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Summary Introduction The drugs used to treat psychiatric illnesses are known as antipsychotics. Antipsychotics have a higher incidence of adverse drug reactions including extrapyramidal side effects and several other metabolic disorders. The main objective of the study is to assess the changes in anthropometric parameters of metabolic risk in patients with severe mental disorders initiated with antipsychotic drug therapy. Materials and methods A prospective observational study was carried out in the psychiatric inpatient unit of a tertiary care teaching hospital for eight months. Eligible patients were enrolled and their baseline and follow-up anthropometric measurements such as body weight, body mass index (BMI), fat index, and waist-hip ratio were taken before and after six weeks of therapy. The changes were documented and analyzed. Results and Discussion The most commonly prescribed antipsychotics were olanzapine, clozapine, risperidone and quetiapine. A considerable mean increase in the body weight of 4.5 kg with a mean increase in body mass index of 1.7 kg/m2, percentage body fat of 1.84% and the waist-hip ratio of 0.027 was observed among patients treated with olanzapine. Similarly, patients who were prescribed with clozapine also revealed a significant increase in the mean body weight of 4.7 kg, an increase in BMI of 1.75 kg/m2, 0.07 of waist-hip ratio and a percentage body fat of 1.4%. On analysis, patients treated with quetiapine and risperidone also showed significant changes in the anthropometric parameters. Conclusion The overall comparison and statistical analysis of different anthropometric parameters suggest that the changes observed within the parameters were a result of antipsychotic drug therapy.

While sociopolitical advances have improved the rights of sexual and gender minorities (i.e., lesbian, gay, bisexual, transgender, queer [LGBTQ+] persons), they continue to face a health system that discriminates against them and does not provide competent, comprehensive care. Despite calls for advancing research, there remains limited sexual and gender minority health research funding, mentorship, and institutional support. Academic medical centers are best suited to systematically tackle disparities and improve care for all sexual and gender minority people through their tripartite missions of patient care, education, and research. In this article, the authors outline discrimination experienced by LGBTQ+ persons and highlight the unique disparities they experience across access and outcomes. The authors posit that by systematically improving clinical care of, incorporating education and training about, and research with LGBTQ+ people into their core missions, academic medical centers can dramatically change the health care landscape. Academic medical centers can eliminate health disparities, expand necessary research endeavors about sexual and gender minorities, and prepare the health care workforce to address the unique needs of these overlooked populations.

Objective To describe clinical characteristics and associated endometrial findings of transgender and gender nonbinary people using gender-affirming testosterone. Design Retrospective case series. Setting Academic medical center and public safety net hospital. Patient(s) Eighty-one patients using gender-affirming testosterone therapy undergoing hysterectomy for the indication of gender affirmation from 2000 to 2018. Intervention(s) None. Main Outcome Measure(s) Preoperative clinical characteristics and endometrium surgical pathology diagnoses. Result(s) Median age was 31 years (interquartile range [IQR] 27–40), and median body mass index 27 kg/m2 (IQR 24–30). Six patients (7%) were parous and 60 (74%) had amenorrhea. Thirty-three patients (40%) had proliferative and 40 (50%) atrophic endometrium. Endometrial polyps were found in nine patients (11%) of the sample. Endometrial findings were similar in the subgroup of 60 patients with preoperative amenorrhea. There were no cases of endometrial hyperplasia or malignancy. In bivariate analysis, those with proliferative endometrium were found to be, on average, 5.6 years younger than those with atrophic endometrium. There were no clinical factors associated with having proliferative versus atrophic endometrium in multivariable models. Conclusion(s) People using gender-affirming testosterone may have either proliferative or atrophic endometrium, including people who present with amenorrhea. Further study is needed to develop evidence-based guidelines for appropriate screening for endometrial hyperplasia or cancer in this population.

Vulnerable populations, such as patients with mental illnesses, are known to be overly influenced during disasters and pandemics. However, little is known about how people with autism spectrum disorder (ASD), one of the most common neurodevelopmental conditions in the world with a prevalence of 1%, are affected by health-related disasters, particularly the current Covid-19 pandemic. We investigated how individuals with ASD responded to Covid-19 in terms of comprehension and adherence to implemented measures; changes in their behavioral problems; and how the anxiety levels of their caregivers relate to these behavioral changes. Our sample consisted of 50 individuals with ASD (30 male and 20 female; ages ranged from 3 to 14). The majority of our participants had trouble grasping what Covid-19 is and the measurements it necessitates. They also encountered difficulties in implementing pandemic-related social distance and hygiene regulations. During this time, the majority of students stopped receiving special education. In terms of increased stereo-types, aggression, hypersensitivity, behavioral problems, and sleep and appetite changes, we observed a Covid-19-related clinical presentation that resembled PTSD in individuals with ASD. Aberrant Behavior Checklist (ABC) subscales differed significantly before and after the pandemic conditions. There were differences among the caregivers’ anxiety levels between the current behavioral problem levels to the behavioral problem levels prior to the pandemic. The difference in ABC total score, and specifically the lethargy/social withdrawal subscale score, predicted the anxiety score of the parents. Our findings suggest that the Covid-19 period poses unique challenges for people with ASD and their caregivers, emphasizing the importance of targeted, distance special education interventions and other support services for this population.

Aquatic macrophytes add structural complexity to the environment, which influences fish species. The structure of macrophytes rafts can vary depending on the hydrological cycle and space availability. Thus, the objective of the present study was to evaluate which predictors associated with environmental conditions, composition of macrophyte species and spatial factors can affect fish communities in different hydrological regimes. The study was carried out in oxbow lakes in the Amazon, in the middle Purus River, Amazonas, Brazil. Samples of fish and macrophytes were collected during the flood, receding and drought periods, and environmental variables were measured in all macrophytes rafts. Partial redundancy analysis was applied to quantify the relative contribution of environmental variables, macrophyte composition and spatial factors in the fish community. Our study revealed that environmental conditions and macrophyte species composition, and both spatially structured as well, were the main factors that explained changes in fish composition in floating meadows of oxbow lakes. Corroborating our predictions, the variations in the fish communities were explained mainly by niche-based processes, including environmental conditions and macrophyte species composition as an environmental component, which varied over the hydrological cycle. The spatial component was more important during flooding, environmental conditions during receding, and macrophyte species composition during the drought hydrological regime. However, the shared explanations that indicated a spatially structured environment, both for environmental conditions and for composition of macrophytes, were greater during all hydrological regimes, also supporting our prediction.

