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© 2023 European Academy of Neurology, Hariz and colleagues [1] argue that the new EAN/MDS GL contradicts the repeated endorsements of pallidotomy by the MDS. The MDS has previously published “evidence based medicine (EBM) reviews,” which appraise each treatment on the basis of welldefined criteria but are not GLs. Clinical GLs, such as the new EAN/MDS GL, also take into consideration other variables, including context, summarizing the current medical knowledge, weighing the benefits and harms of treatments, and giving specific recommendations based on this information. The specific GRADE GL methodology allows for the evaluation of available scientific evidence with a sophisticated evaluation process that includes grading the strength of the evidence and the certainty of that evidence, out of which the recommendations are developed. These steps are well documented in our appendices 1 and 2 for methodology and appendices 3 and 4 for outcomes. Thus, the case of radiofrequency pallidotomy and deep brain stimulation (DBS) of the pallidum, which is discussed by Hariz et al, illustrates the difference between EBM reviews and GLs. The EBM review ranks pallidotomy at the same level as globus pallidus internus (GPi)-DBS: both treatments are considered “efficacious,” “clinically useful,” and coming with a “clinically acceptable risk with specialized monitoring,” but it does not express whether the treatments are equal in their application in patients overall. In our GL using the GRADE methodology, in contrast, GPi-DBS is recommended, whereas pallidotomy is recommended only with restrictions.

[Background and Purpose] This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway., [Methods] Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging–guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered., [Results] Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended., [Conclusions] Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups., The GL development was further supported by travel grants for meetings and support for online meetings by EAN/MDS-ES. Katarzyna Śmiłowska was supported with a stipend of the Medical Faculty of the Christian-Albrechts-University, Kiel. Open Access funding enabled and organized by Projekt DEAL. Mir has received grants from the Spanish Ministry of Science and Innovation, the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional, the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía, and the Consejería de Salud y Bienestar Social de la Junta de Andalucía. A. Schrag has received grants from GE Healthcare.

Background: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. Objectives: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. Search methods: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). Selection criteria: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. Data collection and analysis: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events. Main results: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19. Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence). The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19. Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence). The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19. Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence). The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence). The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19. Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). Authors' conclusions: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally. OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2.We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch.We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules.We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes. We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs). MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available. This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review.Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the efficacy and harms or adverse events of immunomodulatory therapies in people with ALS compared with a placebo, no additional treatment, or a standard-of-care protocol (with or without riluzole, edaravone, or both).

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: We aim to assess population‐level effects of human papillomavirus (HPV) vaccination programmes on HPV‐related disease and harms from vaccination.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: We aim to evaluate the safety and efficacy of WHO pre‐qualified human papillomavirus (HPV) vaccines given in different dose schedules, in females and males, to prevent cervical cancer and other HPV‐related diseases by undertaking a network meta‐analysis (NMA). We will rank the different vaccines and dose schedules according to the critical outcomes.

Protocol for a Cochrane Effective Practice and Organisation of Care (EPOC) review update, Simon Lewin receives additional funding from the South African Medical Research Council

Background\ud Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource‐limited settings.\ud \ud Objectives\ud To determine the accuracy of simple measures of ART adherence (including patient self‐report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non‐suppressed viral load in people living with HIV and receiving ART treatment.\ud \ud Search methods\ud The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African‐Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases.\ud \ud Selection criteria\ud We included studies of all designs that evaluated a simple measure of adherence (index test) such as self‐report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity.\ud \ud Data collection and analysis\ud We screened studies, extracted data, and assessed risk of bias using QUADAS‐2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta‐analysis or comparison of adherence measures. We explored heterogeneity using pre‐defined subgroup analysis.\ud \ud Main results\ud We included 51 studies involving children and adults with HIV, mostly living in low‐ and middle‐income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self‐report.\ud \ud ‐ Self‐report questionnaires (25 studies, 9211 participants; very low‐certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%.\ud \ud ‐ Self‐report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low‐certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%.\ud \ud ‐ Tablet counts (12 studies, 3466 participants; very low‐certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%.\ud \ud ‐ Electronic monitoring devices (3 studies, 186 participants; very low‐certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%.\ud \ud ‐ Pharmacy records or secondary databases (6 studies, 2254 participants; very low‐certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%.\ud \ud ‐ Composite measures (9 studies, 1513 participants; very low‐certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%.\ud \ud Across all included studies, the ability of adherence measures to detect viral non‐suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision.\ud \ud The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results.\ud \ud Authors' conclusions\ud We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non‐suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

Chronic pain in childhood is an international public health problem. We conducted a systematic review and meta-analysis to provide a summary of the published evidence of pharmacological, physical, and psychological therapies for children with chronic pain conditions. We searched CENTRAL, MEDLINE, EMBASE, and PsycINFO from inception to April 2020; clinical trial registries; and other sources for randomised controlled trials or comparative observational trials. We extracted critical outcomes of pain intensity, quality of life, physical functioning, role functioning, emotional functioning, sleep, and adverse events. We assessed studies for risk of bias and certainty of the evidence using GRADE. We included 34 pharmacological (4091 participants), 25 physical therapy (1470 participants), and 63 psychological trials (5025 participants). Participants reported a range of chronic pain conditions. Most studies were assessed to have unclear or high risk of bias across multiple domains. Pharmacological, physical, and psychological therapies showed some benefit for reducing pain, posttreatment, but only physical and psychological therapies improved physical functioning. We found no benefit of any treatment modality for health-related quality of life, role functioning, emotional functioning, or sleep. Adverse events were poorly reported, particularly for psychological and physical interventions. The largest evidence base for the management of chronic pain in children supports the use of psychological therapies, followed by pharmacological and physical therapies. However, we rated most outcomes as low or very low certainty, meaning further evidence is likely to change our confidence in the estimates of effects. This protocol was registered on PROSPERO (CRD42020172451).

