CCPs) have in regenerative cardiology. Human pluripotent embryonic stem cells were differentiated to CCPs on a laminin 521 + 221 matrix, characterized with bulk and single-cell RNA sequencing, and transplanted into infarcted pig hearts. CCPs differentiated for eleven days expressed a set of genes showing higher expression than cells differentiated for seven days. Functional heart studies revealed significant improvement in left ventricular ejection fraction at four and twelve weeks following transplantation. We also observed significant improvements in ventricular wall thickness and a reduction in infarction size after CCP transplantation (p-value < 0.05). Immunohistology analyses revealed in vivo maturation of the CCPs into cardiomyocytes (CM). We observed temporary episodes of ventricular tachyarrhythmia (VT) in four pigs and persistent VT in one pig, but the remaining five pigs exhibited normal sinus rhythm. Importantly, all pigs survived without the formation of any tumors or VT-related abnormalities. We conclude that pluripotent stem cell-derived CCPs constitute a promising possibility for myocardial infarction treatment and that they may positively impact regenerative cardiology., (© 2023. The Author(s).)

Blindness caused by advanced stages of inherited retinal diseases and age-related macular degeneration are characterized by photoreceptor loss. Cell therapy involving replacement with functional photoreceptor-like cells generated from human pluripotent stem cells holds great promise. Here, we generated a human recombinant retina-specific laminin isoform, LN523, and demonstrated the role in promoting the differentiation of human embryonic stem cells into photoreceptor progenitors. This chemically defined and xenogen-free method enables reproducible production of photoreceptor progenitors within 32 days. We observed that the transplantation into rd10 mice were able to protect the host photoreceptor outer nuclear layer (ONL) up to 2 weeks post transplantation as measured by full-field electroretinogram. At 4 weeks post transplantation, the engrafted cells were found to survive, mature, and associate with the host's rod bipolar cells. Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses. Post-transplanted rabbit model also provided congruent evidence for synaptic connectivity with the degenerated host retina. The results may pave the way for the development of stem cell-based therapeutics for retina degeneration., Competing Interests: Declaration of interests K.T. is co-founder and shareholder in BioLamina. K.T. and H.G.T. are co-founders of Alder Therapeutics AB. Other authors declare no competing interests., (Copyright © 2022 Duke-NUS Medical School. Published by Elsevier Inc. All rights reserved.)