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics., Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.

BackgroundTransgender, nonbinary and gender-expansive (TGE) people face barriers to abortion care and may consider abortion without clinical supervision.MethodsIn 2019, we recruited participants for an online survey about sexual and reproductive health. Eligible participants were TGE people assigned female or intersex at birth, 18 years and older, from across the United States, and recruited through The PRIDE Study or via online and in-person postings.ResultsOf 1694 TGE participants, 76 people (36% of those ever pregnant) reported considering trying to end a pregnancy on their own without clinical supervision, and a subset of these (n=40; 19% of those ever pregnant) reported attempting to do so. Methods fell into four broad categories: herbs (n=15, 38%), physical trauma (n=10, 25%), vitamin C (n=8, 20%) and substance use (n=7, 18%). Reasons given for abortion without clinical supervision ranged from perceived efficiency and desire for privacy, to structural issues including a lack of health insurance coverage, legal restrictions, denials of or mistreatment within clinical care, and cost.ConclusionsThese data highlight a high proportion of sampled TGE people who have attempted abortion without clinical supervision. This could reflect formidable barriers to facility-based abortion care as well as a strong desire for privacy and autonomy in the abortion process. Efforts are needed to connect TGE people with information on safe and effective methods of self-managed abortion and to dismantle barriers to clinical abortion care so that TGE people may freely choose a safe, effective abortion in either setting.

Summary Introduction Patient information leaflet contains specific information regarding the medical conditions, medications as well as the lifestyle modifications required to be followed by the patients. The information collected for the leaflet should be in the simplest form possible so that it can be easily interpreted by the targeted population. Objective The present study aims to develop and validate patient information leaflet for cancer patients. Materials and methods The information for the leaflet was gathered from various primary, secondary and tertiary resources. The content of the leaflet was validated by 10 members including general physicians, medical oncologists, academic pharmacists and clinical pharmacists. Readability of the patient information leaflets was assessed using Flesch Reading Ease test, Flesch-Kincaid Grade Level test and user readability method. User opinion on the content, layout and design was also obtained from the enrolled patients. Results and discussion The FRE and FK-GL scores of English version of patient information leaflet were 61.2 and 7.9 respectively. The overall user readability score of English, Kannada and Malayalam versions of PIL improved significantly from a pre-test score of 41.80 ± 23.18 to a post-test score of 70.40 ± 23.03. Ninety percent of the total patients enrolled in the study recorded good opinion about the leaflet in terms of its content, layout and design. Conclusion Patient information leaflet based education had a significant impact in improving the knowledge level of cancer patients.

Objective The objective of this study was to evaluate the outcome of a short interposition using a small-diameter prosthetic graft as a flow-limiting procedure to manage symptomatic high-flow arteriovenous fistula (AVF). Methods A retrospective review of medical records on a case series was conducted. From June 2004 to April 2017, there were 25 patients with clinical symptoms of high output cardiac failure and progressive dilation of aneurysmal fistula vein due to high-flow AVF (≥1.5 L/min) who underwent short interposition with a 5-mm prosthetic graft at Saitama Medical Center. The primary outcome was the relief of clinical symptoms; other outcome measures included technical success, surgical complications, patency of vascular access, and postoperative changes in local and systemic hemodynamics as assessed by Doppler ultrasound. Results Twenty-five patients underwent short interposition for cardiac indications (n = 16) and aneurysmal dilation (n = 9). The technical success rate was 100%. The clinical symptoms were relieved in 24 patients (96.0%). Mean reduction in access blood flow was 52.4%. Cumulative primary unassisted patency rates (± standard error) at 1 year, 2 years, and 3 years were 76.2% ± 9.3%, 70.4% ± 10.3%, and 58.1% ± 11.6%, respectively. Secondary patency rates (± standard error) at 1 year, 2 years, and 3 years were 81.8% ± 8.2%, 71.5% ± 9.9%, and 71.5% ± 9.9%, respectively. Complications included access occlusion due to late thrombosis (n = 5 [21.7%]) and graft infection (n = 1 [4.3%]) in the median follow-up period of 3.9 years. Conclusions Short interposition with a prosthetic graft is a simple, effective, and durable treatment option for end-stage renal disease patients with cardiac symptoms and progressive dilation of the fistula vein due to high-flow AVF, offering clinical symptom resolution while preserving the autologous behavior of the initial access.

The sulfation at the 3-OH position of a glucosamine saccharide is a rare modification, but is critically important for the biological activities of heparan sulfate polysaccharides. Heparan sulfate 3-O-sulfotransferase (3-OST), the enzyme responsible for completing this modification, is present in seven different isoforms in humans. Individual isoforms display substrate selectivity to uniquely sulfated saccharide sequences present in heparan sulfate polysaccharides. Here, we report two ternary crystal structures of heparan sulfate 3-OST isoform 3 (3-OST-3) with PAP (3'-phosphoadenosine 5'-phosphate) and two octasaccharide substrates: non 6-O-sulfated octasaccharide (8-mer 1) and 6-O-sulfated octasaccharide (8-mer 3). The 8-mer 1 is a known favorable substrate for 3-OST-3, whereas the 8-mer 3 is an unfavorable one. Unlike the 8-mer 1, we discovered that the 8-mer 3 displays two binding orientations to the enzyme: productive binding and non-productive binding. Results from the enzyme activity studies demonstrate that 8-mer 3 can contribute to either substrate or product inhibition, possibly attributed to a non-productive binding mode. Our results suggest that heparan sulfate substrates interact with the 3-OST-3 enzyme in more than one orientation, which may regulate the activity of the enzyme. Our findings also suggest that different binding orientations between polysaccharides and their protein binding partners could influence biological outcomes.

