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Comparative effectiveness of behavioral interventions to mitigate the impacts of degeneration-based cognitive decline is not well understood. To better address this gap, we summarize the studies from the Healthy Action to Benefit Independence & Thinking (HABIT®) program, developed for persons with mild cognitive impairment (pwMCI) and their partners. HABIT® includes memory compensation training, computerized cognitive training (CCT), yoga, patient and partner support groups, and wellness education. Studies cited include (i) a survey of clinical program completers to establish outcome priorities; (ii) a five-arm, multi-site cluster randomized, comparative effectiveness trial; (iii) and a three-arm ancillary study. PwMCI quality of life (QoL) was considered a high-priority outcome. Across datasets, findings suggest that quality of life was most affected in groups where wellness education was included and CCT withheld. Wellness education also had greater impact on mood than CCT. Yoga had a greater impact on memory-dependent functional status than support groups. Yoga was associated with better functional status and improved caregiver burden relative to wellness education. CCT had the greatest impact on cognition compared to yoga. Taken together, comparisons of groups of program components suggest that knowledge-based interventions like wellness education benefit patient well-being (e.g., QoL and mood). Skill-based interventions like yoga and memory compensation training aid the maintenance of functional status. Notably, better adherence produced better outcomes. Future personalized intervention approaches for pwMCI may include different combinations of behavioral strategies selected to optimize outcomes prioritized by patient values and preferences., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Objective: To estimate the incidence rate and associated risk factors of severe maternal morbidity (SMM) in commercially and Medicaid-insured women. Materials and Methods: This was a retrospective cohort study of women with a live inpatient delivery recorded in 2016 in the MarketScan ® databases for commercially insured and Medicaid populations. The incidence of SMM, defined by the Center for Disease Control and Prevention's algorithm of International Classification of Diseases, 10th edition diagnostic and procedural codes, was determined. Measurements also included the association of SMM in bivariate analyses with patient characteristics and the association of SMM with delivery type, gestation type, maternal age, and race in multivariate logistic regression analysis, adjusted for pre-existing conditions and pregnancy-related complications. Results: The incidence of SMM per 10,000 deliveries was 111.4 in the Commercial and 109.6 in the Medicaid population. The most frequent SMM indicators were eclampsia and blood transfusion in the Commercial population (35.0 and 25.7 per 10,000 deliveries, respectively) and eclampsia and adult respiratory distress syndrome in the Medicaid population (45.5 and 14.9 per 10,000 deliveries, respectively). A cesarean delivery was associated with SMM in both Commercial (odds ratio [OR] 3.37; 95% confidence interval [CI] 1.51-1.84) and Medicaid populations (OR 1.99; 95% CI 1.80-2.17). A multifetal gestation was also associated with SMM in both Commercial (OR 3.37; 95% CI 2.80-4.10) and Medicaid populations (OR 2.26; 95% CI 1.86-2.75). Conclusion: SMM occurred in 1.1% of live inpatient deliveries. A cesarean delivery, multifetal gestation, race, region, and several pre-existing comorbidities and obstetric complications were associated with SMM.

Background and Objectives: Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are effective treatments for dysplastic Barrett's esophagus (BE). This study evaluates efficacy, durability and safety in a single high-volume UK tertiary centre with 15-years' experience., Methods: Prospective data were collected from Nottingham University Hospitals 2004-2019 for endotherapy of dysplastic BE or intramucosal adenocarcinoma. Procedural outcome measures include complete resection, complications and surgery rates. Efficacy outcomes include complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), recurrence, treatment failure rates, durability of RFA, median follow up and tumor-associated mortality., Results: A total of 319 lesions were resected; 671 RFAs were performed on 239 patients. Median age was 67 (±9.5) years, male:female ratio was 5:1 and median BE length was C3 [interquartile range (IQR): 6] M6 (IQR: 5). The most common lesion was Paris IIa (64%) with a median size of 10 mm (3-70). Final histology was adenocarcinoma in 50%. Complete resection rates were 96%. The multiband mucosectomy technique (91%) was most commonly used. The median number of RFA sessions was 3 (IQR: 2). The rates of CR-D and CR-IM were 90.4%% and 89.8% achieved after a median of 20.1 (IQR: 14) months. The most common complications: EMR was bleeding 2.2% and RFA was stricture (5.4%) requiring a median of 2 (range 1-7) dilatations. Median follow up post CR-IM/CR-D was 38 months (14-60). Metachronous lesions developed in 4.7% after CR-D and tumor-related mortality was 0.8%. Dysplasia and intestinal metaplasia-free survival at 5 years was 95 and 90%, respectively., Conclusion: BE endotherapy is minimally invasive, effective, safe and deliverable in a day-case setting., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The relationship between severe maternal morbidity (SMM) events during inpatient delivery and subsequent hospital readmission is not well understood. Materials and Methods: This was a retrospective cohort study of women with a live inpatient delivery during 2016 recorded in MarketScan ® databases for commercially insured and Medicaid populations. Live inpatient births were identified by the International Classification of Diseases, 10th Revision diagnostic and procedural codes, Current Procedural Terminology, and Diagnosis-Related Group codes. The incidence of hospital readmission within 30 days following a delivery discharge, and primary discharge diagnoses, were determined by SMM status. The association with hospital readmission of SMM status, delivery type, gestation type, and maternal age was determined in multivariable logistic regression analyses, adjusted for pregnancy-related complications and preexisting comorbidities. Results: In the Commercial population there were 1,927 hospital readmissions, for an incidence rate of 11.7 per 1,000 discharges. The readmission rate was 12 times greater for women with SMM than for women without SMM during delivery. The most frequent discharge diagnoses among women readmitted were other complications of the puerperium, endometritis, and infection of obstetric surgical wound of women without SMM during delivery. In multivariable analysis, SMM during delivery was strongly associated with readmission in the Commercial population. Results for the Medicaid population were similar. Conclusion: SMM during delivery hospitalization increased the risk of readmission more than 10 times. The most frequent discharge diagnoses following readmission included obstetric infection and endometritis in women without SMM, and eclampsia in women with SMM during delivery. Awareness of these findings could help health care providers prevent future episodes.