Background Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. Objectives To evaluate the effectiveness and safety of currently used drugs for treating second‐stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g‐HAT). Search methods On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations. Selection criteria Eligible studies were randomized controlled trials that included adults and children with second‐stage g‐HAT, treated with anti‐trypanosomal drugs currently in use. Data collection and analysis Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). Main results We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow‐up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low‐certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow‐up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate‐certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate‐certainty evidence). Authors' conclusions Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence., Plain language summary Medicines for second‐stage human African trypanosomiasis What is the aim of this review? Gambiense human African trypanosomiasis (g‐HAT), or sleeping sickness, is a severe disease transmitted through the bite of infected tsetse flies found in rural parts of sub‐Saharan Africa. Sleeping sickness has two clinical stages. This review only examines treating the second‐stage, where people develop symptoms caused by invasion of the central nervous system (CNS), resulting in changes in the nervous system. Death is inevitable without treatment. Drugs for treatment are few, often require intravenous infusion every day over several weeks, and have serious side effects. In this review we aimed to compare the effects of current drugs for gambiense sleeping sickness and we examined nifurtimox‐eflornithine combination (NECT) with a new drug, fexinidazole, that can be taken orally. Key messages Whilst fexinidazole cures some people, deaths from any cause and treatment failure rates are higher than with conventional treatment. Adverse events were common in both groups. Fexinidazole is more practical to give, and means less time in hospital for intravenous treatment infusion. What was studied in this review? We looked at the evidence about the benefits and harms of current drugs used in people with second stage g‐HAT. We searched for randomized trials, which provide robust evidence about the various treatments. We aimed to determine whether any drug provides a definite advantage over the other, measured in terms of clinical outcomes and in relation to the severity of adverse effects. What are the main results of the review? We only identified one suitable trial, which included 394 people and was conducted in the Democratic Republic of the Congo and the Central African Republic. The trial showed that deaths from any cause at 24 months may be higher with fexinidazole compared with NECT. Nine of the 264 people who took fexinidazole died, compared with two of the 130 people who took NECT. Fexinidazole probably increases the number of people who relapse during two years. Fourteen people in the fexinidazole group relapsed, and none in the NECT group. Adverse events were very common in both groups over the two years, and there is not likely to be much difference between the two drugs (247/264 in the fexinidazole group and 121/130 in the NECT group). We do not know about the effect of fexinidazole on serious adverse events, as the evidence is very uncertain. There were 31/264 serious adverse events in the fexinidazole group and 13/130 in the NECT group at 24 months. How up to date is this review? The evidence is current to 14 May 2021.

Background Refugees, and other forcibly displaced people, face mental distress and may be disproportionately affected by risk factors for suicide. Little is known about suicidal behaviour in these highly mobile populations because collecting timely, relevant, and reliable data is challenging. Methods and findings A systematic review was performed to identify studies of any design reporting on suicide, suicide attempts, or suicidal ideation among populations of displaced people. A sensitive electronic database search was performed in August 2020, and all retrieved studies were screened for relevance by two authors. Studies were categorised by the population being evaluated: refugees granted asylum, refugees living in temporary camps, asylum seekers, or internally displaced people. We distinguished between whether the sampling procedure in the studies was likely to be representative, or the sample examined a specific non-representative subgroup of displaced people (such as those already diagnosed with mental illness). Data on the rates of suicide or the prevalence of suicide attempts or suicidal ideation were extracted by one reviewer and verified by a second reviewer from each study and converted to common metrics. After screening 4347 articles, 87 reports of 77 unique studies were included. Of these, 53 were studies in representative samples, and 24 were based on samples of specific target populations. Most studies were conducted in high-income countries, and the most studied population subgroup was refugees granted asylum. There was substantial heterogeneity across data sources and measurement instruments utilised. Sample sizes of displaced people ranged from 33 to 196,941 in studies using general samples. Suicide rates varied considerably, from 4 to 290 per 100,000 person-years across studies. Only 8 studies were identified that compared suicide rates with the host population. The prevalence of suicide attempts ranged from 0.14% to 15.1% across all studies and varied according to the prevalence period evaluated. Suicidal ideation prevalence varied from 0.17% to 70.6% across studies. Among refugees granted asylum, there was evidence of a lower risk of suicide compared with the host population in 4 of 5 studies. In contrast, in asylum seekers there was evidence of a higher suicide risk in 2 of 3 studies, and of a higher risk of suicidal ideation among refugees living in camps in 2 of 3 studies compared to host populations. Conclusion While multiple studies overall have been published in the literature on this topic, the evidence base is still sparse for refugees in camps, asylum seekers, and internally displaced people. Less than half of the included studies reported on suicide or suicide attempt outcomes, with most reporting on suicidal ideation. International research networks could usefully define criteria, definitions, and study designs to help standardise and facilitate more research in this important area. Registration PROSPERO CRD42019137242.

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox-eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per mu L. Nifurtimox-eflornithine combination therapy remains recommended for patients with 100 leucocytes per mu L or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.

Background Vaccines may reduce antibiotic use and the development of resistance. Objectives To provide a comprehensive, up-to-date assessment of the evidence base relating to the effect of vaccines on antibiotic use. Data sources Ovid MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov and WHO Trials Registry. Study eligibility criteria Randomized controlled trials (RCTs) and observational studies published from January 1998 to March 2018. Participants Any population. Interventions Vaccines versus placebo, no vaccine or another vaccine. Methods Titles, abstracts and full-texts were screened independently by two reviewers. Certainty of RCT evidence was assessed using GRADE. Results In all, 4980 records identified; 895 full-text reports assessed; 96 studies included (24 RCTs, 72 observational). There was high-certainty evidence that influenza vaccine reduces days of antibiotic use among healthy adults (one RCT; n = 4253; rate reduction 28·1%; 95% CI 16·0–38·4); moderate-certainty evidence that influenza vaccines probably reduce antibiotic use in children aged 6 months to 14 years (three RCTs; n = 610; ratio of means 0·62; 95% CI 0·54–0·70) and probably reduce community antibiotic use in children aged 3–15 years (one RCT; n = 10 985 person-seasons; risk ratio 0·69, 95% CI 0·58–0·83); and moderate-certainty evidence that pneumococcal vaccination probably reduces antibiotic use in children aged 6 weeks to 6 years (two RCTs; n = 47 945; rate ratio 0·93, 95% CI 0·87–0·99) and reduces illness episodes requiring antibiotics in children aged 12–35 months (one RCT; n = 264; rate ratio 0·85, 95% CI 0·75–0·97). Other RCT evidence was of low or very low certainty, and observational evidence was affected by confounding. Conclusions The evidence base is poor. Although some vaccines may reduce antibiotic use, collection of high-quality data in future vaccine trials is needed to improve the evidence base. PROSPERO registration CRD42018103881.