Virus infection can alter immune regulatory activity, and thus may be involved in the occurrence of autoimmune diseases. Recently, the pandemic of COVID-19 has posed a huge threat to public health and emerging evidence suggests that coronavirus may be implicated in the development and pathogenesis of autoimmune diseases. However, how coronavirus infection impacts the risk of autoimmune disease remains largely unknown. In this review, we focused on the association between coronavirus and autoimmunity, and elucidated the molecular mechanisms linking coronavirus exposure to autoimmunity. Additionally, we briefly introduced the role that coronavirus plays in several autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and idiopathicthrombocytopenic purpura (ITP)., Competing Interests: Conflicts of Interest The authors report no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Community-based primary-level workers (PWs) are an important strategy for addressing gaps in mental health service delivery in low- and middle-income countries.  OBJECTIVES: To evaluate the effectiveness of PW-led treatments for persons with mental health symptoms in LMICs, compared to usual care.  SEARCH METHODS: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, ICTRP, reference lists (to 20 June 2019).   SELECTION CRITERIA: Randomised trials of PW-led or collaborative-care interventions treating people with mental health symptoms or their carers in LMICs.  PWs included: primary health professionals (PHPs), lay health workers (LHWs), community non-health professionals (CPs).  DATA COLLECTION AND ANALYSIS: Seven conditions were identified apriori and analysed by disorder and PW examining recovery, prevalence, symptom change, quality-of-life (QOL), functioning, service use (SU), and adverse events (AEs).  Risk ratios (RRs) were used for dichotomous outcomes; mean difference (MDs), standardised mean differences (SMDs), or mean change differences (MCDs) for continuous outcomes.  For SMDs, 0.20 to 0.49 represented small, 0.50 to 0.79 moderate, and ≥0.80 large clinical effects.  Analysis timepoints: T1 (<1 month), T2 (1-6 months), T3 ( >6 months) post-intervention.  MAIN RESULTS: Description of studies 95 trials (72 new since 2013) from 30 LMICs (25 trials from 13 LICs).  Risk of bias Most common: detection bias, attrition bias (efficacy), insufficient protection against contamination.  Intervention effects *Unless indicated, comparisons were usual care at T2.  "Probably", "may", or "uncertain" indicates "moderate", "low," or "very low" certainty evidence.   Adults with common mental disorders (CMDs) LHW-led interventions a. may increase recovery (2 trials, 308 participants; RR 1.29, 95%CI 1.06 to 1.56); b. may reduce prevalence (2 trials, 479 participants; RR 0.42, 95%CI 0.18 to 0.96); c. may reduce symptoms (4 trials, 798 participants; SMD -0.59, 95%CI -1.01 to -0.16); d. may improve QOL (1 trial, 521 participants; SMD 0.51, 95%CI 0.34 to 0.69); e. may slightly reduce functional impairment (3 trials, 1399 participants; SMD -0.47, 95%CI -0.8 to -0.15); f. may reduce AEs (risk of suicide ideation/attempts); g. may have uncertain effects on SU. Collaborative-care a. may increase recovery (5 trials, 804 participants; RR 2.26, 95%CI 1.50 to 3.43); b. may reduce prevalence although the actual effect range indicates it may have little-or-no effect (2 trials, 2820 participants; RR 0.57, 95%CI 0.32 to 1.01); c. may slightly reduce symptoms (6 trials, 4419 participants; SMD -0.35, 95%CI -0.63 to -0.08); d. may slightly improve QOL (6 trials, 2199 participants; SMD 0.34, 95%CI 0.16 to 0.53); e. probably has little-to-no effect on functional impairment (5 trials, 4216 participants; SMD -0.13, 95%CI -0.28 to 0.03); f. may reduce SU (referral to MH specialists);  g. may have uncertain effects on AEs (death). Women with perinatal depression (PND) LHW-led interventions a. may increase recovery (4 trials, 1243 participants; RR 1.29, 95%CI 1.08 to 1.54); b. probably slightly reduce symptoms (5 trials, 1989 participants; SMD -0.26, 95%CI -0.37 to -0.14); c. may slightly reduce functional impairment (4 trials, 1856 participants; SMD -0.23, 95%CI -0.41 to -0.04); d. may have little-to-no effect on AEs (death);  e. may have uncertain effects on SU. Collaborative-care a. has uncertain effects on symptoms/QOL/SU/AEs. Adults with post-traumatic stress (PTS) or CMDs in humanitarian settings LHW-led interventions a. may slightly reduce depression symptoms (5 trials, 1986 participants; SMD -0.36, 95%CI -0.56 to -0.15); b. probably slightly improve QOL (4 trials, 1918 participants; SMD -0.27, 95%CI -0.39 to -0.15); c. may have uncertain effects on symptoms (PTS)/functioning/SU/AEs. PHP-led interventions a. may reduce PTS symptom prevalence (1 trial, 313 participants; RR 5.50, 95%CI 2.50 to 12.10) and depression prevalence (1 trial, 313 participants; RR 4.60, 95%CI 2.10 to 10.08);  b. may have uncertain effects on symptoms/functioning/SU/AEs.   Adults with harmful/hazardous alcohol or substance use LHW-led interventions a. may increase recovery from harmful/hazardous alcohol use although the actual effect range indicates it may have little-or-no effect (4 trials, 872 participants; RR 1.28, 95%CI 0.94 to 1.74); b. may have little-to-no effect on the prevalence of methamphetamine use (1 trial, 882 participants; RR 1.01, 95%CI 0.91 to 1.13) and  functional impairment (2 trials, 498 participants; SMD -0.14, 95%CI -0.32 to 0.03); c. probably slightly reduce risk of harmful/hazardous alcohol use (3 trials, 667 participants; SMD -0.22, 95%CI -0.32 to -0.11);  d. may have uncertain effects on SU/AEs. PHP/CP-led interventions a. probably have little-to-no effect on recovery from harmful/hazardous alcohol use (3 trials, 1075 participants; RR 0.93, 95%CI 0.77 to 1.12) or QOL (1 trial, 560 participants; MD 0.00, 95%CI -0.10 to 0.10); b. probably slightly reduce risk of harmful/hazardous alcohol and substance use (2 trials, 705 participants; SMD -0.20, 95%CI -0.35 to -0.05; moderate-certainty evidence); c. may have uncertain effects on prevalence (cannabis use)/SU/AEs. PW-led interventions for alcohol/substance dependence a. may have uncertain effects.  Adults with severe mental disorders *Comparisons were specialist-led care at T1. LHW-led interventions a. may have little-to-no effect on caregiver burden (1 trial, 253 participants; MD -0.04, 95%CI -0.18 to 0.11);  b. may have uncertain effects on symptoms/functioning/SU/AEs.  PHP-led or collaborative-care a. may reduce functional impairment (7 trials, 874 participants; SMD -1.13, 95%CI -1.78 to -0.47); b. may have uncertain effects on recovery/relapse/symptoms/QOL/SU.  Adults with dementia and carers PHP/LHW-led carer interventions a. may have little-to-no effect on the severity of behavioural symptoms in dementia patients (2 trials, 134 participants; SMD -0.26, 95%CI -0.60 to 0.08); b. may reduce carers' mental distress (2 trials, 134 participants; SMD -0.47, 95%CI -0.82 to -0.13);  c. may have uncertain effects on QOL/functioning/SU/AEs. Children with PTS or CMDs LHW-led interventions a. may have little-to-no effect on PTS symptoms (3 trials, 1090 participants; MCD -1.34, 95%CI -2.83 to 0.14); b. probably have little-to-no effect on depression symptoms (3 trials, 1092 participants; MCD -0.61, 95%CI -1.23 to 0.02) or on functional impairment (3 trials, 1092 participants; MCD -0.81, 95%CI -1.48 to -0.13);  c. may have little-or-no effect on AEs. CP-led interventions a. may have little-to-no effect on depression symptoms (2 trials, 602 participants; SMD -0.19, 95%CI -0.57 to 0.19) or on AEs;  b. may have uncertain effects on recovery/symptoms(PTS)/functioning., Authors' Conclusions: PW-led interventions show promising benefits in improving outcomes for CMDs, PND, PTS, harmful alcohol/substance use, and dementia carers in LMICs., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background and Objective: This article explores the need for conceptual advances and practical guidance in the application of the GRADE approach within public health contexts., Methods: We convened an expert workshop and conducted a scoping review to identify challenges experienced by GRADE users in public health contexts. We developed this concept article through thematic analysis and an iterative process of consultation and discussion conducted with members electronically and at three GRADE Working Group meetings., Results: Five priority issues can pose challenges for public health guideline developers and systematic reviewers when applying GRADE: (1) incorporating the perspectives of diverse stakeholders; (2) selecting and prioritizing health and "nonhealth" outcomes; (3) interpreting outcomes and identifying a threshold for decision-making; (4) assessing certainty of evidence from diverse sources, including nonrandomized studies; and (5) addressing implications for decision makers, including concerns about conditional recommendations. We illustrate these challenges with examples from public health guidelines and systematic reviews, identifying gaps where conceptual advances may facilitate the consistent application or further development of the methodology and provide solutions., Conclusion: The GRADE Public Health Group will respond to these challenges with solutions that are coherent with existing guidance and can be consistently implemented across public health decision-making contexts., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This living systematic review is one of several Cochrane Reviews evaluating the medical management of patients with chronic rhinosinusitis. Chronic rhinosinusitis is common. It is characterised by inflammation of the nasal and sinus linings, nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. It occurs with or without nasal polyps.   'Biologics' are medicinal products produced by a biological process. Monoclonal antibodies are one type, already evaluated in other inflammatory conditions (e.g. asthma and atopic dermatitis)., Objectives: To assess the effects of biologics for the treatment of chronic rhinosinusitis., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2020, Issue 9); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished studies. The date of the search was 28 September 2020., Selection Criteria: Randomised controlled trials (RCTs) with at least three months follow-up comparing biologics (monoclonal antibodies) against placebo/no treatment in patients with chronic rhinosinusitis., Data Collection and Analysis: We used standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), disease severity and serious adverse events (SAEs). The secondary outcomes were avoidance of surgery, extent of disease (measured by endoscopic or computerised tomography (CT) score), generic HRQL and adverse effects (nasopharyngitis, including sore throat). We used GRADE to assess the certainty of the evidence for each outcome., Main Results: We included 10 studies. Of 1262 adult participants, 1260 had severe chronic rhinosinusitis with nasal polyps; 43% to 100% of participants also had asthma. Three biologics, with different targets, were evaluated: dupilumab, mepolizumab and omalizumab. All of the studies were sponsored or supported by industry. For this update (2021) we have included two new studies, including 265 participants, which reported data relating to omalizumab. Anti-IL-4Rα mAb (dupilumab) versus placebo/no treatment (all receiving intranasal steroids) Three studies (784 participants) evaluated dupilumab. Disease-specific HRQL was measured with the SNOT-22 (a 22-item questionnaire, with a score range of 0 to 110; minimal clinically important difference (MCID) 8.9 points). At 24 weeks, dupilumab results in a large reduction (improvement) in the SNOT-22 score (mean difference (MD) -19.61, 95% confidence interval (CI) -22.54 to -16.69; 3 studies; 784 participants; high certainty). At between 16 and 52 weeks of follow-up, dupilumab probably results in a large reduction in disease severity, as measured by a 0- to 10-point visual analogue scale (VAS) (MD -3.00, 95% CI -3.47 to -2.53; 3 studies; 784 participants; moderate certainty). This is a global symptom score, including all aspects of chronic rhinosinusitis symptoms. At between 16 and 52 weeks of follow-up, dupilumab may result in a reduction in serious adverse events compared to placebo (5.9% versus 12.5%, risk ratio (RR) 0.47, 95% CI 0.29 to 0.76; 3 studies, 782 participants; low certainty). Anti-IL-5 mAb (mepolizumab) versus placebo/no treatment (all receiving intranasal steroids) Two studies (137 participants) evaluated mepolizumab. Disease-specific HRQL was measured with the SNOT-22. At 25 weeks, the SNOT-22 score may be reduced (improved) in participants receiving mepolizumab (MD -13.26 points, 95% CI -22.08 to -4.44; 1 study; 105 participants; low certainty; MCID 8.9).  It is very uncertain whether there is a difference in disease severity at 25 weeks: on a 0- to 10-point VAS, disease severity was -2.03 lower in those receiving mepolizumab (95% CI -3.65 to -0.41; 1 study; 72 participants; very low certainty). It is very uncertain if there is a difference in the number of serious adverse events at between 25 and 40 weeks (1.4% versus 0%; RR 1.57, 95% CI 0.07 to 35.46; 2 studies; 135 participants, very low certainty). Anti-IgE mAb (omalizumab) versus placebo/no treatment (all receiving intranasal steroids) Five studies (329 participants) evaluated omalizumab. Disease-specific HRQL was measured with the SNOT-22. At 24 weeks omalizumab probably results in a large reduction in SNOT-22 score (MD -15.62, 95% CI -19.79 to -11.45; 2 studies; 265 participants; moderate certainty; MCID 8.9). We did not identify any evidence for overall disease severity. It is very uncertain whether omalizumab affects the number of serious adverse events, with follow-up between 20 and 26 weeks (0.8% versus 2.5%, RR 0.32, 95% CI 0.05 to 2.00; 5 studies; 329 participants; very low certainty)., Authors' Conclusions: Almost all of the participants in the included studies had nasal polyps (99.8%) and all were using topical nasal steroids for their chronic rhinosinusitis symptoms. In these patients, dupilumab improves disease-specific HRQL compared to placebo. It probably also results in a reduction in disease severity, and may result in a reduction in the number of serious adverse events. Mepolizumab may improve disease-specific HRQL. It is very uncertain if there is a difference in disease severity or the number of serious adverse events. Omalizumab probably improves disease-specific HRQL compared to placebo. It is very uncertain if there is a difference in the number of serious adverse events. There was no evidence regarding the effect of omalizumab on disease severity (using global scores that address all symptoms of chronic rhinosinusitis)., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and often polymicrobial infection (involving more than one micro-organism) of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Antibiotics are the most common treatment for CSOM, which act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be administered both topically and systemically, and can be used alone or in addition to other treatments for CSOM such as ear cleaning (aural toileting)., Objectives: To assess the effects of topical versus systemic antibiotics for people with CSOM., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving patients (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. The studies compared topical antibiotics against systemic (oral, injection) antibiotics. We separated studies according to whether they compared the same type of antibiotic in both treatment groups, or different types of antibiotics. For each comparison we considered whether there was background treatment for both treatment groups, for example aural toileting (ear cleaning)., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not, measured at between one week and up to two weeks, two weeks up to four weeks, and after four weeks), health-related quality of life using a validated instrument, ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways., Main Results: Six studies (445 participants), all with high risk of bias, were included. All but two studies included patients with confirmed CSOM, where perforation of the ear drum was clearly documented. None of the studies reported results for resolution of ear discharge after four weeks or health-related quality of life. 1. Topical versus systemic administration of the same type of antibiotics (quinolones) Four studies (325 participants) compared topical versus systemic (oral) administration of ciprofloxacin. Three studies reported resolution of ear discharge at one to two weeks and found that the topical administration may slightly increase resolution (risk ratio (RR) 1.48, 95% confidence interval (CI) 1.24 to 1.76; 285 participants; 3 studies; I 2 = 0%; low-certainty evidence). In these studies, aural toileting was either not mentioned, or limited to the first visit. Three studies (265 participants) reported that they did not suspect ototoxicity in any participants, but it is unclear how this was measured (very low-certainty evidence). No studies reported the outcomes of ear pain or serious complications. No studies reported results for hearing, despite it being measured in three studies. 2. Topical versus systemic administration of different types of antibiotics (quinolones versus aminoglycosides) One study (60 participants) compared topical ciprofloxacin versus gentamicin injected intramuscularly. No aural toileting was reported. Resolution of ear discharge was not measured at one to two weeks. The study did not report any 'side effects' from which we assumed that no ear pain, suspected ototoxicity or serious complications occurred (very low-certainty evidence). The study stated that "no worsening of the audiometric function related to local or parenteral therapy was observed". 