Despite the fact that HIV can be controlled with medication to undetectable levels where it cannot be passed on, stigmatization of women living with HIV persists. Such stigmatization pivots on stereotypes around sex and sexism and has force in women’s lives. Our aim was to create an inspirational resource for women living with HIV regarding sex, relationships, and sexuality: www.lifeandlovewithhiv.ca (launched in July 2018). This paper describes the development and mixed-method evaluation of our first year and a half activities. We situated our work within a participatory arts-based knowledge translation planning framework and used multiple data sources (Google Analytics, stories and comments on the website, team reflections over multiple meetings) to report on interim outcomes and impacts. In our first 1.5 years, we recruited and mentored 12 women living with HIV from around the world (Canada, Australia, New Zealand, Kenya, South Africa, Spain, Nigeria, and the U.S.) to write their own stories, with the support of a mentor/editor, as a way of regaining control of HIV narratives and asserting their right to have pleasurable, fulfilling, and safer sexual lives. Writers published 43 stories about pleasure, orgasm, bodies, identities, trauma, resilience, dating, disclosure, self-love, and motherhood. Our social media community grew to 1600, and our website received approximately 300 visits per month, most by women (70%) and people aged 25–44 years (65%), from more than 50 cities globally, with shifts in use and demographics over time. Qualitative data indicated the power of feminist digital storytelling for opportunity, access, validation, and healing, though not without risks. We offer recommendations to others interested in using arts-based digital methods to advance social equity in sexual health.

Adverse Drug Reactions () are the problem that adds extra burden in the global scenario. Anticancer drugs can lead to severe negative consequences due to these . This study was conducted to assess the causality, severity and preventability of the identified of chemotherapeutic drugs among hospitalized patients diagnosed with cancer and also to analyze its management. A prospective observational study was conducted among cancer patients for a period of eight months. A total of 120 hospitalized patients who developed at least one ADR due to chemotherapy were included in this study. Data were collected and documented in a well-designed data collection form. A total of 166 were detected in 120 patients. 33(19.8%), was found as the most commonly identified ADR. Patients administered with as were found to be reported with the highest number of (36). According to Naranjo’s scale and WHO causality assessment, 110(66.2%) and 105(63.2%) were found probable. & scale of severity showed that 97(58.4%) were moderate and Modified and Thornton scale revealed that 129(77.7%) were not preventable. The patients prescribed with , , regimen should be strictly and continuously monitored for the symptoms of ADR. Early detection of ADR can decrease morbidity and mortality.

Significance As the recall of CD8+ T cell memory promotes rapid recovery in, for example, influenza, we investigated circulating SARS-CoV-2−specific CD8+ T cells from COVID-19 patients. For two HLA-A*02:01 SARS-CoV-2−specific CD8+ T cell epitopes, we found that, while ex vivo frequencies of responding T cells were approximately fivefold higher than for pre−COVID-19 samples, they were ∼10-fold lower than for influenza or EBV-specific memory CD8+ T cells. Additionally, SARS-CoV-2−specific CD8+ T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes. Might this unexpectedly low prevalence of classical effector memory T cells be a negative consequence of the infectious process that could be avoided by prior priming with an appropriately constituted vaccine?, An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2−specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269–277 and A2/Orf1ab3183–3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that A2/S269+CD8+ T cells were detected at comparable frequencies (∼1.3 × 10−5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10−6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein–Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10−4) populations. Phenotyping A2/S269+CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269+CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269+CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.

Everyone of reproductive potential, no matter sex or gender, may have contraceptive needs. However, with no professional society guidelines and scant data on contraceptive use for transgender and gender-diverse (TGD) populations, clinicians’ abilities to counsel patients on use, safety, side effects, and efficacy is severely limited. We know very little about how estrogen- and progestin-containing contraceptive methods interact with gender-affirming testosterone therapy. Consequently, providers must extrapolate from data on use of hormonal contraceptive methods in presumed cisgender women and rely on clinical expertise. Based on available literature and expert opinion, there are important considerations for each method that can help guide contraceptive counseling with TGD patients. Specific considerations include differential experience of side-effects in TGD patients, barriers to access, and potential misconceptions regarding menstruation and reproductive capacity. When counseling a TGD person about their contraception options, providers should engage in shared decision-making, acknowledging the spectrum of identities and experiences within these communities. In order to support gender-affirming patient-centered care, providers should also create a space that is welcoming, use language that promotes inclusivity, and perform physical exams that consider the potential physical and emotional discomforts specific to these patients. Given the lack of population-specific data and guidelines, we encourage providers to integrate what is known about contraceptive use in cisgender women with the unique needs of TGD persons to apply a shared decision-making contraceptive counseling approach with members of these communities.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the p-aminobenzoyl-l-glutamate (pABG) moiety of folate and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a Ki of 34 μM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual-targeted analogs.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has dramatically expedited global vaccine development efforts1-3, most targeting the viral 'spike' glycoprotein (S). S localizes on the virion surface and mediates recognition of cellular receptor angiotensin-converting enzyme 2 (ACE2)4-6. Eliciting neutralizing antibodies that block S-ACE2 interaction7-9, or indirectly prevent membrane fusion10, constitute an attractive modality for vaccine-elicited protection11. However, although prototypic S-based vaccines show promise in animal models12-14, the immunogenic properties of S in humans are poorly resolved. In this study, we characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity. Comparatively low frequencies of B cells or cTFH specific for the receptor binding domain of S were elicited. Notably, the phenotype of S-specific cTFH differentiated subjects with potent neutralizing responses, providing a potential biomarker of potency for S-based vaccines entering the clinic. Overall, although patients who recovered from COVID-19 displayed multiple hallmarks of effective immune recognition of S, the wide spectrum of neutralizing activity observed suggests that vaccines might require strategies to selectively target the most potent neutralizing epitopes.

The purpose of this narrative review is to expand routine prepregnancy counseling and anticipatory guidance to include people of all genders. Transgender, gender diverse, and non-binary (TGNB) individuals who were assigned female at birth may wish to parent, conceive, and carry a pregnancy, but are not included in guidelines for routine prepregnancy counseling. In addition to the topics covered in routine prepregnancy counseling, there are several unique considerations for prepregnancy care for TGNB individuals including perinatal testosterone use, gender dysphoria and distress, chest/breastfeeding, and navigation of clinical environments. Research in the area of TGNB medical care continues to grow as the visibility of these communities increases. However, data are limited surrounding pregnancy and prepregnancy-related care. Therefore, we present prepregnancy medical, surgical, social, and practice of care considerations for TGNB populations in light of other known health and healthcare experiences of TGNB patients. We outline several clinical recommendations to support clinicians in providing inclusive prepregnancy care. These recommendations aim to highlight the unique needs of TGNB individuals while recognizing that each patient’s experience and goals must be individualized to them.