Objectives: To inform point-of-care test (POCT) development, we quantified the primary care demand for laboratory microbiology tests by describing their frequencies overall, frequencies of positives, most common organisms identified, temporal trends in testing and patterns of cotesting on the same and subsequent dates., Design: Retrospective cohort study., Setting: Primary care practices in Oxfordshire., Participants: 393 905 patients (65% female; 49% aged 18-49)., Primary and Secondary Outcome Measures: The frequencies of all microbiology tests requested between 2008 and 2018 were quantified. Patterns of cotesting were investigated with heat maps. All analyses were done overall, by sex and age categories., Results: 1 596 752 microbiology tests were requested. Urine culture±microscopy was the most common of all tests (n=673 612, 42%), was mainly requested without other tests and was the most common test requested in follow-up within 7 and 14 days. Of all urine cultures, 180 047 (27%) were positive and 172 651 (26%) showed mixed growth, and Escherichia coli was the most prevalent organism (132 277, 73% of positive urine cultures). Antenatal urine cultures and blood tests in pregnancy (hepatitis B, HIV and syphilis) formed a common test combination, consistent with their use in antenatal screening., Conclusions: The greatest burden of microbiology testing in primary care is attributable to urine culture ± microscopy; genital and routine antenatal urine and blood testing are also significant contributors. Further research should focus on the feasibility and impact of POCTs for these specimen types., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes-noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules-may serve as a precise therapeutic approach in cancer management.

Background: The most common reason for hospitalization in the United States is childbirth. The costs of childbirth are substantial. Materials and Methods: This was a retrospective cohort study of hospital deliveries identified in the MarketScan ® Commercial and Medicaid health insurance claim databases. Women with an inpatient birth in the calendar year 2016 were included. Severe maternal morbidity (SMM) was identified using the Centers for Disease Control and Prevention algorithm of 21 International Classification of Diseases-10 codes. Mean costs and cost ratios for women with and without SMM were reported. Generalized linear models were used to analyze demographic and clinical variables influencing delivery costs. Results: We identified 1,486 women in the Commercial population, who had a birth in 2016 and met the criteria for SMM. The total mean per-patient costs of care for women with and without SMM were $50,212 and $23,795, respectively. In the Medicaid population there were 29,763 births, of which 342 met the criteria for SMM. The total mean per-patient costs of care for women with and without SMM were $26,513 and $9,652, respectively. A multifetal gestation, a cesarean delivery, maternal age, and pregnancy-related complications were independently predictive of increased delivery costs in both Commercial and Medicaid populations. Conclusions: The occurrence of SMM was associated with an increase in maternity-related costs of 111% in the Commercial and 175% in the Medicaid population. Some of the factors associated with increased delivery hospitalization costs could be treated or avoided., Competing Interests: C.M.B. and V.M. were employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ) and were stockholders of Merck & Co., Inc. at the time of the study. V.M. is currently an employee of GlaxoSmithKline and receives stock in the company. K.K.V., P.O.-S., K.D., and D.S. have no competing financial interests., (© Christopher M. Black et al., 2021; Published by Mary Ann Liebert, Inc.)

Objective: To review the available evidence on the benefit of patient-held health records (PHRs), other than maternal and child health records, for improving the availability of medical information for handover communication between healthcare providers (HCPs) and/or between HCPs and patients in low-income and middle-income countries (LMICs)., Methods: The literature searches were conducted in PubMed, EMBASE, CINAHL databases for manuscripts without any restrictions on dates/language. Additionally, articles were located through citation checking using previous systematic reviews and a grey literature search by contacting experts, searching of the WHO website and Google Scholar., Results: Six observational studies in four LMICs met the inclusion criteria. However, no studies reported on health outcomes after using PHRs. Studies in the review reported patients' experience of carrying the records to HCPs (n=3), quality of information available to HCPs (n=1) and the utility of these records to patients (n=6) and HCPs (n=4). Most patients carry PHRs to healthcare visits. One study assessed the completeness of clinical handover information and found that only 41% (161/395) of PHRs were complete with respect to key information on diagnosis, treatment and follow-up. No protocols or guidelines for HCPs were reported for use of PHRs. The HCPs perceived the use of PHRs improved medical information availability from other HCPs. From the patient perspective, PHRs functioned as documented source of information about their own condition., Conclusion: Limited data on existing PHRs make their benefits for improving health outcomes in LMICs uncertain. This knowledge gap calls for research on understanding the dynamics and outcomes of PHR use by patients and HCPs and in health systems interventions., Prospero Registration Number: CRD42019139365., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recognizing the current opioid crisis among justice-involved individuals and the need to intervene at the intersection of justice and community health, the JCOIN TCU hub study explores outcomes associated with a multi-level hybrid implementation approach. The study capitalizes on facilitated collaboration, training, and cross-system data sharing to leverage improvements in criminal justice (CJ) and community behavioral health (CBH) interagency collaboration. The goal is to improve local community public health and safety outcomes for reentering justice-involved individuals who have a history of (or are at risk for) using opioids. The study compares two implementation strategies: one (vertical) in which all units in a community are trained and begin the program simultaneously and another (horizontal) in which one lead-off unit in the community is trained as a prototype of the program, the prototype is tested and refined, and then the lead-off unit helps to train other units within the community. Specific aims are to 1) increase access to and retention in CBH and medications for opioid use disorder services; 2) improve outcomes associated with public health and safety; 3) compare two implementation strategies on systems-level outcomes designed to increase service initiation and receipt of implementation and services; and 4) examine the impact of these strategies on justice-involved individuals' outcomes. The study examines both implementation and implementation-effectiveness, seeking to answer the questions of which implementation strategy is most effective for rapid and sustainable uptake of evidence-based practices and for increasing service linkage and initiation, services retention, and improved opioid-related public health safety outcomes. The study uses a hybrid type 3 study design. The study's primary aim is to compare two implementation strategies and two interventions at two levels (client and system), with a secondary aim to assess client-level outcomes associated with the trial. The study design integrates 2 robust methodologies (stepped wedge and cluster randomized trial), and plans to include 18 research performance sites (communities) located in Texas, New Mexico, and Illinois. The study will contribute to the JCOIN network's effort to establish a national consortium of investigators examining promising strategies to enhance the capabilities and capacity of the justice system to more effectively address the opioid epidemic., (Published by Elsevier Inc.)