Background: Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed. Objectives: To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high‐standard 14‐day courses. Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies. Selection criteria: Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin‐based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO‐recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days. Data collection and analysis Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow‐up, partner drug, and trial location. We analysed safety data where included. Main results: 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low‐certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low‐certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided. High‐standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low‐certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high‐standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low‐certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded. 0.75 mg/kg/week for eight weeks versus high‐standard 0.5 mg/kg/day for 14 days We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high‐standard 0.5 mg/kg/day for 14 days, at 11 months' follow‐up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low‐certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD‐deficient patients were not randomized but included in the weekly primaquine group (only one patient detected). 1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high‐standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate‐certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high‐standard 0.5 mg/kg/day for 14 days, during 42 days follow‐up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low‐certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high‐standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low‐certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low‐certainty evidence). People with G6PD deficiency were excluded. Other regimens: Two RCTs evaluated other rarely‐used doses of primaquine, one of which had very high loss to follow‐up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded. Authors' conclusions: Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high‐standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high‐standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high‐standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven‐day course in Comparison 4. The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD‐normal patients. Further research will help increase the certainty of the findings and applicability in different settings.

Background The burden of poor sexual and reproductive health (SRH) worldwide is substantial, disproportionately affecting those living in low‐ and middle‐income countries. Targeted client communication (TCC) delivered via mobile devices (MD) (TCCMD) may improve the health behaviours and service use important for sexual and reproductive health. Objectives To assess the effects of TCC via MD on adolescents' knowledge, and on adolescents’ and adults' sexual and reproductive health behaviour, health service use, and health and well‐being. Search methods In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. Selection criteria We included randomised controlled trials of TCC via MD to improve sexual and reproductive health behaviour, health service use, and health and well‐being. Eligible comparators were standard care or no intervention, non‐digital TCC, and digital non‐targeted communication. Data collection and analysis We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross‐checked by a second. We have presented results separately for adult and adolescent populations, and for each comparison. Main results We included 40 trials (27 among adult populations and 13 among adolescent populations) with a total of 26,854 participants. All but one of the trials among adolescent populations were conducted in high‐income countries. Trials among adult populations were conducted in a range of high‐ to low‐income countries. Among adolescents, nine interventions were delivered solely through text messages; four interventions tested text messages in combination with another communication channel, such as emails, multimedia messaging, or voice calls; and one intervention used voice calls alone. Among adults, 20 interventions were delivered through text messages; two through a combination of text messages and voice calls; and the rest were delivered through other channels such as voice calls, multimedia messaging, interactive voice response, and instant messaging services. Adolescent populations TCCMD versus standard care TCCMD may increase sexual health knowledge (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.23 to 1.71; low‐certainty evidence). TCCMD may modestly increase contraception use (RR 1.19, 95% CI 1.05 to 1.35; low‐certainty evidence). The effects on condom use, antiretroviral therapy (ART) adherence, and health service use are uncertain due to very low‐certainty evidence. The effects on abortion and STI rates are unknown due to lack of studies. TCCMD versus non‐digital TCC (e.g. pamphlets) The effects of TCCMD on behaviour (contraception use, condom use, ART adherence), service use, health and wellbeing (abortion and STI rates) are unknown due to lack of studies for this comparison. TCCMD versus digital non‐targeted communication The effects on sexual health knowledge, condom and contraceptive use are uncertain due to very low‐certainty evidence. Interventions may increase health service use (attendance for STI/HIV testing, RR 1.61, 95% CI 1.08 to 2.40; low‐certainty evidence). The intervention may be beneficial for reducing STI rates (RR 0.61, 95% CI 0.28 to 1.33; low‐certainty evidence), but the confidence interval encompasses both benefit and harm. The effects on abortion rates and on ART adherence are unknown due to lack of studies. We are uncertain whether TCCMD results in unintended consequences due to lack of evidence. Adult populations TCCMD versus standard care For health behaviours, TCCMD may modestly increase contraception use at 12 months (RR 1.17, 95% CI 0.92 to 1.48) and may reduce repeat abortion (RR 0.68 95% CI 0.28 to 1.66), though the confidence interval encompasses benefit and harm (low‐certainty evidence). The effect on condom use is uncertain. No study measured the impact of this intervention on STI rates. TCCMD may modestly increase ART adherence (RR 1.13, 95% CI 0.97 to 1.32, low‐certainty evidence, and standardised mean difference 0.44, 95% CI ‐0.14 to 1.02, low‐certainty evidence). TCCMD may modestly increase health service utilisation (RR 1.17, 95% CI 1.04 to 1.31; low‐certainty evidence), but there was substantial heterogeneity (I2 = 85%), with mixed results according to type of service utilisation (i.e. attendance for STI testing; HIV treatment; voluntary male medical circumcision (VMMC); VMMC post‐operative visit; post‐abortion care). For health and well‐being outcomes, there may be little or no effect on CD4 count (mean difference 13.99, 95% CI ‐8.65 to 36.63; low‐certainty evidence) and a slight reduction in virological failure (RR 0.86, 95% CI 0.73 to 1.01; low‐certainty evidence). TCCMD versus non‐digital TCC No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may modestly increase in service attendance overall (RR: 1.12, 95% CI 0.92‐1.35, low certainty evidence), however the confidence interval encompasses benefit and harm. TCCMD versus digital non‐targeted communication No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may increase service utilisation overall (RR: 1.71, 95% CI 0.67‐4.38, low certainty evidence), however the confidence interval encompasses benefit and harm and there was considerable heterogeneity (I2 = 72%), with mixed results according to type of service utilisation (STI/HIV testing, and VMMC). Few studies reported on unintended consequences. One study reported that a participant withdrew from the intervention as they felt it compromised their undisclosed HIV status. Authors' conclusions TCCMD may improve some outcomes but the evidence is of low certainty. The effect on most outcomes is uncertain/unknown due to very low certainty evidence or lack of evidence. High quality, adequately powered trials and cost effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCC delivered by mobile devices. Given the sensitivity and stigma associated with sexual and reproductive health future studies should measure unintended consequences, such as partner violence or breaches of confidentiality., Plain language summary Communicating to young people and adults through their mobile devices to improve sexual and reproductive health Aim of this review We assessed the effect of sending targeted messages by mobile devices to young people and adults about their sexual and reproductive health (SRH). Sexually transmitted infections (STIs) and unintended pregnancies are important causes of illness and early death worldwide. Key messages There are gaps in the evidence regarding the effects of targeted messages by mobile devices to young people and adults about their SRH. These types of messages may have benefits in a few areas. However, the existing evidence is often of low or very low certainty. What was studied in the review? Targeted client communication (TCC) is an intervention in which the health system sends information to particular people, based on their health status or other factors specific to that population group. Common types of TCC are text messages that remind people to go to appointments or that offer healthcare information and support. Our review assessed whether TCC can change people’s behaviour, use of health services, and health and well‐being. We focused on communication about SRH to young people (aged 10 to 24 years), and to adults. What happens when young people receive targeted messages by mobile device? Compared to people who get no messages Young people may have better SRH knowledge and may use contraceptives slightly more. We don't know if the messages affect young people's condom use; use of SRH services; or the number testing positive for STIs, needing abortions, or adhering to HIV medication, because the evidence is missing or of very low certainty. Compared to people who get messages sent in other ways We do not know what the effect of the messages is because the evidence is missing. Compared to people who get untargeted messages We don't know whether the messages improve SRH knowledge or increase condom or contraceptive use because the certainty of the evidence is very low. The messages may reduce the number of people who get STIs (but it is possible they increase, or make little or no difference to, STIs). The messages may increase the number of young people who attend services for testing for STIs/HIV. We don't know whether the messages affect the number of young people having abortions or help them to take their HIV medication because the evidence is missing. We are uncertain if the messages lead to more unintended consequences among young people than no messages, or other types of communication. What happens when adults receive targeted messages by mobile device? Compared to people who get no messages The messages may slightly increase contraceptive use. They may also reduce the number of adults who need repeated abortions, although it is also possible they increase, or make little or no difference to, the number of abortions. We don't know whether the messages affect adults' condom use or the number of STIs because the evidence is of very low certainty, or missing. The messages may slightly increase adults' adherence to HIV medication among adults with HIV, but may make little or no difference to CD4 count and slightly improve viral load. The messages may slightly increase adults' use of SRH services overall, but results were mixed according to type of health service. Compared to people who get messages sent in other ways Adults receiving messages may attend SRH services more overall, but the evidence is mixed. We do not know what the effect of messages is on other behaviours and health because we lack evidence. Compared to people who get untargeted messages Adults receiving messages may attend SRH services more overall, but the evidence is mixed. We don't know what the effect of messages is on other behaviours and health because we lack evidence. We are uncertain if the messages lead to more unintended consequences among adults than no messages, or other types of communication. How up‐to‐date is this review? We searched for studies that had been published up to August 2017. We carried out a search update in July 2019 and relevant studies are reported in the 'Characteristics of studies awaiting classification' section.