3. Topical versus systemic administration of different types of antibiotics (quinolones versus amoxicillin-clavulanic acid) One study compared topical ofloxacin with amoxicillin-clavulanic acid with all participants receiving suction ear cleaning at the first visit. It is uncertain if there is a difference between the two groups in resolution of ear discharge at one to two weeks due to study limitations and the very small sample size (RR 2.93, 95% CI 1.50 to 5.72; 56 participants; very low-certainty evidence). It is unclear if there is a difference between topical quinolone compared with oral amoxicillin-clavulanic acid with regards to ear pain, hearing or suspected ototoxicity (very low-certainty evidence). No studies reported the outcome of serious complications., Authors' Conclusions: There was a limited amount of low-quality evidence available, from studies completed over 15 years ago, to examine whether topical or systemic antibiotics are more effective in achieving resolution of ear discharge for people with CSOM. However, amongst this uncertainty there is some evidence to suggest that the topical administration of antibiotics may be more effective than systemic administration of antibiotics in achieving resolution of ear discharge (dry ear). There is limited evidence available regarding different types of antibiotics. It is not possible to determine with any certainty whether or not topical quinolones are better or worse than systemic aminoglycosides. These two groups of compounds have different adverse effect profiles, but there is insufficient evidence from the included studies to make any comment about these. In general, adverse effects were poorly reported., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM) is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Systemic antibiotics are a commonly used treatment option for CSOM, which act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be used alone or in addition to other treatments for CSOM., Objectives: To assess the effects of systemic antibiotics for people with CSOM., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020., Selection Criteria: We included randomised controlled trials comparing systemic antibiotics (oral, injection) against placebo/no treatment or other systemic antibiotics with at least a one-week follow-up period, involving patients with chronic (at least two weeks) ear discharge of unknown cause or due to CSOM. Other treatments were allowed if both treatment and control arms also received it., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not, measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks); health-related quality of life using a validated instrument; ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways., Main Results: We included 18 studies (2135 participants) with unclear or high risk of bias. 1. Systemic antibiotics versus no treatment/placebo It is very uncertain if there is a difference between systemic (intravenous) antibiotics and placebo in the resolution of ear discharge at between one and two weeks (risk ratio (RR) 8.47, 95% confidence interval (CI) 1.88 to 38.21; 33 participants; 1 study; very low-certainty evidence). The study did not report results for resolution of ear discharge after two weeks. Health-related quality of life was not reported. The evidence is very uncertain for hearing and serious (intracranial) complications. Ear pain and suspected ototoxicity were not reported. 2. Systemic antibiotics versus no treatment/placebo (both study arms received topical antibiotics) Six studies were included of which five presented useable data. There may be little or no difference in the resolution of ear discharge at between one to two weeks for oral ciprofloxacin compared to placebo or no treatment when ciprofloxacin ear drops were used in both intervention arms (RR 1.02, 95% CI 0.93 to 1.12; 390 participants; low-certainty evidence). No results after two weeks were reported. Health-related quality of life was not reported. The evidence is very uncertain for ear pain, serious complications and suspected ototoxicity. 3. Systemic antibiotics versus no treatment/placebo (both study arms received other background treatments) Two studies used topical antibiotics plus steroids as background treatment in both arms. It is very uncertain if there is a difference in resolution of ear discharge between metronidazole and placebo at four weeks (RR 0.91, 95% CI 0.51 to 1.65; 40 participants; 1 study; very low-certainty evidence). This study did not report other outcomes. It is also very uncertain if resolution of ear discharge at six weeks was improved with co-trimoxazole compared to placebo (RR 1.54, 95% CI 1.09 to 2.16; 98 participants; 1 study; very low-certainty evidence). Resolution of ear discharge was not reported at other time points. From the narrative report there was no evidence of a difference between groups for health-related quality of life, hearing or serious complications (very low-certainty evidence). One study (136 participants) used topical antiseptics as background treatment in both arms and found similar resolution of ear discharge between the amoxicillin and no treatment groups at three to four months (RR 1.03, 95% CI 0.75 to 1.41; 136 participants; 1 study; very low-certainty evidence). The narrative report indicated no evidence of differences in hearing or suspected ototoxicity (both very low-certainty evidence). No other outcomes were reported. 4. Different types of systemic antibiotics This is a summary of four comparisons, where different antibiotics were compared to each other. Eight studies compared different types of systemic antibiotics against each other: quinolones against beta-lactams (four studies), lincosamides against nitroimidazoles (one study) and comparisons of different types of beta-lactams (three studies). It was not possible to conclude if there was one class or type of systemic antibiotic that was better in terms of resolution of ear discharge. The studies did not report adverse events well., Authors' Conclusions: There was a limited amount of evidence available to examine whether systemic antibiotics are effective in achieving resolution of ear discharge for people with CSOM. When used alone (with or without aural toileting), we are very uncertain if systemic antibiotics are more effective than placebo or no treatment. When added to an effective intervention such as topical antibiotics, there seems to be little or no difference in resolution of ear discharge (low-certainty evidence). Data were only available for certain classes of antibiotics and it is very uncertain whether one class of systemic antibiotic may be more effective than another. Adverse effects of systemic antibiotics were poorly reported in the studies included. As we found very sparse evidence for their efficacy, the possibility of adverse events may detract from their use for CSOM., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and often polymicrobial infection (involving more than one micro-organism) of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Aural toileting is a term describing a number of processes for manually cleaning the ear. Techniques used may include dry mopping (with cotton wool or tissue paper), suction clearance (typically under a microscope) or irrigation (using manual or automated syringing). Dry mopping may be effective in removing mucopurulent discharge. Compared to irrigation or microsuction it is less effective in removing epithelial debris or thick pus. Aural toileting can be used alone or in addition to other treatments for CSOM, such as antibiotics or topical antiseptics., Objectives: To assess the effects of aural toilet procedures for people with CSOM., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving people (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. We included any aural toileting method as the intervention, at any frequency and for any duration. The comparisons were aural toileting compared with a) placebo or no intervention, and b) any other aural toileting method. We analysed trials in which background treatments were used in both arms (e.g. topical antiseptics or topical antibiotics) separately., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks; health-related quality of life using a validated instrument; and ear pain (otalgia) or discomfort or local irritation. Secondary outcomes were hearing, serious complications, and the adverse events of ear bleeding and dizziness/vertigo/balance problems., Main Results: We included three studies with a total of 431 participants (465 ears), reporting on two comparisons. Two studies included only children with CSOM in the community (351 participants) and the other study (80 participants) included children and adults with chronic ear discharge for at least six weeks. None of the included studies reported the outcomes of health-related quality of life, ear pain or the adverse event of ear bleeding. Daily aural toileting (dry mopping) versus no treatment Two studies (351 children; 370 ears) compared daily dry mopping with no treatment. Neither study presented results for resolution of ear discharge at between one and up to two weeks or between two to four weeks. For resolution of ear discharge after four weeks, one study reported the results per person. We are very uncertain whether there is a difference at 16 weeks (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.60 to 1.72; 1 study; 217 participants) because the certainty of the evidence is very low. No results were reported for the adverse events of dizziness, vertigo or balance problems. Only one study reported serious complications, but it was not clear which group these patients were from, or whether the complications occurred pre- or post-treatment. One study reported hearing, but the results were presented by treatment outcome rather than by treatment group so it is not possible to determine whether there is a difference between the two groups. Daily aural toileting versus single aural toileting on top of topical ciprofloxacin One study (80 participants; 95 ears) compared daily aural toileting (suction) with administration of topical antibiotic (ciprofloxacin) ear drops in a clinic, to a single aural toileting (suction) episode followed by daily self-administered topical antibiotic drops, in participants of all ages. We are unsure whether there is a difference in resolution of ear discharge at between one and up to two weeks (RR 1.09, 95% CI 0.91 to 1.30; 1 study; 80 participants) because the certainty of the evidence is very low. There were no results reported for resolution of ear discharge at between two to four weeks. The results for resolution of ear discharge after four weeks were presented by ear, not person, and could not be adjusted to by person. One patient in the group with single aural toileting and self administration of topical antibiotic ear drops reported the adverse event of dizziness, which the authors attributed to the use of cold topical ciprofloxacin. It is very uncertain whether there is a difference between the groups (RR 0.33, 95% CI 0.01 to 7.95; 1 study; 80 participants, very low-certainty). No results were reported for the other adverse events of vertigo or balance problems, or for serious complications. The authors only reported qualitatively that there was no difference between the two groups in hearing results (very low-certainty)., Authors' Conclusions: We are very uncertain whether or not treatment with aural toileting is effective in resolving ear discharge in people with CSOM, due to a lack of data and the poor quality of the available evidence. We also remain uncertain about other outcomes, including adverse events, as these were not well reported. Similarly, we are very uncertain whether daily suction clearance, followed by antibiotic ear drops administered at a clinic, is better than a single episode of suction clearance followed by self-administration of topical antibiotic ear drops., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM) is a chronic inflammation and often polymicrobial infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Topical antibiotics act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be used alone or in addition to other treatments for CSOM, such as steroids, antiseptics or ear cleaning (aural toileting). Antibiotics are commonly prescribed in combined preparations with steroids., Objectives: To assess the effects of adding a topical steroid to topical antibiotics in the treatment of people with chronic suppurative otitis media (CSOM)., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving participants (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. The interventions were any combination of a topical antibiotic agent(s) of any class and a topical corticosteroid (steroid) of any class, applied directly into the ear canal as ear drops, powders or irrigations, or as part of an aural toileting procedure. The two main comparisons were topical antibiotic and steroid compared to a) placebo or no intervention and b) another topical antibiotic., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks and after four weeks; health-related quality of life; ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity., Main Results: We included 17 studies addressing 11 treatment comparisons. A total of 1901 participants were included, with one study (40 ears) not reporting the number of participants recruited, which we therefore could not account for. No studies reported health-related quality of life. The main comparisons were: 1. Topical antibiotics with steroids versus placebo or no treatment Three studies (210 participants) compared a topical antibiotic-steroid to saline or no treatment. Resolution of discharge was not reported at between one to two weeks. One study (50 'high-risk' children) reported results at more than four weeks by ear and we could not adjust the results to by person. The study reported that 58% (of 41 ears) resolved with topical antibiotics compared with 50% (of 26 ears) with no treatment, but the evidence is very uncertain. One study (123 participants) noted minor side effects in 16% of participants in both the intervention and placebo groups (very low-certainty evidence). One study (123 participants) reported no change in bone-conduction hearing thresholds and reported no difference in tinnitus or balance problems between groups (very low-certainty evidence). One study (50 participants) reported serious complications, but it was not clear which group these patients were from, or whether the complications occurred pre- or post-treatment. One study (123 participants) reported that no side effects occurred in any participants (very low-certainty evidence). 2. Topical antibiotics with steroids versus topical antibiotics (same antibiotics) only Four studies (475 participants) were included in this comparison. Three studies (340 participants) compared topical antibiotic-steroid combinations to topical antibiotics alone. The evidence suggests little or no difference in resolution of discharge at one to two weeks: 82.7% versus 76.6% (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.96 to 1.21; 335 participants; 3 studies (4 study arms); low-certainty evidence). No results for resolution of discharge after four weeks were reported. One study (110 participants) reported local itchiness but as there was only one episode in each group it is uncertain whether there is a difference (very low-certainty evidence). Three studies (395 participants) investigated suspected ototoxicity but it was not possible to determine whether there were differences between the groups for this outcome (very low-certainty evidence). No study reported serious complications. 3. Topical antibiotics with steroids compared to topical antibiotics alone (different antibiotics) Nine studies (981 participants plus 40 ears) evaluated a range of comparisons of topical non-quinolone antibiotic-steroid combinations versus topical quinolone antibiotics alone. Resolution of discharge may be greater with quinolone topical antibiotics alone at between one to two weeks compared with non-quinolone topical antibiotics with steroids: 82.1% versus 63.2% (RR 0.77, 95% CI 0.71 to 0.84; 7 studies; 903 participants, low-certainty evidence). Results for resolution of ear discharge after four weeks were not reported. One study (52 participants) reported usable data on ear pain, two studies (419 participants) reported hearing outcomes and one study (52 participants) reported balance problems. It was not possible to determine whether there were significant differences between the groups for these outcomes (very low-certainty evidence). Two studies (149 participants) reported no serious complications (very low-certainty evidence)., Authors' Conclusions: We are uncertain about the effectiveness of topical antibiotics with steroids in improving the resolution of ear discharge in patients with CSOM because of the limited amount of low-certainty evidence available. Amongst this uncertainty, we found no evidence that the addition of steroids to topical antibiotics affects the resolution of ear discharge. There is also low-certainty evidence that some types of topical antibiotics (without steroids) may be better than topical antibiotic/steroid combinations in improving resolution of discharge. There is also uncertainty about the relative effectiveness of different types of antibiotics; it is not possible to determine with any certainty whether or not quinolones are better or worse than aminoglycosides. These two groups of compounds have different adverse effect profiles, but there is insufficient evidence from the included studies to make any comment about these. In general, adverse effects were poorly reported., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Bacterial pigments are potential substitute of chemical photosensitizer for dye-sensitized solar cell (DSSC) due to its non-toxic property and cost-effective production from microbial fermentation. Serratia nematodiphila YO1 was isolated from waterfall in Malaysia and identified using 16S ribosomal RNA. Characterization of the red pigment produced by the bacteria has confirmed the pigment as prodigiosin. Prodigiosin was produced from the fermentation of the bacteria in the presence of different oil substrates. Palm oil exhibited the best performance of cell growth and equivalent prodigiosin yield compared to olive oil and peanut oil. Prodigiosin produced with palm oil supplementation was 93 mg/l compared to 7.8 mg/l produced without supplementation, which recorded 11.9 times improvement. Specific growth rate of the cells improved 1.4 times when palm oil was supplemented in the medium. The prodigiosin pigment produced showed comparable performance as a DSSC sensitizer by displaying an open circuit voltage of 336.1 mV and a maximum short circuit current of 0.098 mV/cm 2 . This study stands a novelty in proving that the production of prodigiosin is favorable in the presence of palm oil substrate with high saturated fat content, which has not been studied before. This is also among the first bacterial prodigiosin tested as photosensitizer for DSSC application., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In situ boron (B)-doped SiGe (BSG) layer is extensively used in the source (S)/(D) drain of metal-oxide-semiconductor field-effect transistors. An unexpected structural evolution occurs in BSG during metallization and activation annealing during actual fabrication, which involves a correlated interaction between B and SiGe. Herein, the complicated phenomena of the structural evolution of BSG were analyzed by 325 nm micro-Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), reflective second harmonic generation (RSHG), and synchrotron x-ray diffraction (XRD). Optical inspection was integrated into these processes to establish a multi-optical method. 325 nm micro-Raman spectroscopy was used to determine variations in Si-Si, Si-Ge, and Ge-Ge bonds in BSG. XPS exhibited the binding energy evolution of Ge3d during different annealing processes at varied Ge ratios and B concentrations. RSHG revealed the polar Si-B and Ge-B bonds formed during annealing. Synchrotron XRD provided the structure and strain changes of BSG. Secondary-ion mass spectrometer profiles provided the species distribution, which was used to examine the results of multi-optical method. Furthermore, double-layered BSG (DBSG) with different B concentrations were analyzed using the multi-optical method. Results revealed that Ge aggregated in the homogeneous interface of DBSG, and that B dopants in BSG served as carrier providers that strongly influenced the BSG structure. However, BSG with excessive B concentration was unstable and increased the B content (SiB 3 ) through metallization. For BSG with a suitable B concentration, the formation of Si-B and Ge-B bonds suppressed the diffusion of Ge from SiGe, thereby reducing the possibility of Ge loss and further B pipe-up in the heavily doped S/D region.