HIV prevalence in Indonesia is increasing, and only 64% of infected individuals know their status. In a prospective cohort of 1,453 hospitalized patients with unexplained fever, 46 (3.2%) had HIV, including 15 (1.1%) patients without a prior HIV diagnosis. Among 31 subjects previously known to have HIV, 21 (68%) had been receiving combination antiretroviral therapy (cART) at the time of enrollment. Of 39 HIV cases with HIV RNA levels ≥ 100 copies/mL, sequencing for genotype analysis and resistance testing was successful in 30 (77%) subjects. The most common HIV subtypes were AE (90%) and B (10%). Five (16.7%) subjects had resistance mutations to nucleoside and non-nucleoside reverse transcriptase inhibitors, and all of them were on cART. No evidence of transmitted drug resistance was found in newly diagnosed individuals. Hospital-based screening may be an efficient method to expand HIV testing and identify a significant number of new cases. Access to care, close monitoring, expansion of anti-retroviral options, and ensuring availability of CD4 determinations, viral load testing, and genotyping are crucial to control of the epidemic in Indonesia.

Objective: To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS)., Methods: This phase III, randomised, double-blind, placebo-controlled study enrolled patients aged ≥18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to ≥2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society ≥20% improvement (ASAS20) and ≥40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout., Results: 269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (p<0.0001) greater with tofacitinib (56.4%, 75 of 133) versus placebo (29.4%, 40 of 136), and the ASAS40 response rate was significantly (p<0.0001) greater with tofacitinib (40.6%, 54 of 133) versus placebo (12.5%, 17 of 136). Up to week 16, with tofacitinib and placebo, respectively, 73 of 133 (54.9%) and 70 of 136 (51.5%) patients had adverse events; 2 of 133 (1.5%) and 1 of 136 (0.7%) had serious adverse events. Up to week 48, with tofacitinib, 3 of 133 (2.3%) patients had adjudicated hepatic events, 3 of 133 (2.3%) had non-serious herpes zoster, and 1 of 133 (0.8%) had a serious infection; with placebo→tofacitinib, 2 (1.5%) patients had non-serious herpes zoster. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events or opportunistic infections., Conclusions: In adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified., Trial Registration Number: NCT03502616., Competing Interests: Competing interests: AD has received grant/research support from AbbVie, Boehringer Ingelheim, Eli Lilly, GSK, Novartis, Pfizer Inc and UCB, and is a consultant for AbbVie, Amgen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, Gilead Sciences, GSK, Janssen, Novartis, Pfizer Inc and UCB. PS-S and HX have no competing interests to declare. XB is a consultant for AbbVie, Amgen, BMS, Celgene, Eli Lilly, Gilead Sciences, Janssen, MSD, Novartis, Pfizer Inc and UCB. LSG has received grant/research support from Pfizer Inc and UCB, and is a consultant for AbbVie, Eli Lilly, Gilead Sciences, GSK, Novartis and UCB. DF, LW, JW, SM, CW, OD, LF and KSK are employees and shareholders of Pfizer Inc. DvdH is a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eli Lilly, Galapagos, Gilead Sciences, GSK, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi, Takeda and UCB, and is Director of Imaging Rheumatology BV., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is currently limited and mixed evidence for the cognitive benefits of Computerized Cognitive Training (CCT) and yoga in persons with Mild Cognitive Impairment (pwMCI). The objective of this study was to investigate the benefit of computerized cognitive training (CCT) vs. physical (yoga) intervention on cognitive abilities. Participants in this study were part of the larger Mayo Clinic's Healthy Action to Benefit Independence and Thinking (HABIT) program comparative effectiveness trial. The HABIT program is designed for pwMCI and their care partner and consists of five behavioral interventions: CCT, Memory Support System-Calendar (MSS-Calendar), wellness education, support groups, and yoga. The subtractive study design randomly withheld one of the interventions for a total of five study arms. Longitudinal mixed-effects regression models were used to investigate the hypothesis that CCT and yoga has a greater positive impact on psychomotor and basic attention abilities at 12 months post-intervention as compared to the other HABIT interventions. Findings showed CCT had a positive impact compared to yoga on the Cogstate psychomotor/attention composite at 12 months post-intervention (ES = 0.54; unadjusted p value = 0.007, adjusted p value = 0.021). The impact of yoga or combining CCT with yoga did not show statistically significant improvement. Continued CCT practice at home showed further benefit on psychomotor/attention at 12 months post-intervention. There was no significant benefit of CCT or yoga on Cogstate learning/working memory composite.

Adhesive marbles, an innovative concept derived from liquid marble technology that is "remotely breakable on demand" by external stimuli, offer diverse application prospects. Therefore, a chemically linked superomniphobic hybrid perfluorinated carbon black-silica nanoparticle (PCBSN) was realized by functionalizing surface groups and used for encapsulating adhesives. PCBSN successfully encapsulated liquids and adhesives to form water (WM, contact angle 158°), epoxy (EM, contact angle 145°), and silicone (SM, contact angle 135°) marbles, regardless of the surface tension and polarity. Studies on the interface characteristics revealed that the work performed for marble formation maintained an inverse relationship with the surface energy of particles and the surface tension of encapsulated liquids. The marble formation energy was determined to be higher for EM (1.071 × 10 -17 J) and lower for SM (0.946 × 10 -17 J). Upon exposure to laser, marbles showed a rapid photothermal response, and the heat transferability on the surface of marbles followed the order SM > EM > WM. The marbles were remotely rupturable by regulating the applied laser power, with breaking time being tunable from <10 to 500 s. The photothermal efficiency (%) of marbles can be graded as good and falls in the range of 88.6 × 10 -3 (EM) and 162.9 × 10 -3 (SM) at 1.5 W laser power. The marbles possessed high mechanical integrity and repeated cyclability before breaking on the rolling impact test. These adhesive marbles formed from PCBSNs may represent attractive candidates for such applications as "bonding from a distance" through remote means.