Although several studies showed that angiosome-guided endovascular treatment improved wound healing and major amputation rates in patients with chronic limb-threatening ischemia (CLTI), effectiveness of the angiosome concept to the treatment of ischemic foot remains to be elucidated, especially in bypass surgery. Arterial anatomy of the foot and ankle shows that there are multiple supplementary circulation including arterial–arterial connections and choke nexus, which indicates angiosome concept may carry limited importance in bypass surgery for CLTI. On the other hand, patients with diabetes or renal dysfunction have partial occlusion of arterial–arterial connections and, therefore, quite a few patients with CLTI in Japan may present with limited but impaired supplementary circulation around the ankle. This article reviews the arterial anatomy and circulation of the foot and ankle and discusses availability and limitations of angiosome-guided bypass surgery.

Purpose A significant number of patients with traumatic brain injuries (TBI) are diagnosed with elevated blood alcohol concentration (BAC). Recent literature suggests a neuroprotective effect of alcohol on TBI, possibly associated with less morbidity and mortality. Our goal is to analyze the association of different levels of BAC with TBI characteristics and outcome. Methods Adult patients with moderate to severe TBI (AIS ≥ 2) and measured BAC admitted to the Trauma Centre West (TCW), during the period 2010–2015, were retrospectively analyzed. Data included injury severity (AIS), length of hospitalization, admittance to the Intensive Care Unit (ICU) and in-hospital mortality. The association of BAC with ICU admittance and in-hospital mortality was analyzed using multivariable logistic regression analysis with correction for potentially confounding variables. Results BACs were available in 2,686 patients of whom 42% had high, 26% moderate, 6% low and 26% had normal levels. Patients with high BAC’s were predominantly male, were younger, had lower ISS scores, lower AIS-head scores and less concomitant injuries compared to patients in the other BAC subgroups. High BACs were associated with a lower risk for in-hospital mortality (AOR 0.36, 95% CI 0.14–0.97). Also, patients with moderate and high BACs were less often admitted to the ICU (respectively, AOR 0.36, 95% CI 0.25–0.52 and AOR 0.40, 95% CI 0.29–0.57). Conclusion The current study suggests that in patients with moderate to severe TBI, increasing BACs are associated with less severe TBI, less ICU admissions and a higher survival. Further research into the pathophysiological mechanism is necessary to help explain these findings.

Catheter ablation for supraventricular tachycardia (SVT) in adults with congenital heart disease (ACHD) is an important therapeutic option. Cavo-tricuspid isthmus (CTI)-dependent intraatrial re-entrant tachycardia (IART) is common. However, induction of sustained tachycardia at the time of ablation is not always possible. We hypothesised that performing an empiric CTI line in case of non-inducibility leads to good outcomes. Long-term outcomes of empiric versus entrained CTI ablation in ACHD patients were examined. Retrospective, single-centre, case-control study over 7 years. Arrhythmia-free survival after empiric versus entrained CTI ablation was compared. Eighty-seven CTI ablations were performed in 85 ACHD patients between 2010 and 2017. The mean age of the cohort was 43 years and 48% were male. Underlying aetiology included ASD (31%), VSD (11.4%), AVSD (9.1%), AVR (4.8%), Fallot’s (18.4%), Ebstein’s (2.3%), Fontan’s palliation (9.2%) and atrial switch (13.8%). CTI-dependent IART was entrained in 59 patients whereas it was non-inducible in 28. The latter had an empiric CTI ablation. Forty-three percent of procedures were performed under general anaesthesia. There were no reported procedural complications. There was no significant difference in the mean procedure or fluoroscopy times between the groups (empiric vs entrained CTI; 169.1 vs 183.3 and 28.1 vs 19.9 min). Arrhythmia-free survival was 64.3% versus 72.8% (p value 0.44) in the empiric and entrained groups at 21 months follow-up. Long-term outcomes after empiric and entrained CTI ablation for IART in ACHD patients are comparable. This is a safe and effective therapeutic option. In the case of non-inducibility of IART, an empiric CTI line should be considered in this cohort.

In this article, we study a Radio Resource Allocation (RRA) that was formulated as a non-convex optimization problem whose main aim is to maximize the spectral efficiency subject to satisfaction guarantees in multiservice wireless systems. This problem has already been previously investigated in the literature and efficient heuristics have been proposed. However, in order to assess the performance of Machine Learning (ML) algorithms when solving optimization problems in the context of RRA, we revisit that problem and propose a solution based on a Reinforcement Learning (RL) framework. Specifically, a distributed optimization method based on multi-agent deep RL is developed, where each agent makes its decisions to find a policy by interacting with the local environment, until reaching convergence. Thus, this article focuses on an application of RL and our main proposal consists in a new deep RL based approach to jointly deal with RRA, satisfaction guarantees and Quality of Service (QoS) constraints in multiservice celular networks. Lastly, through computational simulations we compare the state-of-art solutions of the literature with our proposal and we show a near optimal performance of the latter in terms of throughput and outage rate.

Sexual and gender minority (SGM) people experience significant disparities in mental health and substances use disorders. This study reached out to mental health professionals (MHPs) who treat SGM ...

BACKGROUND:Little is documented about the experiences of pregnancy for transgender and gender-diverse individuals. There is scant clinical guidance for providing prepregnancy, prenatal, intrapartum, and postpartum care to transgender and gender-diverse people who desire pregnancy.CASE:Our team provi

Highlights • FDA issued a EUA for FFR Decontamination. • Multiple systems exist for FFR decontamination. • Facilities must consider which one works best., During the COVID-19 crisis, disposable N-95 filtering face piece respirators became a critical supply in many health care institutions. Infection preventionists nationwide struggled with ensuring their facilities had personal protective equipment available while utilizing crisis capacity strategies. Many facilities began using US Centers for Disease Control and Prevention and US Food and Drug Administration guidance to disinfect and reprocess N95 respirators for extended use. N95 respirators are collected for all clinical units on a scheduled basis by the sterile processing department (SPD) in individually labeled bins. Bins are checked into SPD and logged into electronic system to track mask volumes by unit. Masks are inspected by SPD team members, packaged in sterile peel packs on the decontamination side and sent to the clean side of the department. Masks are then reprocessed in the appropriate equipment based on the US Food and Drug Administration Emergency Use Authorization guidelines. The facility was able to provide a consistent method of N95 reprocessing throughout the facility. Utilizing an interdisciplinary team to include the operating room, infection preventionist, SPD, and nursing leadership to troubleshoot and identify barriers on a routine basis was key to making the program a success for the many months of the COVID-19 pandemic.