Background: Increasing age is associated with a natural decline in cognitive function and is the greatest risk factor for dementia. Cognitive decline and dementia are significant threats to independence and quality of life in older adults. Therefore, identifying interventions that help to maintain cognitive function in older adults or that reduce the risk of dementia is a research priority. Cognitive training uses repeated practice on standardised exercises targeting one or more cognitive domains and may be intended to improve or maintain optimal cognitive function. This review examines the effects of computerised cognitive training interventions lasting at least 12 weeks on the cognitive function of healthy adults aged 65 or older and has formed part of a wider project about modifying lifestyle to maintain cognitive function. We chose a minimum 12 weeks duration as a trade-off between adequate exposure to a sustainable intervention and feasibility in a trial setting., Objectives: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks on cognitive function in cognitively healthy people in late life., Search Methods: We searched to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois), and we performed additional searches of MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP (www.apps.who.int/trialsearch), to ensure that the search was as comprehensive and as up-to-date as possible to identify published, unpublished, and ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) and quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people, and at least 80% of the study population had to be aged 65 or older. Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; the duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions., Data Collection and Analysis: We performed preliminary screening of search results using a 'crowdsourcing' method to identify RCTs. At least two review authors working independently screened the remaining citations against inclusion criteria. At least two review authors also independently extracted data and assessed the risk of bias of included RCTs. Where appropriate, we synthesised data in random-effects meta-analyses, comparing computerised cognitive training (CCT) separately with active and inactive controls. We expressed treatment effects as standardised mean differences (SMDs) with 95% confidence intervals (CIs). We used GRADE methods to describe the overall quality of the evidence for each outcome., Main Results: We identified eight RCTs with a total of 1183 participants. The duration of the interventions ranged from 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had moderate risk of bias, and the overall quality of evidence was low or very low for all outcomes. We compared CCT first against active control interventions, such as watching educational videos. Negative SMDs favour CCT over control. Trial results suggest slight improvement in global cognitive function at the end of the intervention period (12 weeks) (standardised mean difference (SMD) -0.31, 95% confidence interval (CI) -0.57 to -0.05; 232 participants; 2 studies; low-quality evidence). One of these trials also assessed global cognitive function 12 months after the end of the intervention; this trial provided no clear evidence of a persistent effect (SMD -0.21, 95% CI -0.66 to 0.24; 77 participants; 1 study; low-quality evidence). CCT may result in little or no difference at the end of the intervention period in episodic memory (12 to 17 weeks) (SMD 0.06, 95% CI -0.14 to 0.26; 439 participants; 4 studies; low-quality evidence) or working memory (12 to 16 weeks) (SMD -0.17, 95% CI -0.36 to 0.02; 392 participants; 3 studies; low-quality evidence). Because of the very low quality of the evidence, we are very uncertain about the effects of CCT on speed of processing and executive function. We also compared CCT to inactive control (no interventions). We found no data on our primary outcome of global cognitive function. At the end of the intervention, CCT may lead to slight improvement in episodic memory (6 months) (mean difference (MD) in Rivermead Behavioural Memory Test (RBMT) -0.90 points, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) but can have little or no effect on executive function (12 weeks to 6 months) (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (16 weeks) (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (6 months) (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing because the evidence was of very low quality. We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison., Authors' Conclusions: We found low-quality evidence suggesting that immediately after completion of the intervention, small benefits of CCT may be seen for global cognitive function when compared with active controls, and for episodic memory when compared with an inactive control. These benefits are of uncertain clinical importance. We found no evidence that the effect on global cognitive function persisted 12 months later. Our confidence in the results was low, reflecting the overall quality of the evidence. In five of the eight trials, the duration of the intervention was just three months. The possibility that more extensive training could yield larger benefit remains to be more fully explored. We found substantial literature on cognitive training, and collating all available scientific information posed problems. Duration of treatment may not be the best way to categorise interventions for inclusion. As the primary interest of older people and of guideline writers and policymakers involves sustained cognitive benefit, an alternative would be to categorise by length of follow-up after selecting studies that assess longer-term effects., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: This living systematic review is one of several Cochrane Reviews evaluating the medical management of patients with chronic rhinosinusitis. Chronic rhinosinusitis is common. It is characterised by inflammation of the nasal and sinus linings, nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. It occurs with or without nasal polyps.   'Biologics' are medicinal products produced by a biological process. Monoclonal antibodies are one type, already evaluated in related inflammatory conditions (e.g. asthma and atopic dermatitis)., Objectives: To assess the effects of biologics for the treatment of chronic rhinosinusitis., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2019, Issue 9); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 September 2019., Selection Criteria: Randomised controlled trials (RCTs) with at least three months follow-up comparing biologics (currently, monoclonal antibodies) against placebo/no treatment in patients with chronic rhinosinusitis., Data Collection and Analysis: We used standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), disease severity and serious adverse events (SAEs). The secondary outcomes were avoidance of surgery, extent of disease (measured by endoscopic or computerised tomography (CT) score), generic HRQL and adverse events (nasopharyngitis, including sore throat). We used GRADE to assess the certainty of the evidence for each outcome., Main Results: We included eight RCTs. Of 986 adult participants, 984 had severe chronic rhinosinusitis with nasal polyps; 43% to 100% of participants also had asthma. Three biologics, with different targets, were evaluated: dupilumab, mepolizumab and omalizumab. All the studies were sponsored or supported by industry. Anti-IL-4Rα mAb (dupilumab) versusplacebo/no treatment (all receiving intranasal steroids) Three studies (784 participants) evaluated dupilumab. Disease-specific HRQL was measured with the SNOT-22 (score 0 to 110; minimal clinically important difference (MCID) 8.9 points). At 24 weeks, the SNOT-22 score was 19.61 points lower (better) in participants receiving dupilumab (mean difference (MD) -19.61, 95% confidence interval (CI) -22.54 to -16.69; 3 studies; 784 participants; high certainty). Symptom severity measured on a 0- to 10-point visual analogue scale (VAS) was 3.00 lower in those receiving dupilumab (95% CI -3.47 to -2.53; 3 studies; 784 participants; moderate certainty). The risk of serious adverse events may be lower in the dupilumab group (risk ratio (RR) 0.45, 95% CI 0.28 to 0.75; 3 studies; 782 participants; low certainty).  The number of participants requiring nasal polyp surgery (actual or planned) during the treatment period is probably lower in those receiving dupilumab (RR 0.17, 95% CI 0.05 to 0.52; 2 studies; 725 participants; moderate certainty). Change in the extent of disease using the Lund Mackay computerised tomography (CT) score (0 to 24, higher = worse) was -7.00 (95% CI -9.61 to -4.39; 3 studies; 784 participants; high certainty), a large effect favouring the dupilumab group.  The EQ-5D visual analogue scale (0 to 100, higher = better; MCID 8 points) was used to measure change in generic quality of life. The mean difference favouring dupilumab was 8.59 (95% CI 5.31 to 11.86; 2 studies; 706 participants; moderate certainty). There may be little or no difference in the risk of nasopharyngitis (RR 0.95, 95% CI 0.72 to 1.25; 3 studies; 783 participants; low certainty). Anti-IL-5 mAb (mepolizumab) versusplacebo/no treatment (all receiving intranasal steroids) Two studies (137 participants) evaluated mepolizumab. Disease-specific HRQL measured with the SNOT-22 at 25 weeks was 13.26 points lower (better) in participants receiving mepolizumab (95% CI -22.08 to -4.44; 1 study; 105 participants; low certainty; MCID 8.9).  It is very uncertain whether there is a difference in s ymptom severity: on a 0- to 10-point VAS symptom severity was -2.03 lower in those receiving mepolizumab (95% CI -3.65 to -0.41; 1 study; 72 participants; very low certainty). It is very uncertain if there is difference in the risk of serious adverse events (RR 1.57, 95% CI 0.07 to 35.46; 2 studies; 135 participants, very low certainty). It is very uncertain whether or not the overall risk that patients still need surgery at trial end is lower in the mepolizumab group (RR 0.78, 95% CI 0.64 to 0.94; 2 studies; 135 participants; very low certainty). It is very uncertain whether mepolizumab reduces the extent of disease as measured by endoscopic nasal polyps score (scale range 0 to 8). The mean difference was 1.23 points lower in the mepolizumab group (MD -1.23, 95% -1.79 to -0.68; 2 studies; 137 participants; very low certainty). The difference in generic quality of life (EQ-5D) was 5.68 (95% CI -1.18 to 12.54; 1 study; 105 participants; low certainty), favouring the mepolizumab group. This difference is smaller than the MCID of 8 points. There may be little or no difference in the risk of nasopharyngitis (RR 0.73, 95% 0.36 to 1.47; 2 studies; 135 participants; low certainty). Anti-IgE mAb (omalizumab) versus placebo/no treatment (all receiving intranasal steroids) Three very small studies (65 participants) evaluated omalizumab. We are very uncertain about the effect of omalizumab on disease-specific HRQL, severe adverse events, extent of disease (CT scan scores), generic HRQL and adverse effects., Authors' Conclusions: In adults with severe chronic rhinosinusitis and nasal polyps, using regular topical nasal steroids, dupilumab improves disease-specific HRQL compared to placebo, and reduces the extent of the disease as measured on a CT scan. It probably also improves symptoms and generic HRQL and there is no evidence of an increased risk of serious adverse events. It may reduce the need for further surgery. There may be little or no difference in the risk of nasopharyngitis. In similar patients, mepolizumab may improve both disease-specific and generic HRQL. It is uncertain whether it reduces the need for surgery or improves nasal polyp scores. There may be little or no difference in the risk of nasopharyngitis. It is uncertain if there is a difference in symptom severity and the risk of serious adverse events. We are uncertain about the effects of omalizumab., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Antibiotics and antiseptics kill or inhibit the micro-organisms that may be responsible for the infection. Antibiotics can be applied topically or administered systemically via the oral or injection route. Antiseptics are always directly applied to the ear (topically)., Objectives: To assess the effectiveness of antibiotics versus antiseptics for people with chronic suppurative otitis media (CSOM)., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL; 2019, Issue 4, via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 1 April 2019., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving patients (adults and children) who had chronic ear discharge of unknown cause or CSOM, where ear discharge had continued for more than two weeks. The intervention was any single, or combination of, antibiotic agent, whether applied topically (without steroids) or systemically. The comparison was any single, or combination of, topical antiseptic agent, applied as ear drops, powders or irrigations, or as part of an aural toileting procedure. Two comparisons were topical antiseptics compared to: a) topical antibiotics or b) systemic antibiotics. Within each comparison we separated where both groups of patients had received topical antibiotic a) alone or with aural toilet and b) on top of background treatment (such as systemic antibiotics)., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks; health-related quality of life using a validated instrument; and ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways., Main Results: We identified seven studies (935 participants) across four comparisons with antibiotics compared against acetic acid, aluminium acetate, boric acid and povidone-iodine. None of the included studies reported the outcomes of quality of life or serious complications. A. Topical antiseptic (acetic acid) versus topical antibiotics (quinolones or aminoglycosides) It is very uncertain if there is a difference in resolution of ear discharge with acetic acid compared with aminoglycosides at one to two weeks (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.72 to 1.08; 1 study; 100 participants; very low-certainty evidence). No study reported results for ear discharge after four weeks. It was very uncertain if there was more ear pain, discomfort or local irritation with acetic acid or topical antibiotics due to the low numbers of participants reporting events (RR 0.16, 95% CI 0.02 to 1.34; 2 RCTs; 189 participants; very low-certainty evidence). No differences between groups were reported narratively for hearing (quinolones) or suspected ototoxicity (aminoglycosides) (very low-certainty evidence). B. Topical antiseptic (aluminium acetate) versus topical antibiotics No results for the one study comparing topical antibiotics with aluminium acetate could be used in the review. C. Topical antiseptic (boric acid) versus topical antibiotics (quinolones) One study reported more participants with resolution of ear discharge when using topical antibiotics (quinolones) compared with boric acid ear drops at between one to two weeks (risk ratio (RR) 1.56, 95% confidence interval (CI) 1.27 to 1.92; 1 study; 409 participants; moderate-certainty evidence). This means that one additional person will have resolution of ear discharge for every five people receiving topical antibiotics (compared with boric acid) at two weeks. No study reported results for ear discharge after four weeks. There was a bigger improvement in hearing in the topical antibiotic group compared to the topical antiseptic group (mean difference (MD) 2.79 decibels (dB), 95% CI 0.48 to 5.10; 1 study; 390 participants; low-certainty evidence) but this difference may not be clinically significant. There may be more ear pain, discomfort or irritation with boric acid compared with quinolones (RR 0.56, 95% CI 0.32 to 0.98; 2 studies; 510 participants; low-certainty evidence). Suspected ototoxicity was not reported. D. Topical antiseptic (povidone-iodine) versus topical antibiotics (quinolones) It is uncertain if there is a difference between quinolones and povidone-iodine with respect to resolution of ear discharge at one to two weeks (RR 1.02, 95% CI 0.82 to 1.26; 1 RCT, 39 participants; very low-certainty evidence). The study reported qualitatively that there were no differences between the groups for hearing and no patients developed ototoxic effects (very low-certainty evidence). No results for resolution of ear discharge beyond four weeks, or ear pain, discomfort or irritation, were reported. E. Topical antiseptic (acetic acid) + aural toileting versus topical + systemic antibiotics (quinolones) One study reported that participants receiving topical and oral antibiotics had less resolution of ear discharge compared with acetic acid ear drops and aural toileting (suction clearance every two days) at one month (RR 0.69, 95% CI 0.53 to 0.90; 100 participants). The study did not report results for resolution of ear discharge at between one to two weeks, ear pain, discomfort or irritation, hearing or suspected ototoxicity., Authors' Conclusions: Treatment of CSOM with topical antibiotics (quinolones) probably results in an increase in resolution of ear discharge compared with boric acid at up to two weeks. There was limited evidence for the efficacy of other topical antibiotics or topical antiseptics and so we are unable to draw conclusions. Adverse events were not well reported., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Topical antiseptics, one of the possible treatments for CSOM, inhibit the micro-organisms that may be responsible for the infection. Antiseptics can be used alone or in addition to other treatments for CSOM, such as antibiotics or ear cleaning (aural toileting). Antiseptics or their application can cause irritation of the skin of the outer ear, manifesting as discomfort, pain or itching. Some antiseptics (such as alcohol) may have the potential to be toxic to the inner ear (ototoxicity), with a possible increased risk of causing sensorineural hearing loss, dizziness or tinnitus., Objectives: To assess the effects of topical antiseptics for people with chronic suppurative otitis media., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL; 2019, Issue 4, via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 1 April 2019., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving patients (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. The interventions were any single, or combination of, topical antiseptic agent of any class, applied directly into the ear canal as ear drops, powders or irrigations, or as part of an aural toileting procedure. Two main comparisons were topical antiseptics compared to: a) placebo or no intervention; and b) another topical antiseptic (e.g. topical antiseptic A versus topical antiseptic B). Within each comparison we separated studies where both groups of patients had received topical antiseptics a) alone or with aural toileting and b) on top of antibiotic treatment., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks; health-related quality of life using a validated instrument; ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways., Main Results: Five studies were included. It was not possible to calculate the total number of participants as two studies only provided the number of ears included in the study. A. Topical antiseptic (boric acid) versus placebo or no treatment (all patients had aural toileting) Three studies compared topical antiseptics with no treatment, with one study reporting results we could use (254 children; cluster-RCT). This compared the instillation of boric acid in alcohol drops versus no ear drops for one month (both arms used daily dry mopping). We made adjustments to the data to account for the intra-cluster correlation. The very low certainty of the evidence means it is uncertain whether or not treatment with an antiseptic leads to an increase in resolution of ear discharge at both four weeks (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.20 to 3.16; 174 participants) and at three to four months (RR 1.73, 95% CI 1.21 to 2.47; 180 participants). This study narratively described no differences in suspected ototoxicity or hearing outcomes between the arms (very low-certainty evidence). None of the studies reported results for health-related quality of life, adverse effects or serious complications. B. Topical antiseptic A versus topical antiseptic B Two studies compared different antiseptics but only one (93 participants), comparing a single instillation of boric acid powder with daily acetic acid ear drops, provided any information for this comparison. The very low certainty of the evidence means that it is uncertain whether more patients had resolution of ear discharge with boric acid powder compared to acetic acid at four weeks (RR 2.61, 95% CI 1.51 to 4.53; 93 participants), or whether there was a difference between the arms with respect to ear discomfort due to the low number of reported events (RR 0.10, 95% CI 0.01 to 1.81; 93 participants). Narratively, the study reported no difference in hearing outcomes between the groups. None of the included studies reported any of the other primary or secondary outcomes., Authors' Conclusions: Due to paucity of the evidence and the very low certainty of that which is available the effectiveness and safety profile of antiseptics in the treatment of CSOM is uncertain., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and often polymicrobial infection (involving more than one micro-organism) of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Topical antibiotics, the most common treatment for CSOM, act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be used alone or in addition to other treatments for CSOM, such as antiseptics or ear cleaning (aural toileting)., Objectives: To assess the effects of topical antibiotics (without steroids) for people with CSOM., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 1 April 2019., Selection Criteria: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving participants (adults and children) who had chronic ear discharge of unknown cause or CSOM, where the ear discharge had continued for more than two weeks. The interventions were any single, or combination of, topical antibiotic agent(s) of any class, applied directly into the ear canal as ear drops, powders or irrigations, or as part of an aural toileting procedure. The two main comparisons were topical antibiotic compared to a) placebo or no intervention and b) another topical antibiotic (e.g. topical antibiotic A versus topical antibiotic B). Within each comparison we separated studies where both groups of participants had received topical antibiotic a) alone or with aural toileting and b) on top of background treatment (such as systemic antibiotics)., Data Collection and Analysis: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks and after four weeks; health-related quality of life using a validated instrument; ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways., Main Results: We included 17 studies with a total of 2198 participants. Twelve studies reported the sample size in terms of participants (not ears); these had a total of 1797 participants. The remaining five studies reported both the number of participants and ears, representing 401 participants, or 510 ears. A: Topical antibiotics versus placebo or no treatment (with aural toilet in both arms and no other background treatment) One small study compared a topical antibiotic (ciprofloxacin) with placebo (saline). All participants received aural toilet. Although ciprofloxacin was better than saline in terms of resolution of discharge at one to two weeks: 84% versus 12% (risk ratio (RR) 6.74, 95% confidence interval (CI) 1.82 to 24.99; 35 participants, very low-certainty evidence), the very low certainty of the evidence means that it is very uncertain whether or not one intervention is better or worse than the other. The study authors reported that "no medical side-effects and worsening of audiological measurements related to this topical medication were detected" (very low-certainty evidence). B: Topical antibiotics versus placebo or no treatment (with use of oral antibiotics in both arms) Four studies compared topical ciprofloxacin to no treatment (three studies; 190 participants) or topical ceftizoxime to no treatment (one study; 248 participants). In each study all participants received the same antibiotic systemically (oral ciprofloxacin, injected ceftizoxime). In at least one study all participants received aural toilet. Useable data were only available from the first three studies; ciprofloxacin was better than no treatment, resolution of discharge occurring in 88.2% versus 60% at one to two weeks (RR 1.47, 95% CI 1.20 to 1.80; 2 studies, 150 participants; low-certainty evidence). None of the studies reported ear pain or discomfort/local irritation. C: Comparisons of different topical antibiotics The certainty of evidence for all outcomes in these comparisons is very low. Quinolones versus aminoglycosides Seven studies compared an aminoglycoside (gentamicin, neomycin or tobramycin) with ciprofloxacin (734 participants) or ofloxacin (214 participants). Whilst resolution of discharge at one to two weeks was higher in the quinolones group the very low certainty of the evidence means that it is very uncertain whether or not one intervention is better or worse than the other (RR 1.95, 95% CI 0.88 to 4.29; 6 studies, 694 participants). One study measured ear pain and reported no difference between the groups. Quinolones versus aminoglycosides/polymyxin B combination ±gramicidin We identified three studies but data on our primary outcome were only available in one study. Comparing ciprofloxacin to a neomycin/polymyxin B/gramicidin combination, for an unknown treatment duration (likely four weeks), ciprofloxacin was better (RR 1.12, 95% CI 1.03 to 1.22, 186 participants). A "few" patients experienced local irritation upon the first instillation of topical treatment (numbers/groups not stated). Others Other studies examined topical gentamicin versus a trimethoprim/sulphacetamide/polymixin B combination (91 participants) and rifampicin versus chloramphenicol (160 participants). Limited data were available and the findings were very uncertain., Authors' Conclusions: We are uncertain about the effectiveness of topical antibiotics in improving resolution of ear discharge in patients with CSOM because of the limited amount of low-quality evidence available. However, amongst this uncertainty there is some evidence to suggest that the use of topical antibiotics may be effective when compared to placebo, or when used in addition to a systemic antibiotic. There is also uncertainty about the relative effectiveness of different types of antibiotics; it is not possible to determine with any certainty whether or not quinolones are better or worse than aminoglycosides. These two groups of compounds have different adverse effect profiles, but there is insufficient evidence from the included studies to make any comment about these. In general, adverse effects were poorly reported., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: The objective of the study was to clarify how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept of certainty of evidence applies to certainty ratings of test accuracy., Study Design and Setting: After initial brainstorming with GRADE Working Group members, we iteratively refined and clarified the approaches for defining ranges when assessing the certainty of evidence for test accuracy within a systematic review, health technology assessment, or guideline., Results: Ranges can be defined both for single test accuracy and for comparative accuracy of multiple tests. For systematic reviews and health technology assessments, approaches for defining ranges include some that do not require value judgments regarding downstream health outcomes. Key challenges arise in the context of a guideline that requires ranges for sensitivity and specificity that are set considering possible effects on all critical outcomes. We illustrate possible approaches and provide an example from a systematic review of a direct comparison between two test strategies., Conclusions: This GRADE concept paper provides a framework for assessing, presenting, and making decisions based on the certainty of evidence for test accuracy. More empirical research is needed to support future GRADE guidance on how to best operationalize the candidate approaches., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane Review first published in 2010 and previously updated in 2014., Objectives: To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) compared with non-surgical treatment in the management of children with PFAPA., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2019, Issue 4); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 15 October 2019., Selection Criteria: Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. The primary outcomes were the proportion of children whose symptoms have completely resolved and complications of surgery (haemorrhage and number of days of postoperative pain). Secondary outcomes were: number of episodes of fever and the associated symptoms; severity of episodes; use of corticosteroids; absence or time off school; quality of life. We used GRADE to assess the certainty of the evidence for each outcome., Main Results: Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported., Authors' Conclusions: The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical-quality stem cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein and showed that LN-221 promotes differentiation of pluripotent human embryonic stem cells (hESCs) toward cardiomyocyte lineage and downregulates pluripotency and teratoma-associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical-quality cells for use in regenerative cardiology., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Normal aging is associated with changes in cognitive function that are non-pathological and are not necessarily indicative of future neurocognitive disease. Low cognitive and brain reserve and limited cognitive stimulation are associated with increased risk of dementia. Emerging evidence now suggests that subtle cognitive changes, detectable years before criteria for mild cognitive impairment are met, may be predictive of future dementia. Important for intervention and reduction in disease risk, research also suggests that engaging in stimulating mental activity throughout adulthood builds cognitive and brain reserve and reduces dementia risk. Therefore, midlife (defined here as 40 to 65 years) may be a suitable time to introduce cognitive interventions for maintaining cognitive function and, in the longer term, possibly preventing or delaying the onset of clinical dementia., Objectives: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks for maintaining or improving cognitive function in cognitively healthy people in midlife., Search Methods: We searched up to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois), the specialised register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG). We ran additional searches in MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP at www.apps.who.int/trialsearch, to ensure that the search was as comprehensive and as up-to-date as possible, to identify published, unpublished, and ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) or quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people between 40 and 65 years of age (80% of study population within this age range). Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions., Data Collection and Analysis: For preliminary screening of search results, we used a 'crowd' method to identify RCTs. At least two review authors working independently screened remaining citations against inclusion criteria; independently extracted data; and assessed the quality of the included trial, using the Cochrane risk of bias assessment tool. We used GRADE to describe the overall quality of the evidence., Main Results: We identified one eligible study that examined the effect of computerised cognitive training (CCT) in 6742 participants over 50 years of age, with training and follow-up duration of six months. We considered the study to be at high risk of attrition bias and the overall quality of the evidence to be low.Researchers provided no data on our primary outcome. Results indicate that there may be a small advantage for the CCT group for executive function (mean difference (MD) -1.57, 95% confidence interval (CI) -1.85 to -1.29; participants = 3994; low-quality evidence) and a very small advantage for the control group for working memory (MD 0.09, 95% CI 0.03 to 0.15; participants = 5831; low-quality evidence). The intervention may have had little or no effect on episodic memory (MD -0.03, 95% CI -0.10 to 0.04; participants = 3090; low-quality evidence)., Authors' Conclusions: We found low-quality evidence from only one study. We are unable to determine whether computerised cognitive training is effective in maintaining global cognitive function among healthy adults in midlife. We strongly recommend that high-quality studies be undertaken to investigate the effectiveness and acceptability of cognitive training in midlife, using interventions that last long enough that they may have enduring effects on cognitive and brain reserve, and with investigators following up long enough to assess effects on clinically important outcomes in later life.