Background The global burden of poor maternal, neonatal, and child health (MNCH) accounts for more than a quarter of healthy years of life lost worldwide. Targeted client communication (TCC) via mobile devices (MD) (TCCMD) may be a useful strategy to improve MNCH. Objectives To assess the effects of TCC via MD on health behaviour, service use, health, and well‐being for MNCH. Search methods In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. Selection criteria We included randomised controlled trials that assessed TCC via MD to improve MNCH behaviour, service use, health, and well‐being. Eligible comparators were usual care/no intervention, non‐digital TCC, and digital non‐targeted client communication. Data collection and analysis We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross‐checked by a second. Main results We included 27 trials (17,463 participants). Trial populations were: pregnant and postpartum women (11 trials conducted in low‐, middle‐ or high‐income countries (LMHIC); pregnant and postpartum women living with HIV (three trials carried out in one lower middle‐income country); and parents of children under the age of five years (13 trials conducted in LMHIC). Most interventions (18) were delivered via text messages alone, one was delivered through voice calls only, and the rest were delivered through combinations of different communication channels, such as multimedia messages and voice calls. Pregnant and postpartum women TCCMD versus standard care For behaviours, TCCMD may increase exclusive breastfeeding in settings where rates of exclusive breastfeeding are less common (risk ratio (RR) 1.30, 95% confidence intervals (CI) 1.06 to 1.59; low‐certainty evidence), but have little or no effect in settings where almost all women breastfeed (low‐certainty evidence). For use of health services, TCCMD may increase antenatal appointment attendance (odds ratio (OR) 1.54, 95% CI 0.80 to 2.96; low‐certainty evidence); however, the CI encompasses both benefit and harm. The intervention may increase skilled attendants at birth in settings where a lack of skilled attendants at birth is common (though this differed by urban/rural residence), but may make no difference in settings where almost all women already have a skilled attendant at birth (OR 1.00, 95% CI 0.34 to 2.94; low‐certainty evidence). There were uncertain effects on maternal and neonatal mortality and morbidity because the certainty of the evidence was assessed as very low. TCCMD versus non‐digital TCC (e.g. pamphlets) TCCMD may have little or no effect on exclusive breastfeeding (RR 0.92, 95% CI 0.79 to 1.07; low‐certainty evidence). TCCMD may reduce 'any maternal health problem' (RR 0.19, 95% CI 0.04 to 0.79) and 'any newborn health problem' (RR 0.52, 95% CI 0.25 to 1.06) reported up to 10 days postpartum (low‐certainty evidence), though the CI for the latter includes benefit and harm. The effect on health service use is unknown due to a lack of studies. TCCMD versus digital non‐targeted communication No studies reported behavioural, health, or well‐being outcomes for this comparison. For use of health services, there are uncertain effects for the presence of a skilled attendant at birth due to very low‐certainty evidence, and the intervention may make little or no difference to attendance for antenatal influenza vaccination (RR 1.05, 95% CI 0.71 to 1.58), though the CI encompasses both benefit and harm (low‐certainty evidence). Pregnant and postpartum women living with HIV TCCMD versus standard care For behaviours, TCCMD may make little or no difference to maternal and infant adherence to antiretroviral (ARV) therapy (low‐certainty evidence). For health service use, TCC mobile telephone reminders may increase use of antenatal care slightly (mean difference (MD) 1.5, 95% CI –0.36 to 3.36; low‐certainty evidence). The effect on the proportion of births occurring in a health facility is uncertain due to very low‐certainty evidence. For health and well‐being outcomes, there was an uncertain intervention effect on neonatal death or stillbirth, and infant HIV due to very low‐certainty evidence. No studies reported on maternal mortality or morbidity. TCCMD versus non‐digital TCC The effect is unknown due to lack of studies reporting this comparison. TCCMD versus digital non‐targeted communication TCCMD may increase infant ARV/prevention of mother‐to‐child transmission treatment adherence (RR 1.26, 95% CI 1.07 to 1.48; low‐certainty evidence). The effect on other outcomes is unknown due to lack of studies. Parents of children aged less than five years No studies reported on correct treatment, nutritional, or health outcomes. TCCMD versus standard care Based on 10 trials, TCCMD may modestly increase health service use (vaccinations and HIV care) (RR 1.21, 95% CI 1.08 to 1.34; low‐certainty evidence); however, the effect estimates varied widely between studies. TCCMD versus non‐digital TCC TCCMD may increase attendance for vaccinations (RR 1.13, 95% CI 1.00 to 1.28; low‐certainty evidence), and may make little or no difference to oral hygiene practices (low‐certainty evidence). TCCMD versus digital non‐targeted communication TCCMD may reduce attendance for vaccinations, but the CI encompasses both benefit and harm (RR 0.63, 95% CI 0.33 to 1.20; low‐certainty evidence). No trials in any population reported data on unintended consequences. Authors' conclusions The effect of TCCMD for most outcomes is uncertain. There may be improvements for some outcomes using targeted communication but these findings were of low certainty. High‐quality, adequately powered trials and cost‐effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCCMD. Future studies should measure potential unintended consequences, such as partner violence or breaches of confidentiality., Plain language summary Communicating to pregnant woman and parents through their mobile devices to improve maternal, neonatal, and child health Aim of this review We assessed the effect of sending targeted messages by mobile devices to pregnant women and parents of young children about health and healthcare services. Key messages There are gaps in the evidence regarding the effects of targeted messages by mobile devices to pregnant women and parents of young children about health and healthcare services. Some of these messages may improve some people's health and their use of health services, but others may make little or no difference. The existing evidence is mostly of low or very low certainty. What was studied in the review? Targeted client communication (TCC) is an intervention in which the health system sends information to particular people, based on their health status or other factors specific to that population group. Common types of TCC are text messages reminding people to attend appointments or that offer healthcare information and support. Our review assessed whether TCC can change pregnant women's and parents' behaviour, health service use, health, and well‐being. What happens when pregnant women receive targeted messages by mobile device? Compared to women who get no messages Women may breastfeed more in settings where exclusive breastfeeding is not common. They may also go to more antenatal care appointments. They may use skilled birth attendants more where this is less common. We do not know if the messages affect women's or babies' health because the certainty of the evidence is very low. Compared to women who get messages sent in other ways Women and newborns may have fewer health problems during the first 10 days after birth. The messages may make little or no difference to the number of women who breastfeed. We do not know if they make women use more health services. Compared to women who get untargeted messages The messages may make little or no difference to whether women get influenza vaccines during pregnancy. We do not know if the messages affect women's or babies' health or lead women to use skilled birth attendants more because the evidence is lacking or of very low certainty. What happens when pregnant women living with HIV receive targeted messages by mobile device? Compared to women who get no messages Women may go to slightly more antenatal care appointments. We do not know whether the messages lead more women to give birth in a health facility or improve babies' health because the evidence is of very low certainty. The messages may make little or no difference to whether pregnant women and babies follow antiretroviral (ARV) treatment (used to treat HIV) according to plan. We do not know if the messages affect women's health because the evidence is missing. Compared to women who get messages sent in other ways We do not know what the effect of these messages is because we lack evidence. Compared to women who get untargeted messages More parents may follow their babies' ARV treatment according to plan. We do not know if the messages improve women's or babies' health or their use of services because the evidence is missing. What happens when parents of young children receive targeted messages by mobile device? Compared to parents who get no messages More parents may take their children to healthcare services such as vaccination appointments. But we do not know if the messages improve children's health or their health behaviour because the evidence is missing. Compared to parents who get messages sent in other ways Slightly more parents may take their children to vaccination appointments. The messages may make little or no difference to children's toothbrushing habits. We do not know if the messages affect children's health because the evidence is missing. Compared to parents who get untargeted messages Fewer parents may take their children to vaccination appointments, but this evidence is mixed. We do not know if the messages affect children's health due to lack of evidence. How up‐to‐date is this review? We searched for studies published up to August 2017. We carried out a search update in July 2019 and relevant studies are reported in the 'Characteristics of studies awaiting classification' section.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of hydrogel dressings of donor site wounds following split‐thickness skin grafts (STSGs) for improving healing.