Head-mounted display (HMD)-based virtual reality (VR) is ideally suited for presence and generating compelling visual experiences of self-motion, but users can suffer from side effects associated with head-to-display lag. We used the Oculus Rift HMD (consumer release – CV1) to simulate forward self-motion in depth. Observers made continuous yaw head movements at approximately 0.5 Hz or 1.0 Hz while viewing these self-motion simulations. We examined the perceptual effects of increasing the display lag, by adding lag to the baseline lag of the system (estimated to be approximately 5.3 ms or 0.5 frames per second). We found that increasing the head-to-display lag up to 212 ms reduced the presence and the strength of vection. In addition, faster (1.0 Hz) head oscillations were found to generate weaker presence and vection in the virtual environment than the slower (0.5 Hz) head oscillations. We also found that a positive correlation between vection and presence (found previously) persists across a wide range of head-to-display lags, and, increasing lag from a very low baseline level still impaired both experiences. Both vection and presence in virtual environments can therefore be impaired by either increasing head-display lag or making more rapid angular head movements.

Background In South Africa, there are limited data on the burden of diarrhoea at a community level, specifically in older children and adults. This community survey estimated rates of and factors associated with diarrhoea across all ages and determined the proportion of cases presenting to healthcare facilities. Methods Households were enrolled from an existing urban health and demographic surveillance site. A household representative was interviewed to determine associated factors and occurrence of diarrhoea in the household, for all household members, in the past 2 weeks (including symptoms and health seeking behaviour). Diarrhoeal rate of any severity was calculated for 15 years age groups. Factors associated with diarrhoea and health seeking behaviour were investigated using binomial logistic regression. Results Diarrhoeal rate among respondents (2.5 episodes/person-year (95% CI, 1.8–3.5)) was significantly higher than for other household members (1.0 episodes/person-year (95% CI, 0.8–1.4); IRR = 2.4 (95% CI, 1.5–3.7) p p = 0.039). Oral rehydration solution was used in 44.8% of cases. Having a child between 5 and 15 years in the household was associated with diarrhoea (OR = 2.3 (95% CI, 1.3–3.9), p = 0.003) and, while 26.4% of cases sought healthcare, only 4.6% were hospitalised and only 3.4% of cases had a stool specimen collected. While the majority of cases were mild, 13.8% of cases felt they required healthcare but were unable to access it. Conclusion Diarrhoeal rate was high across all age groups in this community; however, older children and adults were less likely to present to healthcare, and are therefore underrepresented through facility-based clinical surveillance. Current diarrhoeal surveillance represents a fraction of the overall cases occurring in the community.

Background Sexual and gender minority (SGM; i.e., non-heterosexual and transgender or gender-expansive, respectively) people experience physical health disparities attributed to greater exposure to minority stress (experiences of discrimination or victimization, anticipation of discrimination or victimization, concealment of SGM status, and internalization of stigma) and structural stigma. Purpose To examine which components of minority stress and structural stigma have the strongest relationships with physical health among SGM people. Methods Participants (5,299 SGM people, 1,902 gender minority individuals) were from The Population Research in Identity and Disparities for Equality (PRIDE) Study. Dominance analyses estimated effect sizes showing how important each component of minority stress and structural stigma was to physical health outcomes. Results Among cisgender sexual minority women, transmasculine individuals, American Indian or Alaskan Native SGM individuals, Asian SGM individuals, and White SGM individuals a safe current environment for SGM people had the strongest relationship with physical health. For gender-expansive individuals and Black, African American, or African SGM individuals, the safety of the environment for SGM people in which they were raised had the strongest relationship with physical health. Among transfeminine individuals, victimization experiences had the strongest relationship with physical health. Among Hispanic, Latino, or Spanish individuals, accepting current environments had the strongest relationship with physical health. Among cisgender sexual minority men prejudice/discrimination experiences had the strongest relationship with physical health. Conclusion Safe community environments had the strongest relationships with physical health among most groups of SGM people. Increasing safety and buffering the effects of unsafe communities are important for SGM health.

Biomedical waste poses various health and environmental hazards. Hence, it should be handled with the utmost care and disposed off safely. Several lacunas exist in the management of biomedical waste in India, and the pandemic posed by the coronavirus has made it even more challenging. The sudden outbreak of the virus led to an exponential rise in the quantity of biomedical waste. Furthermore, the poor infrastructure and lack of human resources have aggravated this situation. To combat this serious problem in a timely manner, the government has formulated various standard operating procedures and has amended the existing rules and guidelines.

Background Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, which is often complicated by aortic valve stenosis (AoS). In tricuspid aortic valve (TAV), AoS strongly associates with coronary artery disease (CAD) with common pathophysiological factors. Yet, it remains unclear whether AoS in patients with BAV is also associated with CAD. This study investigated the association between the aortic valve morphological features and the extent of CAD. Methods and Results A single‐center study was performed, including all patients who underwent an aortic valve replacement attributable to AoS between 2006 and 2019. Coronary sclerosis was graded on preoperative coronary angiographies using the coronary artery greater even than scoring method, which divides the coronaries in 28 segments and scores nonobstructive (20%–49% sclerosis) and obstructive coronary sclerosis (>49% sclerosis) in each segment. Multivariate analyses were performed, controlling for age, sex, and CAD risk factors. A total of 1296 patients (931 TAV and 365 BAV) were included, resulting in 548 matched patients. Patients with TAV exhibited more CAD risk factors (odds ratio [OR], 2.66; 95% CI, 1.79–3.96; P P P P Conclusions Patients with BAV who are undergoing surgery for AoS carry a lower cardiovascular risk profile, correlating with less coronary sclerosis and a lower incidence of concomitant coronary revascularization compared with patients with TAV.