Purpose/objectives: Readmission prevention strategies are the focus of many hospitals, but despite these efforts, unplanned, all-payer hospital readmission rates are increasing. The purpose of this study was to use root cause analysis (RCA) to explore the main cause (medical, behavioral health, and/or social) for the unplanned 30-day readmissions that the Readmission Prevention Team followed up and then to use this data to change and/or refine discharge planning interventions., Primary Practice Setting: The primary practice setting was the 229-bed study hospital where subjects with 30-day unplanned readmissions who were followed up by the Readmission Prevention Team were admitted. The venues that subjects were readmitted from were noted as home without services, home with home care, skilled nursing facility (SNF), acute rehab, physician office, hospice/palliative care, and refused care., Methodology and Sample: Using a descriptive, correlational, qualitative design, demographic data (age, gender, days between discharge and readmission, and the venue from which the patient was readmitted) were collected from the RCA worksheets of each subject with an unplanned hospital readmission within 30 days., Results: Among the 150 subjects, the main cause for readmission was medical (92%), with 19 of the subjects (13%) demonstrating multiple root causes. Women were readmitted more frequently than men, and the prominent age range was the 70s and 80s. The two main readmission venues were home with home care (54.7%) and skilled nursing facilities (23.3%)., Implications for Case Management: Medical was the chief cause of readmissions in this study, with many case management interventions noted in the literature to address these issues. Behavioral health and social issues were responsible for 13% of the readmissions. These issues are more complex, and hospitals should review the interventions that they have in place and develop others that are needed to decrease these types of readmissions.Home with home care was the main venue of readmission, with return from a skilled nursing facility (SNF) being the second. Potential interventions to decrease these unplanned hospital readmissions might include developing a backup discharge plan (Option B) and developing improved communication avenues between the hospital emergency department and the SNF that might lead to the patient returning to the SNF versus being admitted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

BackgroundInfluenza virus presents a considerable challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid infection diagnosis, rationalising antimicrobial therapy, and supporting infection-control interventions.AimTo evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Oxford Nanopore Technologies (Oxford, United Kingdom (UK)) metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic standards (Xpert Xpress Flu/RSV assay; BioFire FilmArray Respiratory Panel 2 assay). We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsCompared to standard testing, Nanopore metagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses. Of 59 samples with haemagglutinin subtype determined, 40 were H1 and 19 H3. We identified an influenza A(H3N2) genome encoding the oseltamivir resistance S331R mutation in neuraminidase, potentially associated with an emerging distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in a ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant community-circulating strain. We also detected other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Full genome generation can help investigate and manage nosocomial outbreaks.

Background: Asylum evaluations are highly specialized medico-legal encounters to collect physical or mental health evidence for use in immigration proceedings. Although the field of asylum medicine is growing, access to these evaluations is still inadequate, particularly for those in United States immigration detention or other forms of custody, such as under the U.S. Migrant Protection Protocols or "Remain in Mexico" policy. Given advances in telehealth in recent years and growing evidence of similar outcomes with in-person management, it seems prudent to examine whether remote modalities may also be effective for conducting mental health asylum evaluations in hard-to-reach populations., Methods: We analyzed the responses of 12 U.S. clinicians who conducted 25 cross-border remote mental health evaluations with clients in Mexico prior to the COVID-19 pandemic, and completed a post-evaluation survey regarding their impressions and experiences of the remote encounter. Data were coded through a process of thematic analysis., Results: The average evaluation time was 2.3 h, slightly shorter than might be expected from an in-person encounter. Five themes emerged from the coding process: rapport building, achieving overall goal, comparison of in-person vs. remote, technical issues, and coordination. Clinicians encountered a number of challenges including technical difficulties and a decreased ability to establish rapport. Nearly uniformly, however, clinicians noted that despite difficulties, they were able achieve the goals of the evaluation, including rapport building and diagnosis., Conclusion: Remote evaluations appear to achieve their intended goal and may be useful in expanding legal options for hard-to-reach asylum seekers.

Cells have two purine pathways that synthesize adenine and guanine ribonucleotides from phosphoribose via inosylate. A chemical hybrid between adenine and guanine, 2-aminoadenine (Z), replaces adenine in the DNA of the cyanobacterial virus S-2L. We show that S-2L and Vibrio phage PhiVC8 encode a third purine pathway catalyzed by PurZ, a distant paralog of succinoadenylate synthase (PurA), the enzyme condensing aspartate and inosylate in the adenine pathway. PurZ condenses aspartate with deoxyguanylate into dSMP (N6-succino-2-amino-2'-deoxyadenylate), which undergoes defumarylation and phosphorylation to give dZTP (2-amino-2'-deoxyadenosine-5'-triphosphate), a substrate for the phage DNA polymerase. Crystallography and phylogenetics analyses indicate a close relationship between phage PurZ and archaeal PurA enzymes. Our work elucidates the biocatalytic innovation that remodeled a DNA building block beyond canonical molecular biology., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Despite the lack of evidence that bronchodilators, corticosteroids, and antibiotics are useful in treating bronchiolitis, their use is still widespread. This study aimed to determine the consumption of antibiotics for bronchiolitis before and after a procalcitonin-guided clinical pathway (CP) implementation. In December 2019, a CP for lower respiratory tract infection management was implemented at the Department of Women's and Children's Health at Padua University Hospital. This was a pre-post, quasi-experimental study that assessed the changes in the treatment of bronchiolitis during two bimesters preceding the CP implementation (pre-period: January 2018-February 2018 and January 2019-February 2019) and during the bimester after CP implementation (post-period January 2020-February 2020). After the CP implementation, there was a significant reduction in antibiotic prescriptions from 36.2% to 12.5% ( p = 0.036) in patients hospitalized for bronchiolitis. Co-amoxiclav treatment, the antibiotic most commonly administered, decreased from 66.6% to 33.3%. Among outpatients' bronchiolitis episodes, a statistically significant decrease in beta2-agonists' use (from 18.0% to 4.4%, pre and post periods) and a quasi-significant decrease in corticosteroid use (from 8.0% to 0% pre and post periods) were observed. An evidence-based CP supported by educational lectures was associated with significant changes in the physicians' prescribing habits.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis., Methods: For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete., Findings: Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794·6 days [SD 329·2] in long-term extension study, 879·0 days [396·6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48·8 years (SD 11·8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0·1 patients with events [95% CI 0·0-0·3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1·7 (1·2-2·5) for herpes zoster (non-serious and serious); 1·0 (0·6-1·6) for serious infections; 0·4 (0·1-0·8) for opportunistic infections; 0·7 (0·4-1·2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0·9 (0·5-1·5) for NMSC; 0·2 (0·1-0·6) for major adverse cardiovascular events; 0·1 (0·0-0·3) for pulmonary embolism; and 0·4 (0·1-0·8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36., Interpretation: This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies., Funding: Pfizer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Staphylococcus aureus colonizes the nasopharynx in one third of healthy individuals and is also responsible for several infections in pediatrics such as endocarditis, pneumonia and osteoarticular infections. It has several virulence mechanisms, such as Panton Valentine leukocidin (PVL), which is an exotoxin that causes cell death. It is commonly related to methicillin-resistant Staphylococcus aureus (MRSA) and more serious pulmonary and musculoskeletal infections. However, PVL is not exclusive to MRSA. Two clinical cases of patients with infection by methicillin-sensitive Staphylococcus aureus producing this exotoxin are presented.