Background: Increasing age is associated with a natural decline in cognitive function and is also the greatest risk factor for dementia. Cognitive decline and dementia are significant threats to independence and quality of life in older adults. Therefore, identifying interventions that help to maintain cognitive function in older adults or to reduce the risk of dementia is a research priority. Cognitive training uses repeated practice on standardised exercises targeting one or more cognitive domains and is intended to maintain optimum cognitive function. This review examines the effect of computerised cognitive training interventions lasting at least 12 weeks on the cognitive function of healthy adults aged 65 or older., Objectives: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks for the maintenance or improvement of cognitive function in cognitively healthy people in late life., Search Methods: We searched to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois) and performed additional searches of MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP (www.apps.who.int/trialsearch) to ensure that the search was as comprehensive and as up-to-date as possible, to identify published, unpublished, and ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) and quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people, and at least 80% of the study population had to be aged 65 or older. Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions., Data Collection and Analysis: We performed preliminary screening of search results using a 'crowdsourcing' method to identify RCTs. At least two review authors working independently screened the remaining citations against inclusion criteria. At least two review authors also independently extracted data and assessed the risk of bias of included RCTs. Where appropriate, we synthesised data in random-effect meta-analyses, comparing computerised cognitive training (CCT) separately with active and inactive controls. We expressed treatment effects as standardised mean differences (SMDs) with 95% confidence intervals (CIs). We used GRADE methods to describe the overall quality of the evidence for each outcome., Main Results: We identified eight RCTs with a total of 1183 participants. Researchers provided interventions over 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had a moderate risk of bias. Review authors noted a lot of inconsistency between trial results. The overall quality of evidence was low or very low for all outcomes.We compared CCT first against active control interventions, such as watching educational videos. Because of the very low quality of the evidence, we were unable to determine any effect of CCT on our primary outcome of global cognitive function or on secondary outcomes of episodic memory, speed of processing, executive function, and working memory.We also compared CCT versus inactive control (no interventions). Negative SMDs favour CCT over control. We found no studies on our primary outcome of global cognitive function. In terms of our secondary outcomes, trial results suggest slight improvement in episodic memory (mean difference (MD) -0.90, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) and no effect on executive function (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing at trial endpoints because the evidence was of very low quality.We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison., Authors' Conclusions: We found little evidence from the included studies to suggest that 12 or more weeks of CCT improves cognition in healthy older adults. However, our limited confidence in the results reflects the overall quality of the evidence. Inconsistency between trials was a major limitation. In five of the eight trials, the duration of intervention was just three months. The possibility that longer periods of training could be beneficial remains to be more fully explored.