Stereopsis provides critical information for the spatial visual perception of object form and motion. We used virtual reality as a tool to understand the role of global stereopsis in the visual perception of self-motion and spatial presence using virtual environments experienced through head-mounted displays (HMDs). Participants viewed radially expanding optic flow simulating different speeds of self-motion in depth, which generated the illusion of self-motion in depth (i.e., linear vection). Displays were viewed with the head either stationary (passive radial flow) or laterally swaying to the beat of a metronome (active conditions). Multisensory conflict was imposed in active conditions by presenting displays that either: (i) compensated for head movement (active compensation condition), or (ii) presented pure radial flow with no compensation during head movement (active no compensation condition). In Experiment 1, impairing stereopsis by anisometropic suppression in healthy participants generated declines in reported vection strength, spatial presence and severity of cybersickness. In Experiment 2, vection and presence ratings were compared between participants with and without clinically-defined global stereopsis. Participants without global stereopsis generated impaired vection and presence similarly to those found in Experiment 1 by subjects with induced stereopsis impairment. We find that reducing global stereopsis can have benefits of reducing cybersickness, but has adverse effects on aspects of self-motion perception in HMD VR.

Cancer is one of the most common cause of morbidity and mortality. Following the diagnosis of the disease, a patient has to undergo complex treatment regimen, which may result in extensive adverse effects. The physical and psychosocial distress experienced by the patients also affects their quality of life. Oncopharmacist can play a crucial role in improving pharmaceutical care for patients undergoing cancer therapy. The day-to-day care provided by the pharmacist will have a positive impact on their quality of life. As they are regarded as the specialists in the field, direct and indirect services provided by them extending from medication administration to drug safety monitoring are valued more. Key words: Oncopharmacists, Cost Minimization, Patient Safety, Cancer, Clinical Pharmacists.

Candida auris is an invasive healthcare-associated fungal pathogen. Cases of candidemia, defined as illness in patients with Candida cultured from blood, were detected through national laboratory-based surveillance in South Africa during 2016-2017. We identified viable isolates by using mass spectrometry and sequencing. Among 6,669 cases (5,876 with species identification) from 269 hospitals, 794 (14%) were caused by C. auris. The incidence risk for all candidemia at 133 hospitals was 83.8 (95% CI 81.2-86.4) cases/100,000 admissions. Prior systemic antifungal drug therapy was associated with a 40% increased adjusted odds of C. auris fungemia compared with bloodstream infection caused by other Candida species (adjusted odds ratio 1.4 [95% CI 0.8-2.3]). The crude in-hospital case-fatality ratio did not differ between Candida species and was 45% for C. auris candidemia, compared with 43% for non-C. auris candidemia. C. auris has caused a major epidemiologic shift in candidemia in South Africa.

Ribosome assembly is a complex process reliant on the coordination of trans-acting enzymes to produce functional ribosomal subunits and secure the translational capacity of cells. The endoribonuclease (RNase) Las1 and the poly-nucleotide kinase (PNK) Grc3 assemble into a multienzyme complex, herein designated RNase PNK, to orchestrate processing of precursor ribosomal RNA. RNase PNK belongs to the functionally-diverse HEPN nuclease superfamily, whose members rely on distinct cues for nuclease activation. To establish how RNase PNK coordinates its dual enzymatic activities, we solved a series of cryo-electron microscopy structures of Chaetomium thermophilum RNase PNK in multiple conformational states. The structures reveal that RNase PNK adopts a butterfly-like architecture harboring a composite HEPN nuclease active site flanked by discrete RNA kinase sites. We identify two molecular switches that coordinate nuclease and kinase function. Together our structures and corresponding functional studies establish a new mechanism of HEPN nuclease activation essential for ribosome production.

Japan is a high tobacco burden country with over 20 million smokers in 2017. Tobacco control measures in Japan has been criticised as largely inadequate and ineffective despite ratifying the World Health Organization's Framework Convention on Tobacco Control in 2004. Numerous factors such as pro-tobacco legislators, regulatory oversight of the primary Japanese tobacco company from the Ministry of Finance and industry interference on the policy-making process in Japan have prevented aggressive tobacco control efforts. Given the intricate challenges in Japan, it is important to develop feasible and effective smoking cessation strategies. In this paper, we have analysed the trends in tobacco prices, sale and smoking prevalence, major tobacco/smoking policies and some of the industry-related challenges that have prevented the development of effective tobacco control measures in Japan. We have emphasised the need for stronger implementation of the World Health Organization's Framework Convention on Tobacco Control and its MPOWER policy package and to separate the tobacco industry from the tobacco control policymaking process to promote cessation and abstinence from smoking and better sensitisation against exposure to second-hand smoke.

Objective Recognition is growing that to create truly patient‐centred care, health‐care organizations need to partner with patients around care design. More research into the benefits of engaging patients and the most effective ways of partnering with them is needed. Methods This study assessed the process and impact of a collaborative effort to design a new clinic service that balanced the number of patient and clinical provider/staff codesigners involved and recruited patients to represent diverse perspectives. Data sources included interviews with participants, event observation and participant surveys. Results Our evaluation found that including patients as equal partners improved the design process by infusing a real‐world, patient perspective. The pre‐event orientation and interactive methods used in the event fostered positive collaboration, as well as personal growth for the patient codesigners. Conclusion This study demonstrated the feasibility and benefits of including a roughly equal number of patients and clinical providers/staff in design events and ensuring that the patients represent diverse perspectives.

In South Africa, a progressive increase in listeriosis cases was noted from mid-June 2017, heralding what was to become the world's largest listeriosis outbreak. A total of 1060 cases were...

Cybersickness is common during virtual reality experiences with head-mounted displays (HMDs). Previously it has been shown that individual differences in postural activity can predict which people are more likely to experience visually-induced motion sickness. This study examined whether such predictions also generalise to the cybersickness experienced during active HMD-based virtual reality. Multisensory stimulation was generated by having participants continuously turn their heads from left to right while viewing the self-motion simulations. Real-time head tracking was then used to create ecological (‘compensated’) and non-ecological (‘inversely compensated’) head-and-display motion conditions. Ten (out of 20) participants reported feeling sick after being exposed to these self-motion simulations. Cybersickness did not differ significantly between the two compensation conditions. However, individual differences in spontaneous postural instability when standing quietly were found to predict the likelihood of subsequently experiencing cybersickness. These findings support recent proposals that postural measures can help diagnose who will benefit the most/least from HMD-based virtual reality.

Most HIV-1 transmissions occur at mucosae and involve exposure to semen. Semen contains immunomodulatory factors, which inhibit anti-HIV-1 natural killer cell and T cell responses. We demonstrate high concentrations (1:2 dilution) of seminal plasma (SP) inhibit monocyte phagocytosis and anti-HIV-1 Fc-dependent functions of both neutrophils and monocytes. In addition, slightly lower SP concentrations (1:2-1:10 dilutions) inhibit granulocyte phagocytosis and oxidative burst of both monocytes and granulocytes. These observations may have implications for HIV-1 infectivity after mucosal exposure.

Purpose of review To analyze the possible role that the ‘unconventional’ T-cell populations mucosal-associated invariant T cell (MAIT) and iNKT cells play during HIV infection and following antiretroviral therapy (ART) treatment. Recent findings A substantial body of evidence now demonstrates that both MAIT and iNKT cells are depleted in blood during HIV infection. The depletion and dysfunction of MAIT and iNKT cells are only partially restored by suppressive ART, potentially contributing to HIV-related comorbidities. Summary The deficiency and dysfunction of MAIT and iNKT T-cell subsets likely impact on immunity to important coinfections including Mycobacterium tuberculosis. This underscores the importance of research on restoring these unconventional T cells during HIV infection. Future studies in this field should address the challenge of studying tissue-resident cells, particularly in the gut, and better defining the determinants of MAIT/iNKT cell dysfunction. Such studies could have a significant impact on improving the immune function of HIV-infected individuals.

Rix7 is an essential type II AAA-ATPase required for the formation of the large ribosomal subunit. Rix7 has been proposed to utilize the power of ATP hydrolysis to drive the removal of assembly factors from pre-60S particles, but the mechanism of release is unknown. Rix7’s mammalian homolog, NVL2 has been linked to cancer and mental illness disorders, highlighting the need to understand the molecular mechanisms of this essential machine. Here we report the cryo-EM reconstruction of the tandem AAA domains of Rix7 which form an asymmetric stacked homohexameric ring. We trapped Rix7 with a polypeptide in the central channel, revealing Rix7’s role as a molecular unfoldase. The structure establishes that type II AAA-ATPases lacking the aromatic-hydrophobic motif within the first AAA domain can engage a substrate throughout the entire central channel. The structure also reveals that Rix7 contains unique post-α7 insertions within both AAA domains important for Rix7 function., Rix7 is a type II AAA-ATPase that is required for the assembly of the large ribosomal subunit. Here the authors present the 4.5 Å cryo-EM structure of the Rix7 homohexamer with a polypeptide fragment bound in its central channel and provide insights into the function of Rix7 as a molecular unfoldase.

It has been known that activation of protease-activated receptors (PARs) affects gastrointestinal motility. In this study, we tested the effects of PAR agonists on electrical and contractile responses and Ca2+sensitization pathways in simian colonic muscles. The Simian colonic muscle was initially hyperpolarized by PAR agonists. After the transient hyperpolarization, simian colonic muscle repolarized to the control resting membrane potential (RMP) without a delayed depolarization. Apamin significantly reduced the initial hyperpolarization, suggesting that activation of small conductance Ca2+-activated K+(SK) channels is involved in the initial hyperpolarization. In contractile experiments, PAR agonists caused an initial relaxation followed by an increase in contractions. These delayed contractile responses were not matched with the electrical responses that showed no after depolarization of the RMP. To investigate the possible involvement of Rho-associated protein kinase 2 (ROCK) pathways in the PAR effects, muscle strips were treated with ROCK inhibitors, which significantly reduced the PAR agonist-induced contractions. Furthermore, PAR agonists increased MYPT1 phosphorylation, and ROCK inhibitors completely blocked MYPT1 phosphorylation. PAR agonists alone had no effect on CPI-17 phosphorylation. In the presence of apamin, PAR agonists significantly increased CPI-17 phosphorylation, which was blocked by protein kinase C (PKC) inhibitors suggesting that Ca2+influx is increased by apamin and is activating PKC. In conclusion, these studies show that PAR activators induce biphasic responses in simian colonic muscles. The initial inhibitory responses by PAR agonists are mainly mediated by activation of SK channels and delayed contractile responses are mainly mediated by the CPI-17 and ROCK Ca2+sensitization pathways in simian colonic muscles.NEW & NOTEWORTHY In the present study, we found that the contractile responses of simian colonic muscles to protease-activated receptor (PAR) agonists are different from the previously reported contractile responses of murine colonic muscles. Ca2+sensitization pathways mediate the contractile responses of simian colonic muscles to PAR agonists without affecting the membrane potential. These findings emphasize novel mechanisms of PAR agonist-induced contractions possibly related to colonic dysmotility in inflammatory bowel disease.

To determine the epidemiology of Candida auris in South Africa, we reviewed data from public- and private-sector diagnostic laboratories that reported confirmed and probable cases of invasive disease and colonization for October 2012–November 2016. We defined a case as a first isolation of C. auris from any specimen from a person of any age admitted to any healthcare facility in South Africa. We defined probable cases as cases where the diagnostic laboratory had used a nonconfirmatory biochemical identification method and C. haemulonii was cultured. We analyzed 1,692 cases; 93% were from private-sector healthcare facilities, and 92% of cases from known locations were from Gauteng Province. Of cases with available data, 29% were invasive infections. The number of cases increased from 18 (October 2012–November 2013) to 861 (October 2015–November 2016). Our results show a large increase in C. auris cases during the study period, centered on private hospitals in Gauteng Province.

Humans rely on multiple senses to perceive their self-motion in the real world. For example, a sideways linear head translation can be sensed either by lamellar optic flow of the visual scene projected on the retina of the eye or by stimulation of vestibular hair cell receptors found in the otolith macula of the inner ear. Mismatches in visual and vestibular information can induce cybersickness during head-mounted display (HMD) based virtual reality (VR). In this pilot study, participants were immersed in a virtual environment using two recent consumer-grade HMDs: the Oculus Go (3DOF angular only head tracking) and the Oculus Quest (6DOF angular and linear head tracking). On each trial they generated horizontal linear head oscillations along the interaural axis at a rate of 0.5 Hz. This head movement should generate greater sensory conflict when viewing the virtual environment on the Oculus Go (compared to the Quest) due to the absence of linear tracking. We found that perceived scene instability always increased with the degree of linear visual-vestibular conflict. However, cybersickness was not experienced by 7/14 participants, but was experienced by the remaining participants in at least one of the stereoscopic viewing conditions (six of whom also reported cybersickness in monoscopic viewing conditions). No statistical difference in spatial presence was found across conditions, suggesting that participants could tolerate considerable scene instability while retaining the feeling of being there in the virtual environment. Levels of perceived scene instability, spatial presence and cybersickness were found to be similar between the Oculus Go and the Oculus Quest with linear tracking disabled. The limited effect of linear coupling on cybersickness, compared with its strong effect on perceived scene instability, suggests that perceived scene instability may not always be associated with cybersickness. However, perceived scene instability does appear to provide explanatory power over the cybersickness observed in stereoscopic viewing conditions.

Immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is central to long-term control of the current pandemic. Despite our rapidly advancing knowledge of immune memory to SARS-CoV-2, understanding how these responses translate into protection against reinfection at both the individual and population levels remains a major challenge. An ideal outcome following infection or after vaccination would be a highly protective and durable immunity that allows for the establishment of high levels of population immunity. However, current studies suggest a decay of neutralizing antibody responses in convalescent patients, and documented cases of SARS-CoV-2 reinfection are increasing. Understanding the dynamics of memory responses to SARS-CoV-2 and the mechanisms of immune control are crucial for the rational design and deployment of vaccines and for understanding the possible future trajectories of the pandemic. Here, we summarize our current understanding of immune responses to and immune control of SARS-CoV-2 and the implications for prevention of reinfection., The duration of immunity to coronavirus disease 2019 (COVID-19) from prior infection and longer-term risk of reinfection are currently unclear. Cromer and colleagues discuss the immune control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the implications of this for the future control of the pandemic.

Significance Uncorrected refractive error is the main cause of visual impairment globally. Understanding barriers and facilitators underserved individuals face in obtaining eyeglasses will help address high rates of uncorrected refractive error. Purpose The purpose of this study was to understand the barriers and facilitators to obtaining eyeglasses among low-income patients in Michigan. Methods Participants older than 18 years with hyperopia, myopia, or presbyopia and without active eye disease, severe mental illness, or cognitive impairment at Hope Clinic, Ypsilanti, Michigan, were included in this study. The participants answered a sociodemographic survey and underwent autorefraction and an interview. Interviews were audiorecorded, transcribed, and analyzed by two investigators. Results Interviews were completed by 43 participants, and 30 participants' interviews were analyzed. The mean ± standard deviation age of 30 participants was 55 ± 12 years, 70% were female, 57% were African American, 40% had high school diploma or less, 57% earned less than U.S. $25,000 per year, 93% had worn glasses previously, and 87% had some medical insurance. Uncorrected visual acuity was logMAR 0.73 ± 0.61; best-corrected visual acuity was logMAR 0.16 ± 0.21. Thematic saturation was reached after 25 transcripts. Top barriers to using eyeglasses were cost (312 mentions, 29 participants), negative experiences with eyeglasses (263, 29), and limited access to eye care (175, 27). Top facilitators were positive experiences with glasses (230, 29), easy access to eyeglasses (143, 27), and availability of transportation (65, 27). Most participants (97%, 29) reported being negatively impacted by uncorrected refractive error. Most (97%, 29) were skeptical about obtaining eyeglasses online because of possible prescription problems. Conclusions Key barriers to correcting uncorrected refractive error in our community span across multiple health domains but are predominately rooted in external factors such as cost and access to vision care. Online eyeglasses may address access issues, but many participants were uncomfortable or unable to obtain glasses online.

SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation., Current vaccine strategies for SARS-CoV-2 focus on eliciting neutralising antibodies to the spike protein (S), but differences in immunogenicity of full-length S versus receptor binding domain (RBD) only aren’t fully understood. Here, the authors show immunogenicity of different prime-boost strategies with S and/or RBD in mice and macaques.

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection., Longitudinal analyses are needed to show how the immune response to Sars-Cov-2 infection changes over time. Here, the authors use multiple strategies to profile the change in immune cell responses from patients with convalescent COVID-19 over the course of ~5 months, showing that although neutralizing antibody responses drop off after ~4 months, B cell immune responses strengthen.

Nsp15, a uridine specific endoribonuclease conserved across coronaviruses, processes viral RNA to evade detection by host defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly, yet how the enzyme recognizes and processes RNA remains poorly understood. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15, in both apo and UTP-bound states. The cryo-EM reconstructions, combined with biochemistry, mass spectrometry, and molecular dynamics, expose molecular details of how critical active site residues recognize uridine and facilitate catalysis of the phosphodiester bond. Mass spectrometry revealed the accumulation of cyclic phosphate cleavage products, while analysis of the apo and UTP-bound datasets revealed conformational dynamics not observed by crystal structures that are likely important to facilitate substrate recognition and regulate nuclease activity. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics.

Objectives Endemic human coronaviruses (hCoVs) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV‐specific T‐cell memory in adults. Methods We quantified CD4 T‐cell and antibody responses to hCoV spike antigens in 42 SARS‐CoV‐2‐uninfected individuals. Antigen‐specific memory T cells and circulating T follicular helper (cTFH) cells were identified using an activation‐induced marker assay and characterised for memory phenotype and chemokine receptor expression. Results T‐cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS‐CoV‐2 cross‐reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV‐specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung‐draining lymph nodes. Conclusion Overall, hCoV‐specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus‐specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS‐CoV‐2., Adaptive immunity to human coronaviruses includes widespread, low‐level antibody and CD4 T‐cell responses, which are maintained independently. All hCoV‐specific and cross‐reactive SARS‐CoV‐2‐specific CD4 T‐cell responses share a common phenotypic and memory profile. hCoV‐specific CD4 T cells were substantially enriched in human lung‐draining lymph nodes compared with the circulation, suggesting a potential anatomical niche for maintenance of hCoV cellular memory.

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic. Estimates of the levels of neutralizing antibodies necessary for protection against symptomatic SARS-CoV-2 or severe COVID-19 are a fraction of the mean level in convalescent serum and will be useful in guiding vaccine rollouts.