Introduction: Deep Learning (DL) and Artificial Intelligence (AI) have become widespread due to the advanced technologies and availability of digital data. Supervised learning algorithms have shown human-level performance or even better and are better feature extractor-quantifier than unsupervised learning algorithms. To get huge dataset with good quality control, there is a need of an annotation tool with a customizable feature set. This paper evaluates the viability of having an in house annotation tool which works on a smartphone and can be used in a healthcare setting., Methods: We developed a smartphone-based grading system to help researchers in grading multiple retinal fundi. The process consisted of designing the flow of user interface (UI) keeping in view feedback from experts. Quantitative and qualitative analysis of change in speed of a grader over time and feature usage statistics was done. The dataset size was approximately 16,000 images with adjudicated labels by a minimum of 2 doctors. Results for an AI model trained on the images graded using this tool and its validation over some public datasets were prepared., Results: We created a DL model and analysed its performance for a binary referrable DR Classification task, whether a retinal image has Referrable DR or not. A total of 32 doctors used the tool for minimum of 20 images each. Data analytics suggested significant portability and flexibility of the tool. Grader variability for images was in favour of agreement on images annotated. Number of images used to assess agreement is 550. Mean of 75.9% was seen in agreement., Conclusion: Our aim was to make Annotation of Medical imaging easier and to minimize time taken for annotations without quality degradation. The user feedback and feature usage statistics confirm our hypotheses of incorporation of brightness and contrast variations, green channels and zooming add-ons in correlation to certain disease types. Simulation of multiple review cycles and establishing quality control can boost the accuracy of AI models even further. Although our study aims at developing an annotation tool for diagnosing and classifying diabetic retinopathy fundus images but same concept can be used for fundus images of other ocular diseases as well as other streams of medical science such as radiology where image-based diagnostic applications are utilised., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Morya et al.)

Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

Background: In Alzheimer's disease and related disorders (ADRD) research, common outcome measures include cognitive and functional impairment, as well as persons with mild cognitive impairment (pwMCI) and care partner self-reported mood and quality of life. Studies commonly analyze these measures separately, which potentially leads to issues of multiple comparisons and/or multicollinearity among measures while ignoring the latent constructs they may be measuring., Objective: This study sought to examine the latent factor structure of a battery of 12-13 measures of domains mentioned above, used in a multicomponent behavioral intervention (The HABIT® program) for pwMCI and their partners., Methods: Exploratory factor analysis (EFA) involved 214 pwMCI-partner pairs. Subsequent Confirmatory factor analyses (CFA) used 730 pairs in both pre- and post-intervention conditions., Results: EFA generated a three-factor model. Factors could be characterized as partner adjustment (29.9%), pwMCI adjustment (18.1%), and pwMCI impairment (12.8%). The subsequent CFA confirmed our findings, and the goodness-of-fit for this model was adequate in both the pre- (CFI = 0.937; RMSEA = 0.057, p = 0.089) and post-intervention (CFI = 0.942; RMSEA = 0.051, p = 0.430) groups., Conclusion: Results demonstrated a stable factor structure across cohorts and intervention conditions suggesting that three broad factors may provide a straightforward and meaningful model to assess intervention outcome, at least during the MCI phase of ADRD.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal., Methods: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5-20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov (NCT01976364) and is complete., Findings: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI -0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [-0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy)., Interpretation: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety., Funding: Pfizer Inc., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We prove that a set A of at most q non-collinear points in the finite plane F q 2 spans more than | A | / q directions: this is based on a lower bound by Fancsali et al. which we prove again together with a different upper bound than the one given therein. Then, following the procedure used by Rudnev and Shkredov, we prove a new structural theorem about slowly growing sets in Aff ( F q ) for any finite field  F q , generalizing the analogous results by Helfgott, Murphy, and Rudnev and Shkredov over prime fields., (© The Author(s) 2021.)