Asthma is a chronic inflammatory disease of the airway which is often misdiagnosed and undertreated. Early diagnosis and vigilant asthma control are crucial to preventing permanent airway damage, improving quality of life and reducing healthcare burdens. The key approaches to asthma management should include patient empowerment through health education and self-management and, an effective patient-healthcare provider partnership.

Background: Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life., Objectives: To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more., Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018., Selection Criteria: We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months., Data Collection and Analysis: Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more., Main Results: In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38)., Authors' Conclusions: We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.

Background: Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI)., Objectives: To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment., Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018., Selection Criteria: We included randomised or quasi-randomised, placebo-controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies., Data Collection and Analysis: We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random-effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome., Main Results: We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline.We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence.We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects., Authors' Conclusions: The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.

The current expansion of autologous human keratinocytes to resurface severe wound defects still relies on murine feeder layer and calf serum in the cell culture system. Through our characterization efforts of the human skin basement membrane and murine feeder layer 3T3-J2, we identified two biologically relevant recombinant laminins-LN-511 and LN-421- as potential candidates to replace the murine feeder. Herein, we report a completely xeno-free and defined culture system utilizing these laminins which enables robust expansion of adult human skin keratinocytes. We demonstrate that our laminin system is comparable to the 3T3-J2 co-culture system in terms of basal markers' profile, colony-forming efficiency and the ability to form normal stratified epidermal structure in both in vitro and in vivo models. These results show that the proposed system may not only provide safer keratinocyte use in the clinics, but also facilitate the broader use of other cultured human epithelial cells in regenerative medicine.