Background The widespread use of mobile technologies can potentially expand the use of telemedicine approaches to facilitate communication between healthcare providers, this might increase access to specialist advice and improve patient health outcomes. Objectives To assess the effects of mobile technologies versus usual care for supporting communication and consultations between healthcare providers on healthcare providers' performance, acceptability and satisfaction, healthcare use, patient health outcomes, acceptability and satisfaction, costs, and technical difficulties. Search methods We searched CENTRAL, MEDLINE, Embase and three other databases from 1 January 2000 to 22 July 2019. We searched clinical trials registries, checked references of relevant systematic reviews and included studies, and contacted topic experts. Selection criteria Randomised trials comparing mobile technologies to support healthcare provider to healthcare provider communication and consultations compared with usual care. Data collection and analysis We followed standard methodological procedures expected by Cochrane and EPOC. We used the GRADE approach to assess the certainty of the evidence. Main results We included 19 trials (5766 participants when reported), most were conducted in high‐income countries. The most frequently used mobile technology was a mobile phone, often accompanied by training if it was used to transfer digital images. Trials recruited participants with different conditions, and interventions varied in delivery, components, and frequency of contact. We judged most trials to have high risk of performance bias, and approximately half had a high risk of detection, attrition, and reporting biases. Two studies reported data on technical problems, reporting few difficulties. Mobile technologies used by primary care providers to consult with hospital specialists We assessed the certainty of evidence for this group of trials as moderate to low. Mobile technologies: ‐ probably make little or no difference to primary care providers following guidelines for people with chronic kidney disease (CKD; 1 trial, 47 general practices, 3004 participants); ‐ probably reduce the time between presentation and management of individuals with skin conditions, people with symptoms requiring an ultrasound, or being referred for an appointment with a specialist after attending primary care (4 trials, 656 participants); ‐ may reduce referrals and clinic visits among people with some skin conditions, and increase the likelihood of receiving retinopathy screening among people with diabetes, or an ultrasound in those referred with symptoms (9 trials, 4810 participants when reported); ‐ probably make little or no difference to patient‐reported quality of life and health‐related quality of life (2 trials, 622 participants) or to clinician‐assessed clinical recovery (2 trials, 769 participants) among individuals with skin conditions; ‐ may make little or no difference to healthcare provider (2 trials, 378 participants) or participant acceptability and satisfaction (4 trials, 972 participants) when primary care providers consult with dermatologists; ‐ may make little or no difference for total or expected costs per participant for adults with some skin conditions or CKD (6 trials, 5423 participants). Mobile technologies used by emergency physicians to consult with hospital specialists about people attending the emergency department We assessed the certainty of evidence for this group of trials as moderate. Mobile technologies: ‐ probably slightly reduce the consultation time between emergency physicians and hospital specialists (median difference −12 minutes, 95% CI −19 to −7; 1 trial, 345 participants); ‐ probably reduce participants’ length of stay in the emergency department by a few minutes (median difference −30 minutes, 95% CI −37 to −25; 1 trial, 345 participants). We did not identify trials that reported on providers' adherence, participants’ health status and well‐being, healthcare provider and participant acceptability and satisfaction, or costs. Mobile technologies used by community health workers or home‐care workers to consult with clinic staff We assessed the certainty of evidence for this group of trials as moderate to low. Mobile technologies: ‐ probably make little or no difference in the number of outpatient clinic and community nurse consultations for participants with diabetes or older individuals treated with home enteral nutrition (2 trials, 370 participants) or hospitalisation of older individuals treated with home enteral nutrition (1 trial, 188 participants); ‐ may lead to little or no difference in mortality among people living with HIV (RR 0.82, 95% CI 0.55 to 1.22) or diabetes (RR 0.94, 95% CI 0.28 to 3.12) (2 trials, 1152 participants); ‐ may make little or no difference to participants' disease activity or health‐related quality of life in participants with rheumatoid arthritis (1 trial, 85 participants); ‐ probably make little or no difference for participant acceptability and satisfaction for participants with diabetes and participants with rheumatoid arthritis (2 trials, 178 participants). We did not identify any trials that reported on providers' adherence, time between presentation and management, healthcare provider acceptability and satisfaction, or costs. Authors' conclusions Our confidence in the effect estimates is limited. Interventions including a mobile technology component to support healthcare provider to healthcare provider communication and management of care may reduce the time between presentation and management of the health condition when primary care providers or emergency physicians use them to consult with specialists, and may increase the likelihood of receiving a clinical examination among participants with diabetes and those who required an ultrasound. They may decrease the number of people attending primary care who are referred to secondary or tertiary care in some conditions, such as some skin conditions and CKD. There was little evidence of effects on participants' health status and well‐being, satisfaction, or costs., Plain language summary Using mobile technologies to promote communication and management of care between healthcare professionals What is the aim of this review? We aimed to find out if healthcare workers using mHealth services through their mobile phones or other mobile devices to communicate with other healthcare workers provide quicker access to healthcare, and improve patient health outcomes. We collected and analysed all relevant research and found 19 studies. Key messages Mobile technologies probably slightly decrease the time to deliver health care, as well as the number of face‐to‐face appointments, when compared with usual care, and probably increase the number of people receiving clinical examinations for some conditions, including an eye exam for people with diabetes. Mobile technologies may have little or no impact on healthcare workers' and participants' satisfaction, health status or well‐being. What was studied in the review? Many healthcare workers work alone or have little access to colleagues and specialists. This is a common problem for healthcare workers in rural areas or low‐income countries. One possible solution to this problem is to offer healthcare workers advice and support through mobile technologies that allow healthcare workers to get help from colleagues who are not in the same place. For instance, healthcare workers can contact specialists or colleagues with more experience through a phone or the Internet. Healthcare workers can also use their mobile phones or other mobile devices such as tablets. As more healthcare workers use mobile phones and other devices as part of their work, this could make it particularly easy for them to use mHealth services. What are the main results of the review? We found 19 relevant studies, which included more than 5766 people who needed health care. Sixteen studies were from high‐income countries. Two studies reported on technical problems, reporting few difficulties. When primary healthcare workers use mobile technologies to consult with hospital specialists, they: ‐ probably make little or no difference to whether guidelines are followed for people with chronic kidney disease, or to health status or quality of life of people with psoriasis. ‐ may increase the likelihood of retinopathy screening for people with diabetes, or receiving an ultrasound if referred with symptoms, and may reduce referrals or a visit to the clinic for people with a skin condition or referred for clinic follow‐up for different health problems. ‐ may make little or no difference to healthcare worker or patient satisfaction, or to how much it costs to deliver health care. When emergency doctors use mobile technologies to consult with hospital specialists: ‐ patients are probably managed slightly more quickly. We did not find any studies that looked at the effect of mobile technologies on emergency doctors following guidelines, patients’ health and well‐being, healthcare worker or patient satisfaction, or costs. When community health workers or home‐care workers use mobile technologies to consult with clinic staff, they: ‐ probably make little or no difference to the number of times people with a new diabetes‐related foot ulcer have to see a nurse, or elderly people using tube feeding have to see a nurse or go into hospital. ‐ may make no difference to the number of people living with HIV or diabetes who die; and may make little or no difference to the health status or quality of life of people with rheumatoid arthritis. ‐ probably make little or no difference to the satisfaction of people with diabetes or rheumatoid arthritis. We did not find any studies that looked at the effect of mobile technologies on whether community health workers follow guidelines, how quickly people receive care, healthcare worker satisfaction, costs, or technical difficulties. How up‐to‐date is this review? We searched for studies up to 22 July 2019.