Significance: Phytochemicals are important dietary constituents with antioxidant properties. They affect various signaling pathways involved in the overall maintenance of interior milieu of the cell. Arsenic, an environmental toxicant, is well known for its deleterious consequences, such as various diseases, including cancers in humans. Mitochondria are the cell's powerhouse that fuel all metabolic energy requirements. Dysfunctional mitochondria due to stressors may lead to abnormal functioning of the organelle, hampering the crucial cellular cross talks and ultimately leading to cancer. Application of phytochemicals against arsenic-induced mitochondrial disorders may be a preventive measure to counteract the ruinous impacts of the metalloid. Recent Advances: In recent years, extensive research on the role of mitochondria in cancer gives a better understanding of the areas the organelle covers in maintaining a healthy cell or in inducing carcinogenicity. Detailed knowledge of the mitochondrial governances would enable researchers to administer numerous phytochemicals to ameliorate altered oxidative phosphorylation, mitochondrial membrane potential (MMP), mitochondrial oxidative stress, unfolded protein response, glycolysis, or even apoptosis. Critical Issues: In this review, we have addressed how various phytochemicals belonging to diverse classes combat against arsenic-induced mitochondrial oxidative stress, depletion of MMP, cell cycle abrogation, apoptosis, glycolytic damages, oncogenic regulations, chaperones, mitochondrial complexes, and mitochondrial membrane pore formation in both in vitro and in vivo models. Future Directions: Insightful application of mitoprotective phytochemicals against arsenic-induced mitochondrial oxidative stress and carcinogenesis may guide researchers to develop preclinical chemopreventive agents to fight arsenic toxicity in humans.

Antibiotic stewardship programs proved to be effective in improving prescribing appropriateness. This multicenter quasi-experimental study, aimed to assesses the stewardship impact on antibiotics prescribing in different semesters from 2014 to 2019 in three pediatric emergency departments (Center A, B, and C) in Italy. All consecutive patients diagnosed with acute otitis media or pharyngitis were evaluated for inclusion. Two different stewardship were adopted: for Center A and B, clinical pathways were implemented and disseminated, and yearly lectures were held, for Center C, only pathways were implemented. Broad-spectrum prescription rates decreased significantly by 80% for pharyngitis and 29.5 to 55.2% for otitis after the implementation. In Center C, rates gradually increased from the year after the implementation. Amoxicillin dosage adjusted to pharyngitis recommendations in Center C (53.7 vs. 51.6 mg/kg/die; p = 0.011) and otitis recommendations in Center A increasing from 50.0 to 75.0 mg/kg/die ( p < 0.001). Days of therapy in children < 24 months with otitis increased from 8.0 to 10.0 in Center A, while in older children decreased in Center A (8.0 vs. 7.0; p < 0.001) and Center B (10.0 vs. 8.0; p < 0.001). Clinical pathways combined with educational lectures is a feasible and sustainable program in reducing broad-spectrum antibiotic prescribing with stable rates over time.

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.

Background: Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Methods: The multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel found varying quality and availability of evidence and made the following judgments: 1 ) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia, 2 ) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia, 3 ) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia, 4 ) a conditional recommendation for ambulatory liquid-oxygen use in patients who are mobile outside the home and require >3 L/min of continuous-flow oxygen during exertion (very-low-quality evidence), and 5 ) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (best-practice statement). Conclusions: These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.

Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)

Background: Demographic shift in India has prolonged life expectancy. The phenomenon caused episodes of illness to protract and sufferings of the elderly populace to be aggravated. In such a situation, medical attention and hospital-based care emerges as an important choice for many. However, such argument needs scientific validation that is attempted in the present article., Method: Using nationally representative sample, the study attempts a comparative analysis and estimates the major socioeconomic determinants of medical intervention before death, for the senior citizens, aged 60 years and above., Findings: Major findings are as follows: Firstly, gender discrepancy is evident in seeking medical attention and hospitalization when social caste and economic status of household are considered; secondly, medical attention or hospitalization is more familiar among the socioeconomically privileged group segment; thirdly, health-seeking behavior is approaching towards homogeneity with all the four wealth quartiles showing a more or less equal preference for hospital-based care., Conclusion: Receiving medical attention before death is confined in the privileged section of the society and of course gender plays an important role in this regard. Lack of proper treatment still increases the incidences of death among the elderly at the lower segments of society., (© 2020 John Wiley & Sons, Ltd.)

PhD prepared nurse scientists within healthcare systems are uniquely positioned to advance nursing science through research and evidence-based practice (EBP) initiatives due to their ability to closely collaborate with nurses and other healthcare professionals in the clinical setting. The purpose of this paper is threefold: 1) to describe the roles and contributions of Nurse Scientists, from their perspectives, in four different health care systems in the Greater Philadelphia area, three of which are Magnet® designated hospitals; 2) to highlight organizational approaches to increase nursing research and EBP capacity; and 3) to explore strategies that Nurse Scientists used to overcome barriers to build nursing research capacity. Nurse Scientists employed in these healthcare systems share many of the same essential roles and contributions focused on developing nursing research and EBP initiatives through education and mentorship of clinical nurses, conduct and oversight of independent research, and dissemination activities. With supportive executive nurse leadership, the Nurse Scientists within each healthcare system employed different strategies to overcome barriers in building nursing research and EBP capacity. Nurse scientists within healthcare settings have potentially powerful positions to generate and apply new knowledge to guide nursing practice and improve outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Emergence of SARS-CoV-2 in dengue virus (DENV)-endemic areas complicates the diagnosis of both infections. COVID-19 cases may be misdiagnosed as dengue, particularly when relying on DENV IgM, which can remain positive months after infection. To estimate the extent of this problem, we evaluated sera from 42 confirmed COVID-19 patients for evidence of DENV infection. No cases of SARS-CoV-2 and DENV coinfection were identified. However, recent DENV infection, indicated by the presence of DENV IgM and/or high level of IgG antibodies, was found in seven patients. Dengue virus IgM and/or high IgG titer should not exclude COVID-19. SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing is appropriate when dengue nonstructural protein 1 (NS1) or RT-PCR is negative. Given the possibility of coinfection, testing for both DENV and SARS-CoV-2 is merited in the setting of the current pandemic.