Background: This review adds to a series of reviews looking at primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Antifungals have been suggested as a treatment for chronic rhinosinusitis., Objectives: To assess the effects of systemic and topical antifungal agents in patients with chronic rhinosinusitis, including those with allergic fungal rhinosinusitis (AFRS) and, if possible, AFRS exclusively., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 17 November 2017., Selection Criteria: Randomised controlled trials (RCTs) with at least a two-week follow-up period comparing topical or systemic antifungals with (a) placebo, (b) no treatment, (c) other pharmacological interventions or (d) a different antifungal agent. We did not include post-surgical antifungal use., Data Collection and Analysis: We used the standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the significant adverse effects of hepatic toxicity (systemic antifungals). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse effects of gastrointestinal disturbance (systemic antifungals) and epistaxis, headache or local discomfort (topical antifungals). We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics., Main Results: We included eight studies (490 adult participants). The presence of nasal polyps on examination was an inclusion criterion in three studies, an exclusion criterion in one study and the remaining studies included a mixed population. No studies specifically investigated the effect of antifungals in patients with AFRS.Topical antifungal treatment versus placebo or no interventionWe included seven studies (437 participants) that used amphotericin B (six studies; 383 participants) and one that used fluconazole (54 participants). Different delivery methods, volumes and concentrations were used.Four studies reported disease-specific health-related quality of life using a range of instruments. We did not meta-analyse the results due to differences in the instruments used, and measurement and reporting methods. At the end of treatment (one to six months) none of the studies reported statistically significant differences between the groups (low-quality evidence - we are uncertain about the result).Two studies reported disease severity using patient-reported symptom scores. Meta-analysis was not possible. At the end of treatment (8 to 13 weeks) one study showed no difference and the second found that patients in the placebo group had less severe symptoms (very low-quality evidence - we are very uncertain about the result).In terms of adverse effects, topical antifungals may lead to more local irritation compared with placebo (risk ratio (RR) 2.29, 95% confidence interval (CI) 0.61 to 8.62; 312 participants; 5 studies; low-quality evidence) but little or no difference in epistaxis (RR 0.97, 95% CI 0.14 to 6.63; 225 participants; 4 studies, low-quality evidence) or headache (RR 1.26, 95% CI 0.60 to 2.63; 195 participants; 3 studies; very low-quality evidence).None of the studies found a difference in generic health-related quality of life (one study) or endoscopic score (five studies) between the treatment groups. Three studies investigated CT scan; two found no difference between the groups and one found a significant decrease in the mean percentage of air space occluded, favouring the antifungal group.Systemic antifungal treatment versus placebo or no treatmentOne study (53 participants) comparing terbinafine tablets against placebo reported that there may be little or no difference between the groups in disease-specific health-related quality of life or disease severity score (both low-quality evidence). Systemic antifungals may lead to more hepatic toxicity events (RR 3.35, 95% CI 0.14 to 78.60) but fewer gastrointestinal disturbances (RR 0.37, 95% CI 0.04 to 3.36), compared to placebo, although the evidence was of low quality.This study did not find a difference in CT scan score between the groups. Generic health-related quality of life and endoscopic score were not measured.Other comparisonsWe found no studies that compared antifungal agents against other treatments for chronic rhinosinusitis., Authors' Conclusions: Due to the very low quality of the evidence, it is uncertain whether or not the use of topical or systemic antifungals has an impact on patient outcomes in adults with chronic rhinosinusitis compared with placebo or no treatment. Studies including specific subgroups (i.e. AFRS) are lacking.

The efficacy of islet transplantation for diabetes treatment suffers from lack of cadaver-derived islets, islet necrosis and long transfer times prior to transplantation. Here, we developed a method for culturing mouse and human islets in vitro on α5-laminins, which are natural components of islet basement membranes. Adhering islets spread to form layers of 1-3 cells in thickness and remained normoxic and functional for at least 7 days in culture. In contrast, spherical islets kept in suspension developed hypoxia and central necrosis within 16 h. Transplantation of 110-150 mouse islets cultured on α5-laminin-coated polydimethylsiloxane membranes for 3-7 days normalized blood glucose already within 3 days in mice with streptozotocin-induced diabetes. RNA-sequencing of isolated and cultured mouse islets provided further evidence for the adhesion and spreading achieved with α5-laminin. Our results suggest that use of such in vitro expanded islets may significantly enhance the efficacy of islet transplantation treatment for diabetes., (Copyright © 2017. Published by Elsevier B.V.)

Background: Slow-release fluoride devices have been investigated as a potentially cost-effective method of reducing dental caries in people with high risk of disease. This is the second update of the Cochrane Review first published in 2006 and previously updated in 2014., Objectives: To evaluate the effectiveness and safety of different types of slow-release fluoride devices on preventing, arresting, or reversing the progression of carious lesions on all surface types of primary (deciduous) and permanent teeth., Search Methods: Cochrane Oral Health's Information Specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (to 23 January 2018); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (searched 23 January 2018); MEDLINE Ovid (1946 to 23 January 2018); and Embase Ovid (1980 to 23 January 2018). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials (23 January 2018). We placed no restrictions on the language or date of publication when searching the electronic databases., Selection Criteria: Parallel randomised controlled trials (RCTs) comparing slow-release fluoride devices with an alternative fluoride treatment, placebo, or no intervention in all age groups. The main outcome measures sought were changes in numbers of decayed, missing, and filled teeth or surfaces (DMFT/DMFS in permanent teeth or dmft/dmfs in primary teeth), and progression of carious lesions through enamel and into dentine., Data Collection and Analysis: We conducted data collection and analysis using standard Cochrane review methods. At least two review authors independently performed all the key steps in the review such as screening of abstracts, application of inclusion criteria, data extraction, and risk of bias assessment. We resolved discrepancies through discussions or arbitration by a third or fourth review author., Main Results: We found no evidence comparing slow-release fluoride devices against other types of fluoride therapy.We found only one double-blind RCT involving 174 children comparing a slow-release fluoride device (glass beads with fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth) against control (glass beads without fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth). This study was assessed to be at high risk of bias. The study recruited children from seven schools in an area of deprivation that had low levels of fluoride in the water. The mean age at the beginning of the study was 8.8 years and at the termination was 10.9 years. DMFT in permanent teeth or dmft in primary teeth was greater than one at the start of the study and greater than one million colony-forming units of Streptococcus mutans per millilitre of saliva.Although 132 children were still included in the trial at the two-year completion point, examination and statistical analysis was performed on only the 63 children (31 in intervention group, 32 in control group) who had retained the beads (retention rate was 47.7% at 2 years). Among these 63 children, caries increment was reported to be statistically significantly lower in the intervention group than in the control group (DMFT: mean difference -0.72, 95% confidence interval (CI) -1.23 to -0.21; DMFS: mean difference -1.52, 95% CI -2.68 to -0.36 (very low-quality evidence)). Although this difference was clinically significant, it only holds true for those children who maintain the fluoride beads; over 50% of children did not retain the beads.Harms were not reported within the trial report. Evidence for other outcomes sought in this review (progression to of caries lesion, dental pain, healthcare utilisation data) were also not reported., Authors' Conclusions: There is insufficient evidence to determine the caries-inhibiting effect of slow-release fluoride glass beads. The body of evidence available is of very low quality and there is a potential overestimation of benefit to the average child. The applicability of the findings to the wider population is unclear; the study had included children from a deprived area that had low levels of fluoride in drinking water, and were considered at high risk of caries. In addition, the evidence was only obtained from children who still had the bead attached at 2 years (48% of all available children); children who had lost their slow-release fluoride devices earlier might not have benefited as much from the devices.

Background: Acquired hearing loss is common and its incidence increases markedly with age. In most people, 'age-related' hearing loss is sensorineural (due to the loss of cochlear hair cells) and bilateral, affecting both ears to the same degree. Hearing loss categorised as mild, moderate or severe is primarily managed with hearing aids. People with bilateral hearing loss may be offered one aid, fitted to one specific ear, or two aids fitted to both ears. There is uncertainty about the relative benefits to people with hearing loss of these different strategies., Objectives: To assess the effects of bilateral versus unilateral hearing aids in adults with a bilateral hearing impairment., Search Methods: The Cochrane ENT Information Specialist searched the ENT Trials Register; Cochrane Register of Studies Online; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 8 June 2017., Selection Criteria: Randomised controlled trials (RCTs) comparing the fitting of two versus one ear-level acoustic hearing aids in adults (over 18 years) with a bilateral hearing impairment, both ears being eligible for hearing aids., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were patient preference for bilateral or unilateral aids, hearing-specific health-related quality of life and adverse effects (pain or discomfort in the ear, initiation or exacerbation of middle or outer ear infection). Secondary outcomes included: usage of hearing aids (as measured by, for example, data logging or battery consumption), generic health-related quality of life, listening ability and audiometric benefit measured as binaural loudness summation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics., Main Results: We included four cross-over RCTs with a total of 209 participants, ranging in age from 23 to 85 and with a preponderance of men. All the studies allowed the use of hearing aids for a total period of at least eight weeks before questions on preference were asked. All studies recruited patients with bilateral hearing loss but there was considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing.Three of the studies were published before the mid-1990s whereas the fourth study was published in 2011. Therefore, only the most recent study used hearing aids incorporating technology comparable to that currently readily available in high-income settings. Of the four studies, two were conducted in the UK in National Health Service (NHS - public sector) patients: one recruited patients from primary care with hearing loss detected by a screening programme whereas the other recruited patients who had been referred by their primary care practitioner to an otolaryngology department for hearing aids. The other two studies were conducted in the United States: one study recruited only military personnel or veterans with noise-induced hearing loss whereas about half of the participants in the other study were veterans.Only one primary outcome (patient preference) was reported in all studies. The percentage of patients who preferred bilateral hearing aids varied between studies: this was 54% (51 out of 94 participants), 39% (22 out of 56), 55% (16 out of 29) and 77% (23 out of 30), respectively. We have not combined the data from these four studies. The evidence for this outcome is of very low quality.The other outcomes of interest were not reported in the included studies., Authors' Conclusions: This review identified only four studies comparing the use of one hearing aid with two. The studies were small and included participants of widely varying ages. There was also considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing.For the most part, the types of hearing aid evaluated would now be regarded, in high-income settings, as 'old technology', with only one study looking at 'modern' digital aids. However, the relevance of this is uncertain, as this review did not evaluate the differences in outcomes between the different types of technology.We were unable to pool data from the four studies and the very low quality of the evidence leads us to conclude that we do not know if people with hearing loss have a preference for one aid or two. Similarly, we do not know if hearing-specific health-related quality of life, or any of our other outcomes, are better with bilateral or unilateral aids.