Background Uptake of human papillomavirus (HPV) vaccine remains low in many countries, although the bivalent and quadrivalent HPV vaccines given as a three‐dose schedule are effective in the prevention of precancerous lesions of the cervix in women. Simpler immunisation schedules, such as those with fewer doses, might reduce barriers to vaccination, as may programmes that include males. Objectives To evaluate the efficacy, immunogenicity, and harms of different dose schedules and different types of HPV vaccines in females and males. Search methods We conducted electronic searches on 27 September 2018 in Ovid MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) (in the Cochrane Library), and Ovid Embase. We also searched the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov (both 27 September 2018), vaccine manufacturer websites, and checked reference lists from an index of HPV studies and other relevant systematic reviews. Selection criteria We included randomised controlled trials (RCTs) with no language restriction. We considered studies if they enrolled HIV‐negative males or females aged 9 to 26 years, or HIV‐positive males or females of any age. Data collection and analysis We used methods recommended by Cochrane. We use the term 'control' to refer to comparator products containing an adjuvant or active vaccine and 'placebo' to refer to products that contain no adjuvant or active vaccine. Most primary outcomes in this review were clinical outcomes. However, for comparisons comparing dose schedules, the included RCTs were designed to measure antibody responses (i.e. immunogenicity) as the primary outcome, rather than clinical outcomes, since it is unethical to collect cervical samples from girls under 16 years of age. We analysed immunogenicity outcomes (i.e. geometric mean titres) with ratios of means, clinical outcomes (e.g. cancer and intraepithelial neoplasia) with risk ratios or rate ratios and, for serious adverse events and deaths, we calculated odds ratios. We rated the certainty of evidence with GRADE. Main results We included 20 RCTs with 31,940 participants. The length of follow‐up in the included studies ranged from seven months to five years. Two doses versus three doses of HPV vaccine in 9‐ to 15‐year‐old females Antibody responses after two‐dose and three‐dose HPV vaccine schedules were similar after up to five years of follow‐up (4 RCTs, moderate‐ to high‐certainty evidence). No RCTs collected clinical outcome data. Evidence about serious adverse events in studies comparing dose schedules was of very low‐certainty owing to imprecision and indirectness (three doses 35/1159; two doses 36/1158; 4 RCTs). One death was reported in the three‐dose group (1/898) and none in the two‐dose group (0/899) (low‐certainty evidence). Interval between doses of HPV vaccine in 9‐ to 14‐year‐old females and males Antibody responses were stronger with a longer interval (6 or 12 months) between the first two doses of HPV vaccine than a shorter interval (2 or 6 months) at up to three years of follow‐up (4 RCTs, moderate‐ to high‐certainty evidence). No RCTs collected data about clinical outcomes. Evidence about serious adverse events in studies comparing intervals was of very low‐certainty, owing to imprecision and indirectness. No deaths were reported in any of the studies (0/1898, 3 RCTs, low‐certainty evidence). HPV vaccination of 10‐ to 26‐year‐old males In one RCT there was moderate‐certainty evidence that quadrivalent HPV vaccine, compared with control, reduced the incidence of external genital lesions (control 36 per 3081 person‐years; quadrivalent 6 per 3173 person‐years; rate ratio 0.16, 95% CI 0.07 to 0.38; 6254 person‐years) and anogenital warts (control 28 per 2814 person‐years; quadrivalent 3 per 2831 person‐years; rate ratio 0.11, 95% CI 0.03 to 0.38; 5645 person‐years). The quadrivalent vaccine resulted in more injection‐site adverse events, such as pain or redness, than control (537 versus 601 per 1000; risk ratio (RR) 1.12, 95% CI 1.06 to 1.18, 3895 participants, high‐certainty evidence). There was very low‐certainty evidence from two RCTs about serious adverse events with quadrivalent vaccine (control 12/2588; quadrivalent 8/2574), and about deaths (control 11/2591; quadrivalent 3/2582), owing to imprecision and indirectness. Nonavalent versus quadrivalent vaccine in 9‐ to 26‐year‐old females and males Three RCTs were included; one in females aged 9‐ to 15‐years (n = 600), one in females aged 16‐ to 26‐years (n = 14,215), and one in males aged 16‐ to 26‐years (n = 500). The RCT in 16‐ to 26‐year‐old females reported clinical outcomes. There was little to no difference in the incidence of the combined outcome of high‐grade cervical epithelial neoplasia, adenocarcinoma in situ, or cervical cancer between the HPV vaccines (quadrivalent 325/6882, nonavalent 326/6871; OR 1.00, 95% CI 0.85 to 1.16; 13,753 participants; high‐certainty evidence). The other two RCTs did not collect data about clinical outcomes. There were slightly more local adverse events with the nonavalent vaccine (905 per 1000) than the quadrivalent vaccine (846 per 1000) (RR 1.07, 95% CI 1.05 to 1.08; 3 RCTs, 15,863 participants; high‐certainty evidence). Comparative evidence about serious adverse events in the three RCTs (nonavalent 243/8234, quadrivalent 192/7629; OR 0.60, 95% CI 0.14 to 2.61) was of low certainty, owing to imprecision and indirectness. HPV vaccination for people living with HIV Seven RCTs reported on HPV vaccines in people with HIV, with two small trials that collected data about clinical outcomes. Antibody responses were higher following vaccination with either bivalent or quadrivalent HPV vaccine than with control, and these responses could be demonstrated to have been maintained for up to 24 months in children living with HIV (low‐certainty evidence). The evidence about clinical outcomes and harms for HPV vaccines in people with HIV is very uncertain (low‐ to very low‐certainty evidence), owing to imprecision and indirectness. Authors' conclusions The immunogenicity of two‐dose and three‐dose HPV vaccine schedules, measured using antibody responses in young females, is comparable. The quadrivalent vaccine probably reduces external genital lesions and anogenital warts in males compared with control. The nonavalent and quadrivalent vaccines offer similar protection against a combined outcome of cervical, vaginal, and vulval precancer lesions or cancer. In people living with HIV, both the bivalent and quadrivalent HPV vaccines result in high antibody responses. For all comparisons of alternative HPV vaccine schedules, the certainty of the body of evidence about serious adverse events reported during the study periods was low or very low, either because the number of events was low, or the evidence was indirect, or both. Post‐marketing surveillance is needed to continue monitoring harms that might be associated with HPV vaccines in the population, and this evidence will be incorporated in future updates of this review. Long‐term observational studies are needed to determine the effectiveness of reduced‐dose schedules against HPV‐related cancer endpoints, and whether adopting these schedules improves vaccine coverage rates., Plain language summary Comparison of different human papillomavirus (HPV) vaccines and the number of doses administered to prevent HPV‐related disease in females and males Human papillomaviruses (HPV) are a group of viruses that infect the skin and mucous membranes. Some types of HPV are sexually transmitted and are common in young people. Most infections will be cleared by the immune system, but some people will experience persistent infection with certain HPV types that go on to cause abnormalities in infected cells. These changes are called 'precancerous' because they can develop into cancers of the cervix, vagina, vulva, anal canal, penis, and head and neck. Infection with other HPV types causes warts in the genital area or around the anus. Vaccination aims to prevent future HPV infections. Three HPV vaccines are in use – a bivalent one (protects against two HPV types), a quadrivalent one (protects against four HPV types), and a nonavalent one (protects against nine HPV types). In women, three doses of the bivalent or the quadrivalent HPV vaccines protect against precancer of the cervix caused by the HPV types contained in the vaccine. Evidence about the nonavalent vaccine, about the effects of the quadrivalent vaccine in males, and about the effects of HPV vaccines in people with HIV infection, has not yet been reviewed thoroughly. Uptake of HPV vaccines remains low in many countries. Simpler vaccine schedules, or giving the vaccine to both girls and boys, could increase the number of people being vaccinated. Trials of HPV vaccines are not always designed to collect data about precancer and cancer, for several reasons. Firstly, HPV vaccine is routinely given before girls become sexually active, and it is not ethical to take specimens from the cervix of girls who have not had sex. Secondly, HPV‐related precancer and cancer are rare and do not develop until years after HPV infection has occurred. Thirdly, participants in a trial will be offered treatment if precancer develops, so progression to cervical cancer would be even rarer, even without vaccination. An international committee of experts states that, in some circumstances, antibody levels (i.e. showing a strong immune system response), can be used to demonstrate protection against cervical and anal cancer. The antibody levels following vaccination in a trial should not be lower than those found in other studies on adults in whom the vaccine has been shown to protect against severe HPV‐related cervical or anal disease. Review question(s) How effective or harmful are different HPV vaccine schedules (i.e. number and timing of doses) and different HPV vaccines in females and males? Main results These results are based on research evidence to 27 September 2018. We analysed 20 studies involving 31,940 people. Studies comparing two doses of HPV vaccine to three doses, or comparing the time interval between doses, focus on immune system responses rather than infection or disease outcomes. Two doses of HPV vaccine result in similar immune system responses to three doses, and a longer interval (up to 12 months) between doses gives a stronger immune system response than a shorter interval. There is insufficient evidence to determine whether there was a difference between the vaccine schedules for serious adverse events and death. In 16‐ to 26‐year‐old men, one study showed evidence of moderate certainty that a quadrivalent HPV vaccine provides better protection against external genital lesions and genital warts than a dummy treatment (control). In 16‐ to 26‐year‐old women, one study showed that the nonavalent and quadrivalent vaccines provide the same levels of protection against cervical, vaginal, and vulval precancer lesions and cancer (high‐certainty evidence). There was evidence that the quadrivalent vaccine resulted in more local adverse events (such as pain, swelling, and redness at the injection site) than a control treatment in males, and that the nonavalent vaccine resulted in more local adverse events than the quadrivalent vaccine in males and females. Evidence about serious adverse events and deaths from studies comparing different HPV vaccine types or dose schedules was of low or very low‐certainty. In people living with HIV, HPV vaccines result in reasonable levels of immune system response, but evidence about their effects on persistent HPV infection or HPV‐related disease outcomes and harms is limited. Certainty of the evidence No major issues were identified with the methodological quality of the studies for the measurements of infection and disease outcomes, or for immune system responses. Our certainty in the evidence about serious harms and deaths across all the studies comparing different HPV vaccines and vaccine schedules is low, either because of their low frequency, or because the evidence is indirect, or both. Evidence graded as high certainty means that we were confident that further research is unlikely to change our findings. Moderate‐certainty evidence means that there is a possibility that further research may have an important effect on our findings, whilst low‐certainty evidence means that our confidence was limited and further research may have an important impact on our findings. Very low‐certainty evidence means that we were uncertain about the result. Conclusion A two‐dose schedule of HPV vaccines in young females results in immune system responses that are comparable with a three‐dose schedule. In males, the quadrivalent HPV vaccine appears to be effective in the prevention of external genital lesions and genital warts. Quadrivalent and nonavalent HPV vaccines in young women result in similar levels of protection against cervical, vaginal, and vulval precancer lesions and cancer. Evidence about the efficacy and harms in people living with HIV is limited. Further long‐term population‐level studies are needed to continue monitoring safety of these vaccines, to determine for how long two doses of vaccine can provide protection against HPV‐related disease, the effect against HPV‐related cancer, and whether a two‐dose immunisation schedule will increase vaccine coverage.

Plant derivatives such as carotenoids and phytosterols enrich foods have been shown to reduce plasma triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and cholesterol concentrations. The aim of this systematic review and meta-analyses study was to investigate the effects of saffron on lipid profiles, reported in randomized controlled trials (RCTs). We performed a systematic electronic search in PubMed/MEDLINE, Cochrane, and SCOPUS to identify RCTs and screening of relevant articles references up to October 12, 2018. There were no language restrictions. We performed this systematic review and meta-analysis according to the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses guidelines. We identified and analyzed 14 eligible studies in this meta-analysis. Our study found a significant reduction in cholesterol and TG following saffron intervention (weighted mean difference [WMD]: -6.36 mg/dl, 95% confidence interval, CI, [-10.58, -2.18] and WMD: -5.37 mg/dl, 95% CI [-10.25, -0.48], respectively). There was no significant effect on weight and LDL concentration. A meta-regression analysis showed that long-term saffron intervention can increase the high-density lipoprotein (HDL) levels. In conclusions, our study findings indicate some benefits of saffron on cholesterol, HDL, and TG compared with placebo. However, we recommend the conduct of adequately powered, high-quality RCTs with short- and long-term follow-up, evaluating relevant clinical outcomes to allow for making definitive recommendations.

Objective the aim of this study is to evaluate the quality of web pages found by women when carrying out an exploratory search concerning pregnancy, childbirth, the postpartum period and breastfeeding. Design/setting a descriptive study of the first 25 web pages that appear in the search engines Google, Yahoo and Bing, in October 2014 in the Basque Country (Spain), when entering eight Spanish words and seven English words related to pregnancy, childbirth, the postpartum period, breastfeeding and newborns. Web pages aimed at healthcare professionals and forums were excluded. The reliability was evaluated using the LIDA questionnaire, and the contents of the web pages with the highest scores were then described. Findings a total of 126 web pages were found using the key search words. Of these, 14 scored in the top 30% for reliability. The content analysis of these found that the mean score for "references to the source of the information" was 3.4 (SD: 2.17), that for "up-to-date" was 4.30 (SD: 1.97) and the score for "conflict of interest statement" was 5.90 (SD: 2.16). The mean for web pages created by universities and official bodies was 13.64 (SD: 4.47), whereas the mean for those created by private bodies was 11.23 (SD: 4.51) (F (1,124)5.27. p=0.02). The content analysis of these web pages found that the most commonly discussed topic was breastfeeding, followed by self-care during pregnancy and the onset of childbirth. Conclusion in this study, web pages from established healthcare or academic institutions were found to contain the most reliable information. The significant number of web pages found in this study with poor quality information indicates the need for healthcare professionals to guide women when sourcing information online. As the origin of the web page has a direct effect on reliability, the involvement of healthcare professionals in the use, counselling and generation of new technologies as an intervention tool is increasingly essential.

What you need to know Children and young people can have a wide range of life limiting conditions and may sometimes live with such conditions for many years. This guideline recommends that end of life care be managed as a long term process that begins at the time of diagnosis of a life limiting condition and entails planning for the future. Sometimes it may begin before the child’s birth. It is part of the overall care of the child or young person and runs in parallel with other active treatments for the underlying condition itself.1 Finally, it includes those aspects related to the care of the dying. This guideline was commissioned with the aim to standardise end of life care for infants, children, and young people living with a life limiting condition, and thus promote equity and consistency. Important themes are to involve children and young people and their parents or carers in decisions about their care, facilitate their care in their preferred location (most likely home), and plan for day and night care. This article summarises the most recent guidance from the recent National Institute for Health and Care Excellence (NICE) on the planning and management of end of life care in infants, children, and young people.2 For a visual summary, please …