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). We report the interim safety, tolerability, and efficacy of tofacitinib in PsA patients in OPAL Balance, a 3-year, open-label, long-term extension study (data cut-off: August 2017; database not locked, data may change)., Methods: Eligible patients from two phase (P) 3 (P3) tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered OPAL Balance ≤ 3 months after completing the P3 study or discontinuing for reasons other than study-drug-related adverse events (AEs). Patients received open-label tofacitinib 5 mg twice daily (BID), with adjustments to 10 mg BID permitted post-month (M) 1. Certain concomitant conventional synthetic disease-modifying antirheumatic drugs were allowed. Primary endpoints were incidence/severity of AEs and laboratory abnormalities, and changes from baseline in laboratory parameters (reported up to M36 and M30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30., Results: A total of 686 patients were treated; at data cut-off, 68.2% remained in the study. Mean (range) treatment duration was 641 (1-1032) days; total treatment duration was 1153.2 patient-years. By M36, 79.6, 13.8, and 8.6% of patients reported AEs, serious AEs, and discontinuations due to AEs, respectively. Five deaths occurred; one within the risk period (incidence rate [IR; patients with events/100 patient-years] 0.1). IRs for AEs of special interest were: all (non-serious and serious) herpes zoster, 1.7; serious infections, 0.9; opportunistic infections, 0.3 (all disseminated/multi-dermatomal herpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0; major adverse cardiovascular events, 0.3; pulmonary embolisms, 0.1; and arterial thromboembolisms, 0.4. No patients had deep vein thrombosis. Alanine aminotransferase and aspartate aminotransferase levels were elevated  ≥  3-fold the upper limit of normal in 4.0 and 2.2% of patients, respectively. Changes in laboratory parameters were generally stable over time, although lymphocyte counts decreased slightly. Efficacy was maintained through M30., Conclusions: In this interim analysis of OPAL Balance, tofacitinib safety and efficacy in patients with PsA appeared to be consistent with those of the P3 studies. Efficacy was maintained over time., Trial Registration: ClinicalTrials.gov identifier: NCT01976364.

The World Health Organization (WHO) recommended maximum contaminant level (MCL) of arsenic (As) in drinking water at 10 μg/L. Many Asian countries still have their MCL for As at 50 μg/L. The current cross sectional study was conducted on asymptomatic females (without As related skin lesions) selected from rural areas of West Bengal, Baruipur and Dhamakhali [low As 11-50 μg/L; N,93]; Kamardanga & Sibhati [high As>50 μg/L; N,70] and Boria [Control; As<10 μg/L N,118] of West Bengal, India. The study was designed to compare the status of peripheral blood and lung function due to prolonged As exposure. The lung function parameters were considered according to Miller's prediction quadrant - FVC less than 80% indicated restrictive lung, FEV1/FVC less than 70% showed obstructive lung and both FVC and FEV1/FVC less than predicted percentage exhibited combined lung function decrement. The study showed that groundwater As concentration [22.5 ± 19.2 (low), 67.8 ± 26.9 (high) and 1.02 ± 2.3 μg/L (control)] was correlated with nail As content of the enrolled women. Linear regression depicted that nail As content influenced reduction of haemoglobin (β: 0.43; 95%CI: 0.02 to -0.006; p = 0.0001) and CD56 + NK cells (β: 0.53; 95%CI: 0.07 to -0.03; p = 0.0001) per 1 μg/g increase in As in nails. Multivariate logistic regression exhibited that nail As content was associated with reduction of lung function parameters [FEV1 (Exp B:1.04; 95%CI: 1.022 to 1.055; p = 0.0001) and FVC (Exp B:1.05; 95%CI: 1.03 to 1.07; p = 0.0001) per 1 μg/g increase in As in nails. Hence the study may be indicative of the fact that even in asymptomatic women, increase in chronic As exposure may weaken immune surveillance and provoke respiratory ailments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Primaquine is an effective anti-hypnozoite drug for Plasmodium vivax and Plasmodium ovale. However, it can trigger erythrocyte hemolysis in people with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In a previous report from South Central Timor (SCT), Indonesia, we described the prevalence of Vanua Lava, Chatham, and Viangchan variants; in this study, other G6PD variants (Kaiping, Coimbra, Gaohe, Canton, and Mahidol) were subsequently analyzed. For clarity, all of these results are described together. The 381 DNA samples from the previous study during 2013-2014 were analyzed for G6PD variants by using PCR-restriction fragment length polymorphism (RFLP). The prevalence of G6PD deficiency in SCT was 6.3% (24/381 cases), including 4.2% (16/381 cases), 0.5% (2/381 cases), and 1.6% (6/381 cases) for Coimbra, Kaiping, and Vanua Lava variants, respectively. No other variants were found in this population. A significant association was found between ethnicity and the distribution of G6PD Kaiping in female subjects. A positive association was shown between G6PD activity and heterozygous females carrying Coimbra genotype, hemizygous males carrying Vanua Lava, Plasmodium falciparum infection in female subjects, and P. vivax infection in male subjects. Further molecular analysis of heterozygous females, particularly in malaria-endemic areas, is needed for mapping distribution of G6PD deficiency status in Indonesia.

Background: Current tobacco treatment guidelines have established the efficacy of available interventions, but they do not provide detailed guidance for common implementation questions frequently faced in the clinic. An evidence-based guideline was created that addresses several pharmacotherapy-initiation questions that routinely confront treatment teams. Methods: Individuals with diverse expertise related to smoking cessation were empaneled to prioritize questions and outcomes important to clinicians. An evidence-synthesis team conducted systematic reviews, which informed recommendations to answer the questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in the estimated effects and the strength of recommendations. Results: The guideline panel formulated five strong recommendations and two conditional recommendations regarding pharmacotherapy choices. Strong recommendations include using varenicline rather than a nicotine patch, using varenicline rather than bupropion, using varenicline rather than a nicotine patch in adults with a comorbid psychiatric condition, initiating varenicline in adults even if they are unready to quit, and using controller therapy for an extended treatment duration greater than 12 weeks. Conditional recommendations include combining a nicotine patch with varenicline rather than using varenicline alone and using varenicline rather than electronic cigarettes. Conclusions: Seven recommendations are provided, which represent simple practice changes that are likely to increase the effectiveness of tobacco-dependence pharmacotherapy.

Competing Interests: All authors have nothing to disclose.

Objective: Patients present to EDs with various medication-related problems (MRPs). MRPs are also associated with ED care, occurring during ED presentation or shortly afterwards. The aim of the present study is to describe the prevalence and nature of MRPs that occur prior to, during or shortly after leaving ED., Methods: We undertook a prospective, observational study in nine Australian EDs. Blocks of 10 consecutive adult patients who were not seen by a pharmacist in ED and who presented at pre-specified times were identified. Within 1 week of ED discharge, a pharmacist interviewed patients and undertook a medical record review to determine their medication history, patients' understanding of treatment, potential MRP risk factors and manage any identified MRPs., Results: A total of 904 patients were recruited: 14.8% aged ≥80 years, 18.9% taking more than eight regular medications; 581 MRPs were identified; 287 (49.4%, 95% confidence interval [CI] 45.3-53.5%) of moderate-high significance. Most highly significant MRPs involved high-risk medications, particularly strong opioids, insulin and anti-coagulants. The most common types of MRPs were prescribing errors (46.8%), patient adherence/knowledge issues (31.2%) and adverse drug reactions (7.4%). Of all patients, 381 (42.1%, 95% CI 38.9-45.5%) had at least one MRP; 31.4% (95% CI 28.4-34.6%) had MRPs that could be identified or managed by screening at ED presentation and 12.4% (95% CI 10.4-14.8%) had MRPs that could be identified or managed by screening at ED discharge., Conclusions: Patients experienced a range of MRPs throughout the ED continuum of care. From these data, screening tools will be developed so that ED clinicians may identify patients at greatest risk of MRPs., (© 2020 Australasian College for Emergency Medicine.)

Objective: We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 ( RFC1 ) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America., Methods: A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1 , resulting in a combined 911 subjects tested., Results: In the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37)., Conclusions: In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Lung cancer is one of the major causes of cancer-related deaths worldwide. Stimuli-responsive polymers and nanoparticles, which respond to exogenous or endogenous stimuli in the tumor microenvironment, have been widely investigated for spatiotemporal chemotherapeutic drug release applications for cancer chemotherapy. We developed glutathione (GSH)-responsive polyurethane nanoparticles (GPUs) using a GSH-cleavable disulfide bond containing polyurethane that responds to elevated levels of GSH within lung cancer cells. The polyurethane nanoparticles were fabricated using a single emulsion and mixed organic solvent method. Cisplatin-loaded GSH-sensitive nanoparticles (CGPU) displayed a GSH-dose dependent release of cisplatin. In addition, a significant reduction in in vitro survival fraction of A549 lung cancer cells was observed compared to free cisplatin of equivalent concentration (survival fraction of ~0.5 and ~0.7, respectively). The in vivo biodistribution studies showed localization of fluorescently labeled GPUs (~7% of total injected dose per gram tissue) in the lung tumor regions after mouse-tail IV injections in xenograft A549 lung tumor models. The animals exposed to CGPUs also exhibited the inhibition of lung tumor growth compared to animals administered with saline (tumor growth rate of 1.5 vs. 13 in saline) and free cisplatin (tumor growth rate of 5.9) in mouse xenograft A549 lung tumor models within 14 days. These nanoparticles have potential to be used for on-demand drug release for an enhanced chemotherapy to effectively treat lung cancer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Human metapneumovirus (HMPV) infection causes a spectrum of respiratory tract disease, and may be a significant pathogen in the context of immunocompromise. Here, we report direct-from-sample metagenomic sequencing of HMPV using Oxford Nanopore Technology., Methods: We applied this sequencing approach to 25 respiratory samples that had been submitted to a clinical diagnostic laboratory in a UK teaching hospital. These samples represented 13 patients under the care of a haematology unit over a 20-day period in Spring 2019 (two sampled twice), and ten other patients elsewhere in the hospital between 2017-2019., Results: We generated HMPV reads from 20/25 samples (sensitivity 80% compared to routine diagnostic testing) and retrieved complete HMPV genomes from 15/20 of these. Consensus sequences from Nanopore data were identical to those generated by Illumina, and represented HMPV genomes from two distinct sublineages, A2b and B2. Sequences from ten haematology patients formed a unique genetic group in the A2b sublineage, not previously reported in the UK. Among these, eight HMPV genomes formed a cluster (differing by ≤3 SNPs), likely to reflect nosocomial transmission, while two others were more distantly related and may represent independent introductions to the haematology unit., Conclusion: Nanopore metagenomic sequencing can be used to diagnose HMPV infection, although more work is required to optimise sensitivity. Improvements in the use of metagenomic sequencing, particularly for respiratory viruses, could contribute to antimicrobial stewardship. Generation of full genome sequences can be used to support or rule out nosocomial transmission, and contribute to improving infection prevention and control practices., Competing Interests: Declaration of Competing Interest MC, RV and STP have previously received consumables free of charge from ONT, but not for the study presented here., (Copyright © 2020. Published by Elsevier Ltd.)

Aim: To assess age- and gender-associated differences in cognitive and psychomotor abilities measured by the Complex Reactionmeter Drenovac (CRD-series) tests., Methods: This cross-sectional study, conducted between 2009 and 2019, enrolled 3420 participants (2012 women) in the age ranging from 18 to 88 years. The participants solved three CRD-series chronometric tests: discrimination of the light signal position (CRD311), complex psychomotor coordination (CRD411), and simple arithmetic operations (CRD11). We analyzed total test solving time (TTST), minimum single task solving time (MinT), number of errors, initial dissociation, and start, end, and total ballasts as measures of wasted time in the first half of the test, second half of the test, and total test time, respectively., Results: Age was positively associated with MinT and TTST in all used tests (P<0.001), while initial dissociation, start ballast, and end ballast significantly increased with age (P<0.001). On the CRD11 test, men had shorter TTST than women (P=0.012), shorter start, end, and total ballasts (P<0.001), and made fewer errors than women (P<0.001). On the CRD311 test, women had shorter start (P=0.002), end, and total ballast (P<0.001) than men. On the CRD411 test, men performed better than women on all variables (P<0.001)., Conclusion: Decreased cognitive and psychomotor abilities measured by the CRD-series tests were associated with advanced age. Men performed better than women on simple arithmetic and complex psychomotor coordination tests, whereas women lost less time on the test of light signal position discrimination.