Background: The main clinical intervention for mild to moderate hearing loss is the provision of hearing aids. These are routinely offered and fitted to those who seek help for hearing difficulties. By amplifying and improving access to sounds, and speech sounds in particular, the aim of hearing aid use is to reduce the negative consequences of hearing loss and improve participation in everyday life., Objectives: To evaluate the effects of hearing aids for mild to moderate hearing loss in adults., Search Methods: The Cochrane ENT Information Specialist searched the ENT Trials Register; the Cochrane Register of Studies Online; MEDLINE; PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 March 2017., Selection Criteria: Randomised controlled trials (RCTs) of hearing aids compared to a passive or active control in adults with mild to moderate hearing loss., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. The primary outcomes in this review were hearing-specific health-related quality of life and the adverse effect pain. Secondary outcomes were health-related quality of life, listening ability and the adverse effect noise-induced hearing loss. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics., Main Results: We included five RCTs involving 825 participants. The studies were carried out in the USA and Europe, and were published between 1987 and 2017. Risk of bias across the studies varied. Most had low risk for selection, reporting and attrition bias, and a high risk for performance and detection bias because blinding was inadequate or absent.All participants had mild to moderate hearing loss. The average age across all five studies was between 69 and 83 years. The duration of the studies ranged between six weeks and six months.There was a large beneficial effect of hearing aids on hearing-specific health-related quality of life associated with participation in daily life as measured using the Hearing Handicap Inventory for the Elderly (HHIE, scale range 1 to 100) compared to the unaided/placebo condition (mean difference (MD) -26.47, 95% confidence interval (CI) -42.16 to -10.77; 722 participants; three studies) (moderate-quality evidence).There was a small beneficial effect of hearing aids on general health-related quality of life (standardised mean difference (SMD) -0.38, 95% CI -0.55 to -0.21; 568 participants; two studies) (moderate-quality evidence). There was a large beneficial effect of hearing aids on listening ability (SMD -1.88, 95% CI -3.24 to -0.52; 534 participants; two studies) (moderate-quality evidence).Adverse effects were measured in only one study (48 participants) and none were reported (very low-quality evidence)., Authors' Conclusions: The available evidence concurs that hearing aids are effective at improving hearing-specific health-related quality of life, general health-related quality of life and listening ability in adults with mild to moderate hearing loss. The evidence is compatible with the widespread provision of hearing aids as the first-line clinical management in those who seek help for hearing difficulties. Greater consistency is needed in the choice of outcome measures used to assess benefits from hearing aids. Further placebo-controlled studies would increase our confidence in the estimates of these effects and ascertain whether they vary according to age, gender, degree of hearing loss and type of hearing aid.

Background: Tonsillectomy is a very common operation and is performed using various surgical methods. Coblation is a popular method because it purportedly causes less pain than other surgical methods. However, the superiority of coblation is unproven., Objectives: To compare the effects of coblation tonsillectomy for chronic tonsillitis or tonsillar hypertrophy with other surgical techniques, both hot and cold, on intraoperative morbidity, postoperative morbidity and procedural cost., Search Methods: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2017, Issue 3); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 20 April 2017., Selection Criteria: Randomised controlled trials (RCTs) of children and adults undergoing tonsillectomy with coblation compared with any other surgical technique. This review is limited to trials of extracapsular (traditional) tonsillectomy and excludes trials of intracapsular tonsil removal (tonsillotomy)., Data Collection and Analysis: We used the standard Cochrane methods. Our primary outcomes were: patient-reported pain using a validated pain scale at postoperative days 1, 3 and 7; intraoperative blood loss; primary postoperative bleeding (within 24 hours) and secondary postoperative bleeding (more than 24 hours after surgery). Secondary outcomes were: time until resumption of normal diet, time until resumption of normal activity, duration of surgery and adverse effects including blood transfusion and the need for reoperation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics., Main Results: We included 29 studies, with a total of 2561 participants. All studies had moderate or high risk of bias. Sixteen studies used an adequate randomisation technique, however the inability to mask the surgical teams and/or provide adequate methods to mitigate the risk of bias put nearly all studies at moderate or high risk of detection and measurement bias for intraoperative blood loss, and primary and secondary bleeding. In contrast most studies (20) were at low risk of bias for pain assessment. Most studies did not report data in a manner permitting meta-analysis.Most studies did not clearly report the participant characteristics, surgical indications or whether patients underwent tonsillectomy or adenotonsillectomy. Most studies reported that tonsillitis (infection) and/or tonsillar hypertrophy (obstruction) were the indication for surgery. Seven studies included only adults, 16 studies included only children and six studies included both. Pain At postoperative day 1 there is very low quality evidence that patients in the coblation group had less pain, with a standardised mean difference (SMD) of -0.79 (95% confidence interval (CI) -1.38 to -0.19; 538 participants; six studies). This effect is reduced a SMD of -0.44 (95% CI -0.97 to 0.09; 401 participants; five studies; very low-quality evidence) at day 3, and at day 7 there is low quality evidence of little or no difference in pain (SMD -0.01, 95% CI -0.22 to 0.19; 420 participants; five studies). Although this suggests that pain may be slightly less in the coblation group between days 1 and 3, the clinical significance is unclear. Intraoperative blood loss Methodological differences between studies in the measurement of intraoperative blood loss precluded meta-analysis. Primary and secondary bleeding The risk of primary bleeding was similar (risk ratio (RR) 0.99, 95% CI 0.48 to 2.05; 2055 participants; 25 studies; low-quality evidence). The risk of secondary bleeding was greater in the coblation group with a risk ratio of 1.36 (95% CI 0.95 to 1.95; 2118 participants; 25 studies; low-quality evidence). Using the median of the control group as the baseline risk, the absolute risk in the coblation group was 5% versus 3.6% in the control group. The difference of 1.3% has a 95% CI of 0.2% lower in the coblation group to 3.5% higher. Secondary outcomes Differences in study design and data reporting precluded the identification of differences in the time to resumption of normal diet or activity, or whether there was a difference in the duration of surgery.Although we could not feasibly compare the costs of equipment or operative facility, anaesthetic and surgical fees across different healthcare systems we used duration of surgery as a proxy for cost. Although this outcome was commonly reported in studies, it was not possible to pool the data to determine whether there was a difference.Adverse events other than bleeding were not well reported. It is unclear whether there is a difference in postoperative infections or the need for reoperation., Authors' Conclusions: The coblation technique may cause less pain on postoperative day 1, but the difference is small and may be clinically meaningless. By postoperative day 3, the difference decreases further and by postoperative day 7 there appears to be little or no difference. We found similar rates of primary bleeding but we cannot rule out a small increased risk of secondary bleeding with coblation. The evidence supporting these findings is of low or very low quality, i.e. there is a very high degree of uncertainty about the results. Moreover, for most outcomes data were only available from a few of the 29 included studies.The current evidence is of very low quality, therefore it is uncertain whether or not the coblation technique has any advantages over traditional tonsillectomy techniques. Despite the large number of studies, failure to use standardised or validated outcome measures precludes the ability to pool data across studies. Therefore, well-conducted RCTs using consistent, validated outcome measures are needed to establish whether the coblation technique has a benefit over other methods. In the included studies we identified no clear difference in adverse events. However, given the rarity of these events, randomised trials lack the power to detect a difference. Data from large-scale registries will provide a better estimate of any difference in these rare outcomes.

Background: Fluoride mouthrinses have been used extensively as a caries-preventive intervention in school-based programmes and by individuals at home. This is an update of the Cochrane review of fluoride mouthrinses for preventing dental caries in children and adolescents that was first published in 2003., Objectives: The primary objective is to determine the effectiveness and safety of fluoride mouthrinses in preventing dental caries in the child and adolescent population.The secondary objective is to examine whether the effect of fluoride rinses is influenced by:• initial level of caries severity;• background exposure to fluoride in water (or salt), toothpastes or reported fluoride sources other than the study option(s); or• fluoride concentration (ppm F) or frequency of use (times per year)., Search Methods: We searched the following electronic databases: Cochrane Oral Health's Trials Register (whole database, to 22 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 3), MEDLINE Ovid (1946 to 22 April 2016), Embase Ovid (1980 to 22 April 2016), CINAHL EBSCO (the Cumulative Index to Nursing and Allied Health Literature, 1937 to 22 April 2016), LILACS BIREME (Latin American and Caribbean Health Science Information Database, 1982 to 22 April 2016), BBO BIREME (Bibliografia Brasileira de Odontologia; from 1986 to 22 April 2016), Proquest Dissertations and Theses (1861 to 22 April 2016) and Web of Science Conference Proceedings (1990 to 22 April 2016). We undertook a search for ongoing trials on the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform. We placed no restrictions on language or date of publication when searching electronic databases. We also searched reference lists of articles and contacted selected authors and manufacturers., Selection Criteria: Randomised or quasi-randomised controlled trials where blind outcome assessment was stated or indicated, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years of age. Study duration had to be at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in permanent teeth (D(M)FS)., Data Collection and Analysis: At least two review authors independently performed study selection, data extraction and risk of bias assessment. We contacted study authors for additional information when required. The primary measure of effect was the prevented fraction (PF), that is, the difference in mean caries increments between treatment and control groups expressed as a percentage of the mean increment in the control group. We conducted random-effects meta-analyses where data could be pooled. We examined potential sources of heterogeneity in random-effects metaregression analyses. We collected adverse effects information from the included trials., Main Results: In this review, we included 37 trials involving 15,813 children and adolescents. All trials tested supervised use of fluoride mouthrinse in schools, with two studies also including home use. Almost all children received a fluoride rinse formulated with sodium fluoride (NaF), mostly on either a daily or weekly/fortnightly basis and at two main strengths, 230 or 900 ppm F, respectively. Most studies (28) were at high risk of bias, and nine were at unclear risk of bias.From the 35 trials (15,305 participants) that contributed data on permanent tooth surface for meta-analysis, the D(M)FS pooled PF was 27% (95% confidence interval (CI), 23% to 30%; I(2) = 42%) (moderate quality evidence). We found no significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration in metaregression analyses. A funnel plot of the 35 studies in the D(M)FS PF meta-analysis indicated no relationship between prevented fraction and study precision (no evidence of reporting bias). The pooled estimate of D(M)FT PF was 23% (95% CI, 18% to 29%; I² = 54%), from the 13 trials that contributed data for the permanent teeth meta-analysis (moderate quality evidence).We found limited information concerning possible adverse effects or acceptability of the treatment regimen in the included trials. Three trials incompletely reported data on tooth staining, and one trial incompletely reported information on mucosal irritation/allergic reaction. None of the trials reported on acute adverse symptoms during treatment., Authors' Conclusions: This review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries-preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability.