Senile retinoschisis (SR) is a rare eye disease characterized by the abnormal separation of the neurosensory retina layers typically at the outer plexiform layer. Retinal detachment (RD) can be associated with SR in approximately 0.05% of the cases in which urgent treatments are indicated. The utility of spectral domain optical coherent tomography (SD-OCT) is helpful in diagnosing SR and distinguishing it from RD. This is a case of a 63-year-old man who presented with right eye floaters for a duration of two months. There were no other optic symptoms such as flashes of light, decreased vision, or pain. The best-corrected visual acuity was 20/25 in both eyes. Dilated fundus examination of the right eye revealed two elevated dome-shaped, mobile, transparent, smooth, and round peripheral retinal lesions in the inferotemporal quadrant suggestive of SR. SD-OCT was utilized to diagnose SR and rule out RD. In conclusion, SD-OCT is a very valuable diagnostic tool that can be utilized for SR which is a rare condition that can have serious visual consequences if not diagnosed and managed properly. Senile retinoschisis (SR), either acquired or degenerative, is a rare and hard-to-diagnose eye disease characterized by the abnormal separation of the neurosensory retina layers due to microcystic degeneration, typically at the outer plexiform layer . The reaProgressive and symptomatic retinal detachment (RD) associated with SR is rare, occurring in approximately 0.05% of the cases . It is tA 63-year-old man presented to the ophthalmic outpatient clinic complaining of floaters in the right eye (OD) for a duration of two months. There were no flashes of light, decreased vision, pain, history of trauma, or previous ocular disease. The medical history was significant only for bronchial asthma with albuterol inhalers as the sole medication used while the past surgical history reported a gastric sleeve operation which was done five years ago.On examination, the best-corrected visual acuity was 20/25 OD and 20/25 in the left eye (OS). Intraocular pressure was measured by air-puff tonometer and showed 17 mmHg OD and 16 mmHg OS. Meanwhile, no relative afferent pupillary defect was noted. Slit-lamp anterior segment examination of both eyes was normal except for mild nuclear sclerosis cataracts. Dilated fundus examination of the right eye revealed two elevated dome-shaped, mobile, transparent, smooth, and round peripheral retinal lesions in the inferotemporal quadrant. The lesions were extending from 7:30 to 9 meridians and posteriorly with an estimated distance of one and a half-disc diameters (Figure SD-OCT is increasingly favored over conventional time-domain OCT for the evaluation of a variety of retinal disorders due to its higher resolution imaging and easier interpretation . Faster This case presented with symptomatic unilateral SR in the inferotemporal quadrant which is uncommon. Most patients are asymptomatic and this is an incidental finding without ocular or visual complaints. Although the location of SR in the inferotemporal quadrant was found to be more common than other quadrants , 5, the In this case, the patient was treated with a barrage argon laser photocoagulation that created a posterior pigmented demarcation photocoagulation scar which prevented the posterior extension of SR and macular involvement. This goes in line with Yassur et al.  results SD-OCT is an instrumental tool that is utilized to diagnose SR which is a rare condition that can have serious visual consequences if not diagnosed and managed properly. In addition, early laser photocoagulation treatment is considered a safe uncomplicated simple outpatient procedure that is beneficial in preventing the possible complications of long-standing retinoschisis.


I2 > 75%); others did not include additional analysis for publication bias; none checked for evidence of p–hacking in the primary studies nor used recent methods  to estimate the average population-size effect. These inconsistencies may contribute to contradictory results in the research evaluating COVID-19 treatments. A prominent example of this is the use of hydroxychloroquine, where some studies reported a large positive effect, whereas others indicated no significant effect or even increased mortality when hydroxychloroquine was used with the antibiotic azithromycin. In this paper, we first recall the benefits and fundamental steps of good quality meta-analysis. Then, we examine various meta-analyses on hydroxychloroquine treatments for COVID-19 patients that led to contradictory results and causes for this discrepancy. We then highlight recent tools that contribute to evaluate publication bias and p-hacking  and conclude by making technical recommendations that meta-analyses should follow even during extreme global events such as a pandemic.Despite the massive distribution of different vaccines globally, the current pandemic has revealed the crucial need for an efficient treatment against COVID-19. Meta-analyses have historically been extremely useful to determine treatment efficacy but recent debates about the use of hydroxychloroquine for COVID-19 patients resulted in contradictory meta-analytical results. Different factors during the COVID-19 pandemic have impacted key features of conducting a good meta-analysis. Some meta-analyses did not evaluate or treat substantial heterogeneity ( The 2020 COVID-19 pandemic has highlighted the urgent need for the development and administration of a new treatment for COVID-19. Despite the rollout of several different vaccines globally, the need to find treatment remains essential given the uncertainty and shortcomings with equal distribution of vaccines and vaccine availability. Meta-analyses have historically been used to establish the existence, size, and confidence of therapeutic effects or causes of particular diseases.I2 > 75%); none checked for evidence of p–hacking in the primary studies nor used recent techniques  to estimate average population-size effect. Journals greatly favor publishing significant findings in comparison to non-significant findings, resulting in publication bias which can overestimate effect sizes (the strength of the relationship between two variables). These discrepancies may contribute to opposing results in the research evaluating COVID-19 treatments. A prominent example of this is the use of hydroxychloroquine (HCQ), where some studies reported a large protective effect, whereas others indicated no significant effect or even increased mortality when HCQ was administered with the antibiotic azithromycin.Meta-analysis is an important tool to determine the effectiveness of COVID-19 treatments, but it is essential that the strength of evidence be maintained by adhering to all components of the methodology. Various factors during the COVID-19 pandemic, including time pressure, have resulted in alterations and omissions of key aspects of meta-analysis that lower the quality of evidence. Some meta-analyses did not evaluate publication bias, nor treat substantial heterogeneity  .Compute the mean effect sizes across different studies .Evaluate the level of heterogeneity .Determine the impact of publication bias .Run meta-regressions and subgroup analyses to control for the effects of studies' characteristics  and sample .I2 > 80%) or meta-analyzed small sets of studies [k ≤ 3 implying low statistical power  . The meaal power ]. None up-uniform, p-curve)  , 10. A gp-curve) .Recent advances in techniques question the reliance on estimates presented in the original studies for meta-analysis due to significant limitations . SystemaI2 > 75%), which negatively affects precision and thus statistical power. For example, the statistical power to detect a small effect size (d = 0.2) with 25 participants per group in 6 different studies using a random-effects model with moderate heterogeneity (I2 = 50%) and a 5% of type I error is only 26.7% .A major strength of meta-analysis is the relatively high statistical power associated with compiling several studies . The median number of studies in the Cochrane Database for Systematic Reviews is six, according to Borenstein et al. . This isQ statistic, the variance between studies (τ2), and the relationship between the real heterogeneity and the observed total variation (I2).The objective of meta-analysis is not simply to calculate an average weighted effect estimate but also to make sense of the pattern of effects. An intervention that consistently reduces the risk of mortality by 30% in numerous studies is different from an intervention that reduces the risk of mortality by 30% on average, with a risk reduction ranging from 10 to 80% across studies. We must determine the true variance to provide different perspectives on the dispersion of the results based on the Publication bias affects both researchers conducting meta-analyses and physicians searching for primary studies in a database. If the missing studies are a random subset of all studies, excluding them will result in less evidence, wider confidence intervals, and lower statistical power, but will not have a systematic influence on the effect size . HoweverDifferent techniques have been developed to detect publication bias . A widel.S. Food and Drug Administration (FDA) to issue an emergency-use (EUA) authorization on March 28, 2020 allowing for HCQ sulfate and CQ phosphate to be donated to the Strategic National Stockpile for use in hospitalized COVID-19 patients. Given its multiple antiviral effects, it is plausible that HCQ could be beneficial in COVID-19 patients  have been used for decades to manage and treat malaria and several autoimmune conditions. At the beginning of the pandemic, preliminary studies –20 suggepatients . In vitrsomal pH  and by rsomal pH –25. Shorsomal pH  , which suggests the presence of confounders not being accounted for across studies, and neither study performed subgroup analysis to better explore the high heterogeneity. Study selection was problematic in both studies. For instance, Million and colleagues did not publish a flow diagram with the different phases of a systematic review as recommended by the PRISMA Statement  and pooled results  will have effect estimates distributed on either side of the average effect, creating a funnel-shaped plot.p-curve  than values around the arbitrary significant threshold of p < 0.05, a flat p-curve or a p-curve indicating a higher proportion of p-values between 0.04 and 0.05 is more likely to be an indicator of questionable research practices, sometimes referred to as p-hacking. Van Assen et al. .Although funnel plots are a widely used and reliable way to evaluate publication bias, another useful tool is the p-curve . The p-cp-curve and p-uniform to estimate the average population effect sizes for each subgroup analysis , subjective reporting bias (selective reporting of the results), duplicate reporting bias (results published in multiple sources), and language bias (non-native English speakers tend to publish non-significant findings in their native tongue) .Tensions over the use of HCQ for COVID-19 patients have unfortunately led some authors to disregard basic meta-analytical protocols. Concern over the quality of studies included in meta-analyses has also emerged in a recent comparative psychological study between meta-analytical findings and registered replication studies. The authors found that meta-analytical effect sizes significantly differed from the replication effect sizes for 12 of the 15 meta-replication pairs, and meta-analytic effect sizes were almost three times larger than the replication effect sizes (The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JB and OZ contributed to the original idea and wrote the original manuscript. JB, OZ, and CR analyzed the relevant literature and updated the manuscript. JB, OZ, CR, and AH were all contributor in writing the final manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This case-control study examines the association between counties that adopted state mask mandates in Kansas with COVID-19 cases, hospitalizations, and deaths. This study examined the association between mask mandates in Kansas counties and COVID-19 cases, hospitalizations, and deaths. The Kansas executive order that took effect on July 3 was adopted by only 15 counties, and 68 counties did not have a mandate through October. A second mask mandate order took effect on November 25, and 40 additional counties adopted it.New York Times1 and hospitalizations by county of residence were collected from the Kansas Department of Health and Environment2 (eMethods and eReferences in the STROBE) reporting guideline.For this case-control study, data for the daily number of cases and deaths per county were from the 3 to classify counties by mask mandate and other restrictions . All models include controls for county and day fixed effects and use 95% CIs for statistical significance.We used linear regression difference-in-differences models.The The 5 and reduced the spread in states.6 Our results comparing mask-only policies with masks plus additional restrictions suggest that mask-wearing is associated with these reductions.Counties that adopted the July mask mandate in Kansas experienced significantly lower rates of COVID-19 cases, hospitalizations, and deaths compared with those that did not. These findings corroborate previous studies that found that mask mandates slowed the growth of COVID-19 cases in Kansas countiesThis study was limited because it did not control for daily testing rates by county in the state of Kansas, which were not available. Mask mandates are not the same as compliance, and our results should be considered lower-bound estimates of the association between mask-wearing and COVID-19. Our results suggest that mask mandates may provide an effective way to reduce cases of COVID-19, hospitalizations, and deaths.


Before 2020, mental disorders were leading causes of the global health-related burden, with depressive and anxiety disorders being leading contributors to this burden. The emergence of the COVID-19 pandemic has created an environment where many determinants of poor mental health are exacerbated. The need for up-to-date information on the mental health impacts of COVID-19 in a way that informs health system responses is imperative. In this study, we aimed to quantify the impact of the COVID-19 pandemic on the prevalence and burden of major depressive disorder and anxiety disorders globally in 2020.We conducted a systematic review of data reporting the prevalence of major depressive disorder and anxiety disorders during the COVID-19 pandemic and published between Jan 1, 2020, and Jan 29, 2021. We searched PubMed, Google Scholar, preprint servers, grey literature sources, and consulted experts. Eligible studies reported prevalence of depressive or anxiety disorders that were representative of the general population during the COVID-19 pandemic and had a pre-pandemic baseline. We used the assembled data in a meta-regression to estimate change in the prevalence of major depressive disorder and anxiety disorders between pre-pandemic and mid-pandemic (using periods as defined by each study) via COVID-19 impact indicators . We then used this model to estimate the change from pre-pandemic prevalence (estimated using Disease Modelling Meta-Regression version 2.1 [known as DisMod-MR 2.1]) by age, sex, and location. We used final prevalence estimates and disability weights to estimate years lived with disability and disability-adjusted life-years (DALYs) for major depressive disorder and anxiety disorders.B] 0·9  for human mobility, 18·1  for daily SARS-CoV-2 infection) and anxiety disorders  and younger age groups were more affected than older age groups . We estimated that the locations hit hardest by the pandemic in 2020, as measured with decreased human mobility and daily SARS-CoV-2 infection rate, had the greatest increases in prevalence of major depressive disorder and anxiety disorders. We estimated an additional 53·2 million (44·8 to 62·9) cases of major depressive disorder globally (an increase of 27·6% [25·1 to 30·3]) due to the COVID-19 pandemic, such that the total prevalence was 3152·9 cases (2722·5 to 3654·5) per 100 000 population. We also estimated an additional 76·2 million (64·3 to 90·6) cases of anxiety disorders globally (an increase of 25·6% [23·2 to 28·0]), such that the total prevalence was 4802·4 cases (4108·2 to 5588·6) per 100 000 population. Altogether, major depressive disorder caused 49·4 million (33·6 to 68·7) DALYs and anxiety disorders caused 44·5 million (30·2 to 62·5) DALYs globally in 2020.We identified 5683 unique data sources, of which 48 met inclusion criteria (46 studies met criteria for major depressive disorder and 27 for anxiety disorders). Two COVID-19 impact indicators, specifically daily SARS-CoV-2 infection rates and reductions in human mobility, were associated with increased prevalence of major depressive disorder (regression coefficient [This pandemic has created an increased urgency to strengthen mental health systems in most countries. Mitigation strategies could incorporate ways to promote mental wellbeing and target determinants of poor mental health and interventions to treat those with a mental disorder. Taking no action to address the burden of major depressive disorder and anxiety disorders should not be an option.Queensland Health, National Health and Medical Research Council, and the Bill and Melinda Gates Foundation. Evidence before this studyFor our study, we did a systematic literature review of the peer-reviewed and grey literature for studies published between Jan 1, 2020, and Jan 29, 2021, investigating prevalence of depressive and anxiety disorders during the COVID-19 pandemic. Most of the identified work consisted of surveys done for a specific location, at a snapshot in time, and indicated an increase in prevalence of depressive and anxiety disorders during the COVID-19 pandemic. We also found several systematic reviews and meta-analyses to summarise these studies; however, these studies were either qualitative syntheses or simply presented pooled estimates across studies. We did not find any studies that attempted to synthesise the global prevalence and burden of depressive and anxiety disorders due to the COVID-19 pandemic for the year 2020.Added value of this studyThis study is the first to quantify the prevalence and burden of depressive and anxiety disorders by age, sex, and location globally. We compiled available evidence of the change in the prevalence of major depressive disorder and anxiety disorders during the COVID-19 pandemic. We then developed a model to estimate the prevalence of major depressive disorder and anxiety disorders by age, sex, and location on the basis of available indicators of the location-specific impact of the COVID-19 pandemic. We then used prevalence to estimate the burden of major depressive disorder and anxiety disorders due to the COVID-19 pandemic in 2020.Implications of all the available evidenceWe found that depressive and anxiety disorders increased during 2020 due to the COVID-19 pandemic. Even before the COVID-19 pandemic, depressive and anxiety disorders featured as leading causes of burden globally, despite the existence of intervention strategies that can reduce their effects. Meeting the added demand for mental health services due to COVID-19 will be difficult, but not impossible. Mitigation strategies should promote mental wellbeing and target determinants of poor mental health exacerbated by the pandemic, as well as interventions to treat those who develop a mental disorder.Mental disorders are among the leading causes of the global health-related burden. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 showed that the two most disabling mental disorders were depressive and anxiety disorders, both ranked among the top 25 leading causes of burden worldwide in 2019.The emergence of the COVID-19 pandemic in 2020 against this backdrop has raised many questions around the resulting effects on mental health via its direct psychological effects and long-term economic and social consequences.GBD 2020 is in the process of estimating the burden of 370 diseases and injuries 88 risk factors across 204 countries and territories. GBD 2020 is quantifying the burden using disability-adjusted life-years (DALYs), which represent the number of years of healthy life lost to either mortality or disability. Here, as part of GBD 2020, we present a method built on the mental disorder estimates presented in GBD 2019 by incorporating the effect of the COVID-19 pandemic. We quantify the impact of COVID-19 on the prevalence and burden of major depressive disorder and anxiety disorders by location, age, and sex in 2020.code used in the analyses can be found online.First, we conducted a systematic literature review to assemble data from surveys measuring the effect of COVID-19 on the prevalence of depressive and anxiety disorders. Second, we used these data in a meta-analysis to (1) estimate the change in prevalence of major depressive disorder and anxiety disorders before versus during the COVID-19 pandemic, (2) predict (through the use of selected indicators of COVID-19 impact) the resulting change in prevalence of each disorder across all GBD locations, and (3) translate changes in prevalence to corresponding changes in burden estimates as years lived with disability (YLDs) and DALYs. A conceptual overview of this process is shown in the To ensure comparability in measurement, we used case definitions for major depressive disorder and anxiety disorders used within the GBD framework. These definitions adhere to criteria presented in the Diagnostic and Statistical Manual of Mental Disorder fourth edition text revision (DSM-IV-TR)We conducted a systematic literature search to identify population surveys reporting on the prevalence of depressive or anxiety disorders, or both, during the COVID-19 pandemic. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines;Eppi-centre, The DEPRESSD Project, Google Scholar, The Neurology and Neuropsychiatry of COVID-19 Blog, the WHO COVID 19 literature database, COVID-Minds, and the MedRxiv and PsyArXiv preprint servers), and expert consultation. Search strings for each search are in the We searched for data sources published between Jan 1, 2020, and Jan 29, 2021. The search involved electronic searches of the peer-reviewed literature using PubMed, the grey literature  collected since 2013 to assess the change in prevalence. Longitudinal studies using samples representative of the general population were preferred, but cross-sectional studies were also included if comparable pre-pandemic prevalence data existed. Studies using random sampling were preferred; however, due to challenges imposed by the COVID-19 pandemic, there were few studies of this type. Studies using market research quota sampling were also included but were controlled for with a covariate in our analysis. Market research quota sampling is a non-probabilistic sampling strategy whereby participants are identified from a database to match the population of interest  over the course of the pandemic. Our process of selecting the COVID-19 impact indicators is detailed in the 13The estimation of human mobility, daily SARS-CoV-2 infection rate, and daily excess mortality rate was done by the Institute for Health Metrics and Evaluation (IHME) COVID-19 Forecasting Team and is described in detail elsewhere.13Global Health Data Exchange library), and consultation with experts. GBD 2020 uses Disease Modelling Meta-Regression version 2.1 (known as DisMod-MR 2.1), a Bayesian disease modelling meta-regression tool, to analyse these data and generate internally consistent estimates of prevalence, incidence, remission, and mortality by sex, location, year, and age group for each disorder.GBD conducts routine systematic reviews of the epidemiology of major depressive disorder and anxiety disorders as part of the estimation of YLDs . The compiled epidemiological data for GBD 2020 includes studies done from 1980 to 2019 on the prevalence, incidence, remission, duration, and excess mortality of major depressive disorder and anxiety disorders. These data were identified through routine electronic searches of PubMed, PsycINFO, Embase, grey literature sources  and the need for age, sex, and bias covariates to be treated as effect modifiers on the impact indicators, we developed prevalence adjustment models via a two-step process. In step one, we used indicator models to develop a so-called index for the impact of COVID-19. Human mobility, daily SARS-CoV-2 infection rate, and daily excess mortality rate were included simultaneously in a meta-regression on the change in logit prevalence to quantify their independent effect on prevalence change. We used the coefficients from these models to calculate a single COVID-19 impact indicator for each disorder. In step two, we developed a final model for each disorder via backward elimination to regress the COVID-19 impact indicator, age, sex, and the bias covariates on the change in logit prevalence. The least significant covariate was iteratively removed until no improvement was seen in the Akaike information criterion. We assessed the generalisability of the model using a leave-one-country-out cross-validation analysis .We used the final disorder-specific models to predict the change in logit prevalence of major depressive disorder and anxiety disorders and adjust the DisMod-MR 2.1 prevalence estimates for the year 2020 via a Markov chain Monte Carlo simulation. We extracted 1000 samples from the probability distributions of the change in logit prevalence of major depressive disorder and anxiety disorders, and their logit prevalences from DisMod-MR 2.1, by age, sex, and location for every day of the year 2020, based on daily estimates of the significant COVID-19 impact indicators. We adjusted the logit prevalence by the change and inverse-logit transformed the result to estimate the adjusted daily prevalence. We estimated the average daily prevalence for the year 2020 by age, sex, and location as the point prevalence for the year .The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report.Of the 5683 unique data sources obtained from the systematic review, 1674 remained following title and abstract screening. In total, 46 studies met inclusion criteria for major depressive disorder and 27 for anxiety disorders , which was less of an issue shared between the daily SARS-CoV-2 infection rate and human mobility (r = 0·5).Human mobility and daily SARS-CoV-2 infection rate were significantly associated with the change in major depressive disorder and anxiety disorder prevalence . After cIncreases in the COVID-19 impact index (informed by the significant indicators of human mobility and daily SARS-CoV-2 infection rate) were associated with an increase in prevalence of major depressive disorder (0·4 [95% UI 0·1–0·6]) and anxiety disorders  per 100 000 population, equivalent to 193 million (167–224) people . After aBefore adjustment for the COVID-19 pandemic, the estimated global prevalence of anxiety disorders in 2020 was 3824·9 (95% UI 3283·3–4468·1) per 100 000 population, which is equivalent to 298 million (256–348) people . After aBefore adjustment for the COVID-19 pandemic, major depressive disorder was responsible for 38·7 million (95% UI 26·4–53·9) DALYs globally, equivalent to 497·0 DALYs (338·3–691·1) per 100 000 population. After adjustment for the COVID-19 pandemic, major depressive disorder was responsible for 49·4 million (33·6–68·7) DALYs, equivalent to 634·1 DALYs (431·3–881·0) per 100 000 population . We estiBefore adjustment for the COVID-19 pandemic, anxiety disorders were responsible for 35·5 million (95% UI 23·9–50·1) DALYs globally, equivalent to 454·8 DALYs (307·0–642·5) per 100 000 population . After aIn this study, we estimated a substantial increase in the prevalence and burden of major depressive disorder and anxiety disorders as a result of the COVID-19 pandemic. This is, to our knowledge, the first study to systematically identify and analyse population mental health survey data and quantify the resulting impact of the COVID-19 pandemic on the prevalence of these two disorders by location, age, and sex in 2020.Increases in the prevalence of major depressive disorder and anxiety disorders during 2020 were both associated with increasing SARS-CoV-2 infection rates and decreasing human mobility. These two COVID-19 impact indicators incorporated the combined effects of the spread of the virus, lockdowns, stay-at-home orders, decreased public transport, school and business closures, and decreased social interactions, among other factors. We estimated that countries hit hardest by the pandemic during 2020 had the greatest increases in prevalence of these disorders.The two COVID-19 impact indicators used in our model should not be interpreted as risk factors for major depressive disorder and anxiety disorders. The risk factor of interest was the COVID-19 pandemic, with these two indicators acting as proxies for the effect of COVID-19 in the population. The COVID-19 pandemic is occurring against a complex backdrop of a range of social determinants of mental health, as well as well known inequalities within these determinants. The greater increase in disorder prevalence among females than among males, which resulted in an even greater sex difference in prevalence than before the pandemic, was anticipated because females are more likely to be affected by the social and economic consequences of the pandemic.Our study is not the first to show how population shocks  can increase the prevalence of depressive and anxiety disorders. In their review of mental health outcomes after the economic crisis in 2009, Frasquilho and colleaguesBoth major depressive disorder and anxiety disorders increase the risk of other diseases and suicide.Even before the emergence of the COVID-19 pandemic, major depressive disorder and anxiety disorders  were among the leading causes of health burden globally, with the mental health system in most countries being under-resourced and disorganised, despite evidence that effective prevention and intervention tools exist.In the wake of the impact of the COVID-19 pandemic on the prevalence and burden of major depressive disorder and anxiety disorders, taking no action cannot be an option. Resources exist to guide the development of mitigation strategies for reducing the mental health burden imposed by COVID-19. These resources include strategies that make efficient use of already limited resources, consider the local context and vulnerable populations, and prioritise key principles such as inclusivity, stigma reduction, and human rights.. However, this assumption has the potential to bias our estimates. For example, high scores on anxiety disorder symptom scales might reflect a natural psychological and physiological reaction to a perceived threat  rather than a probable anxiety disorder. At the time of publication, not enough data were available to assess this assumption. We identified only three diagnostic mental health surveys that had been done since the beginning of the pandemic. Increases in prevalence were observed in two of the three diagnostic surveys.Here, we estimated the change in disorder prevalence in 2020 using the best data at our disposal, but these data will continue to be updated throughout the different phases of the pandemic. This ongoing work will also explore ways to improve the following limitations in the analyses reported here. First, we were limited by the data available to consistently measure the effect of COVID-19 across all GBD locations using our choice of COVID-19 indicators. Human mobility and SARS-CoV-2 infection rates are unlikely to have captured the full impact of the pandemic on mental health across all countries. The precision in these two indicators can be improved, for example, in countries where infection rates are not consistently measured or reported. Reliance on mobile phone tracking technology to monitor human mobility will also not be accurate in locations where subgroups of the population  have little or no mobile phone use. Some subgroups might not be able to reduce their mobility because of their employment type and might be more prone to infection, and so reductions in human mobility might be exaggerated in these locations. As we progress through the pandemic and the full economic effects on some populations emerge, re-evaluation of available indicators will be important. For example, we made no distinction in prevalence between those with and without previous SARS-CoV-2 infection within the population. Emerging evidence suggests people with post-acute sequelae of COVID-19 (sometimes known as long COVID) might develop depressive and anxiety disorder symptoms,At the time of writing this Article, the COVID-19 pandemic is ongoing and its full impact on mental health outcomes is not known. We continue to observe shifts in SARS-CoV-2 infection rates and human mobility as lockdown and stay-at-home orders are re-implemented or eased and COVID-19 vaccination programmes are rolled out. Our work is ongoing and will continue to be updated over the course of the COVID-19 pandemic. To inform this ongoing work, high quality surveys conducted during the COVID-19 pandemic are needed within regions that are not represented by available data. Researchers planning surveys during the pandemic should strive to align their sample representation and measures of mental health with existing pre-pandemic baseline estimates to ensure appropriate comparable data from before and during the pandemic. Where feasible, researchers should consider including diagnostic measures of mental disorders, alongside widely used screening questionnaires . With the addition of more estimates derived via diagnostic instruments, we could explore the robustness of (or correct for) our assumption that the predictive validity of screening questionnaires for diagnosis of probable cases is unchanged by the pandemic, and explore any shifts in the severity distribution among individuals diagnosed with major depressive disorder or anxiety disorders.Unlike other population shocks, COVID-19 has become global, disrupting many aspects of life for most, if not all, of the world's populations. Our analysis suggests that the impacts on the prevalence and burden of major depressive disorder and anxiety disorders were substantial, particularly among females and younger populations. Ongoing and additional mental health surveys are necessary to quantify the duration and severity of this impact. Unfortunately, even before the emergence of the COVID-19 pandemic, major depressive disorder and anxiety disorders were leading causes of disease burden, with the mental health-care system in most countries being under-resourced and disorganised in their service delivery. Therefore, tackling this increased mental health burden will present immediate challenges in most nations, but it is also an opportunity for countries to broadly reconsider their mental health service response. Recommended mitigation strategies should incorporate ways to promote mental wellbeing and target determinants of poor mental health exacerbated by the pandemic, as well as interventions to treat those who develop a mental disorder. Taking no action in the face of the estimated impact of the COVID-19 pandemic on the prevalence and burden of major depressive disorder and anxiety disorders should not be an option.code used in these analyses, please visit the GitHub page. Data sources are also listed by location and institution in the To download the C Adolph reports support from the Benifcus Foundation. A Flaxman holds stock in Agathos, and consults and advises Janssen, SwissRe, Sanofi, and Merck for Mothers on simulation modeling, outside of the submitted work. S Nomura reports support from the Ministry of Education, Culture, Sports, Science and Technology of Japan. All other authors declare no competing interests.


R/S configurations and optical activities (OAs) were chosen as symmetry-breaking agents for inducing chiral mesostructured BiOBr films (CMBFs) under hydrothermal conditions. Multiple levels of chirality with different handedness were identified in the CMBFs. Density functional theory (DFT) calculations and molecular dynamics (MD) simulations suggest that asymmetric defects in the Br–Bi tetragonal cone caused by physically adsorbed DSAs on the surfaces of the BiOBr crystals are the geometric basis for triggering the chiral twist in the BiOBr monolayer. Our findings provide new insights for understanding the origin of chirality and the chiral transfer mechanism underlying the assembly of achiral species.Chiral molecule-driven asymmetric structures are known to be elusive because of the intriguing chirality transfer from chiral molecules to achiral species. Here, we found that the chiral assembly of BiOBr is independent of the chirality of the organic molecular inducer but dependent on geometric structural matching between the inducer and inorganic species. Diastereoisomeric sugar alcohols (DSAs) with identical numbers of carbon chiral centers and functional groups but with different  The chirality transfer is dependent on geometrical matching between the chiral inducer and inorganic species. As expected from their names, d-Sor and d-Alt exhibit negative transmitted circular dichroism (TCD) signals, while l-Idi exhibits a positive TCD signal at wavelengths of 185–200 nm (θ ∝ εL − εR) at the particular absorption bands, which is determined by a combination vector of the electric dipole transition moment (μ) and magnetic dipole transition moment (m) induced by incident circularly polarized electromagnetic waves.37,38 Thus, the spectra can show deviations from the baseline that are positive, negative or zero, indicating their different chiralities.5–200 nm . The ord39 DSAs  surface and then gradually grow into dense films as the reaction proceeded  reflections of all CMBFs can be well indexed to the pure tetragonal phase of BiOBr (JCPDS No. 85-0862) (vide post).Here, CMBFs with different chiralities were fabricated through a hydrothermal method from a homogeneous solution composed of DSA, bismuth and bromide salts.s Fig. S1 were sel85-0862) . The grovide post).As shown in d-Sor and CMBFl-Idi exhibit right-handed tertiary vortices (d-Alt (vide post).vortices 2 and b2,s and black (DRCDB) backgrounds  and All ), and d-Man , respectively  and left-handed CMBFs were induced with six carbon DSAs of two mesomers  monolayer crystalline surface of BiOBr was chosen as a basis model due to its exposed essence analyzed by TEM results. DFT calculations show that linear DSAs interact with BiOBr monolayers by weak physical adsorption rather than covalent bonds, and the linear adsorption pattern parallel to the (001) crystal plane and along the X- or Y-direction is the most stable state . The BiOBr monolayer, which was originally a planar structure, rapidly underwent continuous twisting after 1 ns relaxation, and a left-handed helix was obtained for CMBFFig. S18c, which wFig. S18c.d-Sor and CMBFl-Idi, in contrast to CMBFd-Alt, which was considered as the secondary chirality  as an example, the absorption of d-Sor generated left-handed defects, which triggered the formation of left-handed primary BiOBr nanoflakes and right-handed secondary chiral arrangement of these primary nanoflakes. l-Idi with a configuration of  by changing the configuration of carbon 2 induced left-handed defects, which triggered the similar chirality as the d-Sor. Changing the configuration of carbons 3 and 4, the mesomeric Gal and All with a configuration of  and  were obtained, respectively. No chirality was formed. However, the d-Man with the configuration of  by changing the configuration of carbon 5 induced the formation of right-handed defects, which triggered the formation of right-handed primary BiOBr nanoflakes and left-handed secondary chiral arrangement of these primary nanoflakes, and this phenomenon could also be observed in the d-Alt  by changing the configuration of both carbons 3 and 5. Changing the conformation of any other two or three carbon chiral centres in a sugar alcohol molecule and the resulting molecule is enantiomerically identical to the molecule mentioned above.Therefore, the chiral center configuration of the DSA molecule plays an important role in determining the chirality of CMBFs. It determines the spatial geometrical matching of the DSA molecule and the BiOBr crystal surface, which further influences the multilevel chirality of BiOBr. Taking By summarizing the laws, it was found that the chirality of CMBFs was dependent on the geometric matching of BiOBr and DSA molecules at the adsorption interface rather than the DSA stereochemistry. When the hydroxyl groups at the positions of carbon atoms 3, 4 and 5 in the DSA molecule are aligned parallelly on the surfaces of BiOBr, left-handed primary chiral BiOBr nanoflakes are formed, while when the hydroxyl groups at the positions of carbon atoms 2, 3 and 5 are aligned anti-parallelly, right-handed primary chirality is formed. The primary chiral BiOBr nanoflakes are arranged in an opposite chiral arrangement to form the secondary chiral nanoplate. The tertiary chirality of CMBFs is induced by the chiral arrangements of DSA molecules under hydrothermal conditions. Therefore, the chiral molecules with multiple chiral centers could be used as symmetry-breaking agents to induce the desired chirality of materials by changing the configurations of the chiral centers. However, this principle may be different for different synthetic systems and materials, depending on the interactions of the material with the chosen chiral molecules.To the best of our knowledge, this is the first report describing chirality transfer from diastereoisomers to achiral inorganic species. The theoretical calculations reveal that the geometric matching and chiral defect densities could affect the tortuosity and pitches of the assembly of achiral inorganic nanoparticles. These insights not only provide a promising strategy for fabricating chiral inorganic nanostructures but also provide valuable information for understanding the origin of homochirality in organisms.Raw data are available upon request from the authors.K. D. carried out the experimental synthesis and SEM, XRD, and CD characterization studies; J. A. conducted the TEM measurement; Z. Q performed DFT calculations and MD simulations; K. D. is responsible for all data processing and creating the original draft and revising the manuscript under the supervision of Y. D., L. H., Z. Q., and S. C.There are no conflicts to declare.SC-013-D1SC05601H-s001


Is the addition of dapagliflozin to guideline-directed medical therapy cost-effective for the treatment of heart failure with reduced ejection fraction?In this economic evaluation of a simulated cohort of US adults with heart failure, adding dapagliflozin to guideline-directed medical therapy was projected to prolong survival by 0.63 quality-adjusted life-years while increasing lifetime costs by $42 800, producing an incremental cost-effectiveness ratio of $68 300 per quality-adjusted life-year. Results in individuals with and without diabetes were similar.These results suggest that widespread uptake of dapagliflozin for the treatment of heart failure with reduced ejection fraction has the potential to improve long-term clinical outcomes and is likely to meet conventional cost-effectiveness thresholds. This economic evaluation examined the cost-effectiveness of adding dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction in a simulated cohort of patients with or without diabetes. Heart failure with reduced ejection fraction produces substantial morbidity, mortality, and health care costs. Dapagliflozin is the first sodium-glucose cotransporter 2 inhibitor approved for the treatment of heart failure with reduced ejection fraction.To examine the cost-effectiveness of adding dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction in patients with or without diabetes.This economic evaluation developed and used a Markov cohort model that compared dapagliflozin and guideline-directed medical therapy with guideline-directed medical therapy alone in a hypothetical cohort of US adults with similar clinical characteristics as participants of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial. Dapagliflozin was assumed to cost $4192 annually. Nonparametric modeling was used to estimate long-term survival. Deterministic and probabilistic sensitivity analyses examined the impact of parameter uncertainty. Data were analyzed between September 2019 and January 2021.Lifetime incremental cost-effectiveness ratio in 2020 US dollars per quality-adjusted life-year (QALY) gained.The simulated cohort had a starting age of 66 years, and 41.8% had diabetes at baseline. Median (interquartile range) survival in the guideline-directed medical therapy arm was 6.8 (3.5-11.3) years. Dapagliflozin was projected to add 0.63  QALYs at an incremental lifetime cost of $42 800 , for an incremental cost-effectiveness ratio of $68 300 per QALY gained . Findings were similar in individuals with or without diabetes but were sensitive to drug cost.In this study, adding dapagliflozin to guideline-directed medical therapy was projected to improve long-term clinical outcomes in patients with heart failure with reduced ejection fraction and be cost-effective at current US prices. Scalable strategies for improving uptake of dapagliflozin may improve long-term outcomes in patients with heart failure with reduced ejection fraction. As heart failure is a leading cause of hospitalization in the US, dapagliflozin may improve health outcomes and reduce health care costs by averting heart failure hospitalizations downstream, but widespread uptake at a list price of $6188 per year of treatment could produce a large increase in pharmaceutical expenditures. A systematic cost-effectiveness evaluation from a US health care sector perspective would quantify the trade-off between increased health care costs and improved health outcomes and therefore help inform pricing and adoption strategies. This is particularly important for SGLT2 inhibitors because diabetes therapies have historically seen large manufacturer discounts, suggesting that actual prices faced by payers may be highly variable and subject to negotiation with manufacturers.9; and (2) dapagliflozin (10 mg once daily) added to GDMT. The analysis adopted a US health care sector perspective and a lifetime analytic horizon. Future costs and outcomes were discounted at 3% annually.10 We adhered to the recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine to the extent feasible.10 Given that the study relied on publicly available data sets, this was deemed to not be human participants research and institutional review board approval was not required per the Common Rule. This study was conducted independently from the commercial sponsor of the DAPA-HF trial.We developed a Markov cohort model to compare 2 treatment strategies among patients with HFrEF: (1) GDMT, comprised of an angiotensin converting enzyme inhibitor, an angiotensin-receptor blocker, or an angiotensin receptor neprilysin inhibitor, in addition to a β-blocker and a mineralocorticoid receptor antagonistModel creation and analyses were performed using TreeAge Pro Healthcare 2020 (TreeAge Software), and Microsoft Excel version 16 (Microsoft Corporation). Additional modeling details are provided in eMethods in the 2 of body surface were excluded. The cohort was stratified by baseline diabetes status to capture the heterogeneity of outcomes by diabetes status in the control arm of the DAPA-HF trial .26Key model inputs were derived from published primary and secondary analyses of the DAPA-HF, publicly available US regulatory review documents, published clinical and epidemiologic studies, national health care claims data, and the Medical Expenditure Panel Survey .4,11,12,11The model was calibrated to reproduce rates of 18-month survival, urgent heart failure visits, and HFrEF hospitalizations observed in the DAPA-HF trial. Therefore, hospitalizations for HFrEF exacerbations were more frequent in patients with diabetes compared with patients without diabetes, but rates of urgent care visits for heart failure were similar in the 2 groups .1111 The base case assumed that the effectiveness of dapagliflozin would be sustained over the lifetime of the patients, but a sensitivity analysis assumed a linear decline in effectiveness of dapagliflozin beyond the trial duration such that dapagliflozin would become ineffective 5 years after trial completion. The base case assumed that dapagliflozin would reduce the risk of incident diabetes among individuals without diabetes at baseline by 32%26; a sensitivity analysis assumed no reduction in the risk of incident diabetes.We assumed that the use of dapagliflozin would reduce HFrEF hospitalization, urgent care visits, and all-cause mortality as observed in the DAPA-HF trial (with the effect size stratified by patients’ diabetes status) .11 The b11 we did not model any additional costs or quality-of-life penalties caused by adverse drug events. As patients in the GDMT arm would already be receiving pills on a daily basis , we did not model any additional pill-related disutility .27 The base case assumed that patients on dapagliflozin would be adherent to the therapy; a sensitivity analysis examined the effect of nonadherence by incorporating a 0.27% monthly probability of discontinuing dapagliflozin for the first 2 years .4As there were no observed differences in safety outcomes in the DAPA-HF trial,28 This rate ratio was applied to the age-specific mortality in the general US population to estimate the age-specific survival in the control arms beyond trial completion . Next, we compared the observed mortality rate in the control arms in the last 6 months of the trial with the mortality rate in the age-matched US general population, yielding a mortality rate ratio of 8.66 in patients with HFrEF and diabetes and 4.88 in patients with HFrEF but without diabetes at baseline.The age-specific mortality rate in the intervention arms was estimated by applying the hazard ratio for all-cause mortality observed in the DAPA-HF trial to the control survival curves (separately for patients with or without diabetes). Additional modeling details are available in eMethods in the 7 so that the net price paid by payers is substantially lower than the list price. As recommended by the Second Panel on Cost-Effectiveness, our base case incorporated the drug cost reported in the Federal Supply Schedule ($4192 for a year’s supply in August 2020).15 In deterministic sensitivity analyses, we varied the annual cost of dapagliflozin from $953 (a heavily discounted net price at which dapagliflozin is available to some US payers) to $6188 .16 We also identified the cost at which the addition of dapagliflozin to GDMT would become cost-effective at thresholds of $50 000, $100 000, and $150 000 per quality-adjusted life-year (QALY) gained  was used in the DAPA-HF trial to measure the heart failure–specific health status of patients at baseline and at 4-month and 8-month follow-up.34 but also examined the value of the intervention per the cost/value methodology recommendations of the American College of Cardiology and American Heart Association .35 In addition to the probabilistic analyses described above, we performed deterministic sensitivity analyses to reflect uncertainty in key input parameters by varying 1 input at a time across the range specified in Our primary outcome was the incremental cost-effectiveness ratio (ICER) of adding dapagliflozin to GDMT compared with GDMT alone (in US dollars per life-year gained and US dollars per QALY gained), for the entire cohort and stratified by baseline diabetes status. We ran 10 000 simulations using input parameter values randomly drawn from prespecified statistical distributions to generate 95% uncertainty intervals (UI) for key outcome measures and to determine the proportion of simulations in which dapagliflozin would be cost-effective at varying willingness-to-pay thresholds. We assumed a cost-effectiveness threshold of $100 000 per QALY gained,The simulated cohort in the model had a starting age of 66 years, and 41.8% of patients in the simulation had diabetes at baseline. Median (interquartile range) undiscounted survival in the GDMT arm was 6.8 (3.5-11.3) years . The model replicated the rates of all-cause mortality, HFrEF hospitalization, and urgent heart failure visits observed in the DAPA-HF trial   to 0.07  per person-year and improve quality-adjusted survival by 0.63  QALYs . Patientlations) .The cost-effectiveness of adding dapagliflozin to GDMT compared with GDMT alone was sensitive to the annual cost of dapagliflozin , the ass35 Remarkably, the ICER was similar in patients with or without diabetes at baseline. This is because, compared with patients without diabetes, patients with diabetes receive a larger clinical benefit (given their higher baseline risk of major adverse cardiovascular events) but also accrue higher health care costs for every year of prolonged survival. The observation that dapagliflozin therapy was cost-effective in 94% of 10 000 probabilistic simulations suggests that our findings are robust across a wide range of estimates of key model parameters.In a simulation model of HFrEF in the US, we found that the addition of dapagliflozin to GDMT was projected to improve quality-adjusted survival in patients with HFrEF, and its use would be cost-effective relative to GDMT alone at 2020 Federal Supply Schedule prices. The lifetime ICER of $68 300 per QALY gained compared with GDMT alone would make the use of dapagliflozin for the treatment of HFrEF an “intermediate-value” intervention per the American College of Cardiology/American Heart Association Cost/Value framework.39 For instance, our estimates of long-term effectiveness of dapagliflozin (a gain of 0.63 QALYs) is comparable to the gain of 0.48 to 0.50 QALYs in the British and European models, but somewhat higher than the gains in the Chinese (0.38) and Australian (0.29) models. The annual cost of dapagliflozin is substantially higher in the US compared with other health systems .39 Furthermore, we included all background health care costs (in line with current recommendations) whereas the European analysis only included costs related to diabetes and heart failure.10 As a result, despite comparable health gains, the ICER was substantially higher in our analysis .To our knowledge, this is the first systematic cost-effectiveness analysis of dapagliflozin for patients with HFrEF from a US health care sector perspective. Prior analyses performed from the perspective of other health systems  also projected dapagliflozin to be cost-effective in those health systems, but substantial cross-country differences in drug and health care costs and HFrEF outcomes preclude direct comparisons.40 Treatments for HFrEF may potentially have an outsized impact on health care budgets because a large number of patients may be eligible for lifelong therapy, which necessitates the prioritization of cost-effective therapies. However, the slow initial uptake of sacubitril-valsartan suggests that evidence of cost-effectiveness alone cannot surmount the constellation of patient-, physician-, and health system–related barriers that can impede widespread adoption of new therapies.42 Key among them is the fragmented US health care system, where financial incentives for various stakeholders are frequently misaligned. For instance, pharmaceutical and medical coverage may be offered by different payers, so that the pharmaceutical plan does not have the incentive to pay for high-cost medications that prevent hospitalizations, the savings of which accrue to the medical plan. Even when insurers are responsible for both medical and pharmaceutical benefits, as with many commercial insurers and Medicare Advantage plans, payers may not benefit from savings that occur several years in the future, at which point the patient may have switched to a different plan. As a result, payers frequently impose prior authorization requirements or high copayments to restrict uptake of high-cost therapies. Copayments are typically based on the list price of the drug before any manufacturer discounts and vary from month-to-month based on the benefit structure of the insurance plan43; they therefore pose a substantial financial burden on patients and adversely affect persistence. Until policy reforms address the misalignment of financial incentives for payers in the US health system and cap or eliminate copayments for cost-effective therapies ,44 clinicians should discuss medication affordability with their patients at regular intervals in order to preempt cost-related nonadherence.Cost-effectiveness analysis provides a formal mechanism to quantify the gains or losses in population health as a result of a particular intervention.46 3 factors justify our cautious optimism that the experience with SGLT2 inhibitors will be different. First, diabetes therapies, including SGLT2 inhibitors, receive some of the largest manufacturer discounts observed in the US pharmaceutical market, and these discounts have fully offset increases in list prices in recent years.7 Second, the availability of several SGLT2 inhibitors with proven benefit in HFrEF treatment may allow payers to negotiate better prices in return for preferential formulary placement.47 As a result, the majority of US payers will be able to continue to access at least 1 SGLT2 inhibitor at a reasonable price. Finally, recently proposed policy reforms would force payers to pass on at least some of the manufacturer discounts to patients.7 Collectively, these changes could substantially lower total costs for payers and out-of-pocket costs for patients, and expand access to this cost-effective therapy.Although total and out-of-pocket costs have slowed uptake of novel cardiovascular therapies in the recent past,48 The price of dapagliflozin is likely to decline after expiration of the market exclusivity period and entry of multiple generics. We modeled contemporary US prices so that our findings could inform current pricing and uptake. We explored a wide range of drug prices in sensitivity analyses, but our findings should be updated when new data on pricing, effectiveness, or safety become available. We used a novel approach to convert KCCQ-OSS to health-related quality-of-life. However, any bias in the conversion would not have materially affected our findings as it would affect both the control and intervention arms, and the health gains in the dapagliflozin arm were primarily because of improved survival .This study had several limitations. The efficacy and safety of dapagliflozin were estimated from a single randomized clinical trial with a mean follow-up of 18 months. We estimated long-term survival based on a combination of trial and vital statistics data, and examined alternative survival models in sensitivity analyses, but our results should be updated when data from longer follow-up become available. We did not examine heterogeneity other than by diabetes status . However, the goal of this study was to evaluate population-level effects on health and health care spending, which are adequately reflected in our use of population-level estimates of risk, benefit, and cost. If future studies demonstrate that treatment with dapagliflozin reduces the need for kidney replacement therapy in patients with HFrEF, our model would have underestimated the economic benefits of SGLT2 inhibitor therapy.In a simulation model calibrated to the results of the DAPA-HF trial, adding dapagliflozin to GDMT was projected to produce substantial clinical gains in patients with HFrEF, with an acceptable increase in associated costs. At a willingness-to-pay threshold of $100 000 per QALY gained, treatment with dapagliflozin, at an annual cost of $4192, would be cost-effective therapy in patients with HFrEF regardless of whether treated patients have diabetes. Scalable strategies to ensure affordable access to and widespread uptake of dapagliflozin are urgently needed.


COVID-19 pandemic and associated supply-chain disruptions emphasise the requirement for antimicrobial materials for on-demand manufacturing. Besides aerosol transmission, SARS-CoV-2 is also propagated through contact with virus-contaminated surfaces. As such, the development of effective biofunctional materials that can inactivate SARS-CoV-2 is critical for pandemic preparedness. Such materials will enable the rational development of antiviral devices with prolonged serviceability, reducing the environmental burden of disposable alternatives. This research reveals the novel use of Laser Powder Bed Fusion (LPBF) to 3D print porous Cobalt-Chromium-Molybdenum (Co-Cr-Mo) superalloy with potent antiviral activity . The porous material was rationally conceived using a multi-objective surrogate model featuring track thickness ( Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the third human coronavirus ,2,3,4 thMany disinfectants such as household bleach, hand soap solution, ethanol, povidone-iodine, chloroxylenol, chlorhexidine and benzalkonium chloride have shown potent antiviral activity against SARS-CoV-2 so far . Thus, nEscherichia coli [Candida albicans [Staphylococcus aureus (MRSA) and the methichillin-resistant Staphylococcus epidermidis (MRSE).Cranberry extracts have shown antiviral activity against other enveloped viruses such as the herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) due to the presence of antimicrobial A-type proanthocyanidins (PACs) that provoke alterations of their envelope glycoproteins. However, although HSV-1 and HSV-2 belong to a different Baltimore group I  than SARhia coli  and antialbicans , we hypoThe existence and evolution of SARS-CoV-2 coronavirus variants are spreading more effectively than earlier ones ,43 due tThe development of effective materials with antiviral capacity is critical in the development of reusable protective devices such as mask filters, high-efficiency particulate air filters (HEPA) and other antiviral devices . AntivirThe development of antiviral face mask that contain porous filters or antiviral face shields made of antiviral materials capable of inactivating SARS-CoV-2 is an effective strategy to provide extra protection against the COVID-19 transmission ,27,28,55According to Doremalen et al. , aerosolWhen it comes to 3D printed metallic materials, only Cu coating deposited using cold spray have reported 99.2% virus inactivation at 5 h . AntivirBacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Shigella flexneri, Proteus vulgaris and Staphylococcus aureus. Recently, Kota et al. [S. aureus and P. acnes proliferation both in vitro and in vivo infection models. Overall, Co-based alloys seem to offer a broad-spectrum antimicrobial possibility making them worthy candidates to explore for potential antiviral activity. Currently, literature on the antiviral properties of Co-based alloys is scarce let alone their performance against SARS-CoV-2.According to Hatamie et al. , cobalt a et al.  showed CThis research, therefore, is the first step towards drastically improving the state-of-the-art antiviral alloys against SARS-CoV-2 at the interface of 3D printing and surrogate modelling. The research reveals the first Co-Cr-Mo porous material with superior antiviral activity that can be 3D printed on-demand where the innovation pipeline is kept open. The study is directed towards a process-structure–property relationship where both the material and its processing parameters collectively inform an optimum functional architecture. The influence of the LPBF 3D printing process on the structure-property relationship at the sub-micrometre is also analysed to make the digital and on-demand fabrication of the antiviral material accessible and easily scalable.Overall, the development, analysis, and optimisation Co-Cr-Mo LPBF porous superalloy that feature high antiviral activity against an enveloped virus such as SARS-CoV-2 are demonstrated for the first time. The effect of LPBF process parameters on the characteristics of the porous architecture such as the thickness of the laser melted track , coefficient of determination 2 also indicates that the surrogate model is accurate for all the responses analysed.The accuracy of the surrogate models was evaluated using the analysis of variance (ANOVA) technique where the significant model terms are as summarised in te model . A closeThe relationship between actual responses and those based on the surrogate model are shown in When the laser scans over the powder layer, the absorbed energy from the laser beam heat the Co-Cr-Mo particles creating a melt pool. Heating, time-evolution of the melt pool, and the solidification process depend on the powder and process characteristics . The proAlthough there is a consistent increase in terature ,100,101.When it comes to the influence of laser power on the pore size b, a lineThe scanning rate is the speed at which the laser spot travels across the powder bed. The first consideration when choosing the parameter is to achieve a consistent, fully dense track. For any given build, the powder characteristics and layer thickness are constant parameters. As such, using a fixed laser spot size leaves laser power, scanning rate, and hatch spacing as the process variables. Generally, all three of these parameters required being carefully controlled, for example, a high scanning rate can result in insufficient energy at the powder bed. This will lead to an unmelted or partially melted track featuring ‘lack of fusion’ porosity. In contrast, lowering the scanning rate leads to a high energy density that can overheat the melt pool, causing deeper energy penetration leading to keyhole formation and an unstable track. Therefore, there is an optimum scanning rate window that achieves a continuously fused material track. A fully dense material track is generally the aim, while the target of laser processing in this study, however, was to identify the thinnest most stable track.The effect of scanning rate on the track thickness and the pore shape were analysed at a constant laser power and hatch spacing of 110 W and 0.37 mm respectively. The entire scanning rate range resulted in fully melted tracks. However, at a low scan rate, the laser interacts with the powder longer resulting in a thicker track. It can be seen from Studies by Bayat et al. , King etOverall, the highest track thickness of 121 µm was observed at a scanning rate of 825 mm/s which reduced by 22% when the scanning rate was increased to 1025 mm/s. This is because as the scanning rate increases, the residence time of the laser per unit area reduces engaging in a lesser number of powdered particles leading to smaller melt-pool width. Nevertheless, The next level of complexity is the melting of multiple tracks to fill the designated part area based on the design. The part area is build-up of adjacent tracks, where their overlap distance is dictated by the hatch spacing. It is measured from the centre of one laser spot to the adjacent. To have process-induced porosity such as the ones targeted in this study, a large hatch spacing is required. Otherwise, the laser tracks will overlap resulting in a fully dense part.Evaluating Laser power, scanning rate, and hatch spacing are the three variables considered in this study. Although these parameters can be varied independently, their interaction has the most significant effect on the melt pool characteristics. Therefore, studying the interaction effects between the process parameters and identifying their order of influence is critical in identifying the optimum parametric combination. The thickness of Co-Cr-Mo track has a significant influence on the overall pore size and the surface area achievable. Ideally, a stable but thinner track offers a higher opportunity for functional porosity as opposed to thicker tracks. As such identifying and accurately characterising the interaction effects between the LPBF process parameters is carried out to inform the optimised microporous material.The interaction effects between the process parameters affecting the Co-Cr-Mo track thickness are shown in As shown in The pore diameter is primarily dictated by the hatch spacing, as evident from The influence of process parameters on both track thickness and pore diameter reveals that the interaction effects can be used to simplify the Co-Cr-Mo microporous printing process. Overall, the targeted porosity can be achieved by carefully modulating the process parameters, which allows ease of customisability, and scalability. The influence of the process parameters on the material has also been analytically represented, which allows identifying the most optimal parametric combination based on the requirement. For the study under consideration a fine  that meets the desirable range for each response Co-Cr-Mo samples were additively manufactured using the predicted LPBF process parameter combinations listed in The results from the experimentally measured optimum Cu-W-Ag microporous material when compared to the surrogate model can be seen to be in good agreement as listed in n = 3) against the biosafe vrial model of SARS-CoV-2. The antiviral performance is summarised in The optimised microporous Co-Cr-Mo material was printed, and antiviral tests were performed  against phage phi 6 used as enveloped RNA viral model of SARS-CoV-2. The antiviral performance of the Co-Cr-Mo porous material is also superior to the current state-of-the-art copper , which swt. %) of the atomised Co-Cr-Mo alloy used as feedstock at the powder bed. The LPBF process parameters namely the laser power   at the pThe parametric combination of the randomised training matrix for the surrogate model was conceived based on the Box-Behnken design (BBD) principle. BBD was chosen as it allows for higher-order response surfaces using fewer required runs than a normal factorial technique in the training matrix. As such it is an alternative to the The limits of the LPBF process parameters considered for the coded BBD factorial matrix are summarised in The steps that led to the development of an accurate surrogate model is summarised in Pseudomonas syringae from the DSMZ-German collection of microorganisms and cell cultures (DSM 21482) in solid Tryptic Soy Agar . Post culture, the bacteria were incubated in liquid Tryptic Soy Broth  at 120 rpm and at 25° C. Pseudomonas phage phi6 titration was carried out in accordance with specifications for phage infection.The phage phi6 host culture was carried using Pseudomonas phage phi6 can be used as models of SARS-CoV-2 considering biosafety [Phi6 is a double-stranded RNA virus with three-part, segmented, totalling ~13.5 kb in length. This type of lytic bacteriophage belongs to Group III Baltimore classification and was chosen as SARS-CoV-2 viral model (Group IV: positive-sense single-stranded RNA viruses) as it features a lipid membrane around their nucleocapsid. According to Kitajima et al.  low pathiosafety . Furtheriosafety .vol.%) solution for 5 min at 25 °C and UV radiated for an hour on each side.LPBF processed Co-Cr-Mo porous samples  and 5mM CaCl2 were introduced to the phage-bacteria mix. The mixture was poured on TSA plates that were incubated for 24–48 h in an oven at 25 °C.The antiviral activity of the samples was measured at 30 min and five hours of contact with the biosafe viral model. A 50 μL volume of phage suspension in TSB was introduced into each sample at a concentration of This study demonstrates the use of Laser Powder Bed Fusion for on-demand manufacturing of a novel Co-Cr-Mo porous material that shows superior antiviral activity outperforming common antiviral metals such as silver and copper. The paper reveals a surrogate model that allows porosity personalisation without the need for complex geometry data. This is achieved through controlling the LPBF process parameters such as laser power, scanning rate and hatch spacing. The proposed methodology simplifies the data requirement and pre-processing often required for printing porous materials. The surrogate model developed in this study showed that the most significant parameters for Co-Cr-Mo track thickness (


Covid-19 pandemic has had huge impact on health care system and put the health care system under strain, so efforts made to minimize the elective surgeries however some surgeries especially those for high risk malignant tumors cannot be postponed.The aim of this case report is to highlight the importance of screening cancer patients and those with co-morbidities such as renal impairment for Covid-19 and encouraging them to get vaccinated before undergoing elective surgeries.We report a case of an 80 year old male patient with renal impairment who developed Covid-19 infection after transurethral resection of high grade transitional cell carcinoma of urinary bladder.Although intra-hospital contagion of Covid-19 is not rare, increased risk of acquiring Covid-19 among cancer patient particularly if they have co-morbidities like renal impairment should be kept in mind and strict protective measures for Covid-19 for those patients should be done before, during and after the procedure.We theorized that patients with high grade transitional cell carcinoma of urinary bladder should be screened for Covid-19 and get vaccinated before the procedure. •High grade bladder cancer needs strict and close cystoscopic surveillance.•Cancer patients are vulnerable to develop severe Covid-19 infection.•Patients should be screened for Covid-19 before elective procedures.•Covid-19 vaccination is a priority before elective procedures. The surgery was performed by an experienced senior urologist.The histopathology showed high grade T1 transitional cell carcinoma consistent with T1N0M0 stage .Fig. 2MiOn the second post-operative day, a new creatinine was same as baseline (1.9 mg/dl) and the patient was doing well so he discharged to home.On the third postoperative day, at his home the patient started to feel hotness, chills and rigors, with no cough and no new urinary symptoms.On the fifth postoperative day, a new Covid-19 test was done at another hospital and it was positive.On the seventh postoperative day, he started to have shortness of breath, productive cough and generalized weakness, so he presented to another hospital and found to have raised creatinine (8 mg/dl), he was offered admission but he preferred to observe himself at home.On the ninth postoperative day, he came to emergency department at our hospital and found to have serum creatinine of (9 mg/dl), a new computed tomography scan showed no new finding compared to the previous one .Fig. 3ThThe nephrologist advised hemodialysis for the patient and to be admitted to intensive care unit, there were no available intensive care unit bed at our hospital, so he was transferred to another hospital where hemodialysis was performed for him.One month after the procedure, the patient is still hospitalized under medical care due to Covid-19 infection and its complications.This case has been reported in line with the SCARE 2020 criteria .3Bladder cancer is one of tenth most common cancer worldwide, with an estimated 549,000 new cases and 200,000 deaths each year [Covid-19 infection is a serious pandemic with high morbidity and mortality . That afIt is well known that bladder cancer especially high risk group need strict cystoscopic surveillance to pick the disease up before invasion of the muscularis propria with its serious sequel and increased need for cystectomies and high risk of metastasis . So a baIt is believed that patients with malignancy are at increased risk to develop Covid-19 . Other sThe relationship between cancer and increased risk of severe Covid-19 infection may be explained by co morbidities, aging, and innate and cognate immunosuppression .It is believed that Covid-19 virus trigger apoptosis and necroptosis of T lymphocytes and reduce lymphopoietin and interleukin-7 as an immunosuppressive strategy ,11.A lot of authors emphasized the interplay between renal impairment and severe Covid-19 infection, and the effect of the baseline kidney impairment on the prognosis and intensive care unit admission rate of Covid-19 patients .4Increased risk of Covid-19 transmission among cancer patients should be kept in mind particularly if they have co-morbidities like renal impairment and good protective measures should be taken. We recommend that patients with bladder cancer should be screened for Covid-19 infection and get vaccinated before the procedure and we adopted this policy in our institution.None.The authors declare that they have no conflict of interest to disclose.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Mujalli Murshidi: main surgeon, concept, initiation of the idea, critical analysis, revision of the text and preparation of the final text.Mohammad Ihmeidan: concept, preparation of the manuscript draft, computer work, and preparation of the final text.Muayyad Mujalli Murshidi: concept, preparation of the manuscript.Rand Mujalli (Sheik Moh'd) Murshidi: concept, preparation of the manuscript, and critical analysis.Raghad Mujalli Murshidi: concept, preparation of the manuscript, and critical analysis.Not applicable.Mujalli Murshidi.Mohammad Ihmeidan.Not commissioned, externally peer-reviewed.The authors declare that they have no conflict of interest to disclose.


With advances in allogeneic hematopoietic stem cell transplant , disease relapse has replaced transplant-related mortality as the primary cause of treatment failure for patients with acute myeloid leukemia (AML). The efficacy of allo-HCT in AML is a consequence of a graft-versus-leukemia (GVL) effect that is mediated by T lymphocytes, and unique mechanisms of immune evasion underlying post-allo-HCT AML relapses have recently been characterized. Relapsed AML following allo-HCT presents a particularly vexing clinical challenge because transplant-related toxicities, such as graft-versus-host (GVHD) and infections, increase the risk of treatment-related morbidity and mortality. In general, the prognosis of relapsed AML following allo-HCT is poor with most patients failing to achieve a subsequent remission and 2-year survival consistently <15%. The two factors that have been found to predict a better prognosis are a longer duration of post-transplant remission prior to relapse and a lower disease burden at the time of relapse. When considered in combination with a patient’s age; co-morbidities; and performance status, these factors can help to inform the appropriate therapy for the treatment of post-transplant relapse. This review discusses the options for the treatment of post-transplant AML relapse with a focus on the options to achieve a subsequent remission and consolidation with cellular immunotherapy, such as a second transplant or donor lymphocyte infusion (DLI). While intensive reinduction therapy and less intensive approaches with hypomethylating agents have long represented the two primary options for the initial treatment of post-transplant relapse, molecularly targeted therapies and immunotherapy are emerging as potential alternative options to achieve remission. Herein, we highlight response and survival outcomes achieved specifically in the post-transplant setting using each of these approaches and discuss how some therapies may overcome the immunologic mechanisms that have been implicated in post-transplant relapse. As long-term survival in post-transplant relapse necessarily involves consolidation with cellular immunotherapy, we present data on the efficacy and toxicity of both DLI and second allo-HCT including when such therapies are integrated with reinduction. Finally, we provide our general approach to the treatment of post-transplant relapse, integrating both novel therapies and our improved understanding of the mechanisms underlying post-transplant relapse. Allogeneic hematopoietic stem cell transplant  represents the most effective consolidation strategy to prevent disease relapse for the majority of adult acute myeloid leukemia (AML) patients who achieve remission. Patients with intermediate or poor-risk cytogenetics comprise more than 90% of all newly diagnosed AML patients , and myeAmong AML patients who relapse following allo-HCT, the single factor that most consistently predicts subsequent survival is the post-transplant remission duration. In retrospective analyses, the Center for International Bone Marrow Transplant Registry (CIBMTR) demonstrated a 3-year OS of just 4% among AML patients relapsing within 6 months of allo-HCT , while tThere is compelling evidence to support a GVL effect in AML that is mediated by T lymphocytes and correlates with the development of GVHD. The occurrence of both acute and chronic GVHD following transplant has been shown to lead to a reduced risk of post-transplant relapse , 12. Third of relapsed patients, and donor lymphocytes do not respond to these relapsed leukemic blasts in vitro (+Eomes+T-bet-) predicts relapse, and memory T cells in relapsing patients have increased expression of inhibitory receptors when compared to those who maintain remission at one year  that may increase with additional agents. In prospective randomized trials in relapsed/refractory AML, the addition of a second agent to high-dose cytarabine leads to an increased response rate without yielding a statistically significant improvement in OS , 23, 33.Hypomethylating agents (HMAs), specifically azacitidine and decitabine, serve as the backbone of lower intensity approaches to reinduction therapy for post-transplant relapse based on their known, modest efficacy in AML, and pre-clinical data suggesting that they can potentially enhance the GVL effect without exacerbating GVHD. In older patients (age ≥65 years) with newly diagnosed AML, azacitidine yields remission in 24.8% of patients and improves OS compared to conventional care regimens (CCR) when censoring for subsequent therapy . In addiWhile most large studies describing treatment with HMAs for post-transplant relapse include response assessment following subsequent DLI, it is clear that HMAs can be effective as single agents with particular efficacy as an early intervention for molecular relapse. In a series of ten patients with AML and MDS who relapsed a median of 16 months after transplant (range 0-132 months), Bolaños-Meade et al. demonstrated a CR rate of 60% with azacitidine without unexpected or severe toxicities and survival >1 year in 5 patients of whom only 2 received subsequent DLI . While t2 daily on days 1-7 or decitabine 20 mg/m2 daily on days 1-5). A large German series of patients treated with azacitidine for post-transplant relapse demonstrated that duration of post-transplant remission (>=6 months vs. <6 months) and the type of relapse (molecular vs. morphologic) could be used to stratify patients into three groups with markedly different rates of remission (71% for late molecular relapse vs. 29% for early morphologic relapse) and OS (2-year OS: 64% for late molecular relapse vs. 27% for early morphologic relapse)  are much more modest in spite of the frequent addition of DLI. Four studies of HMAs for morphologic post-transplant relapse in which the majority of patients had relapsed within a year of transplant and received DLI demonstrate remission rates of 14-17% with 2-year OS of 11-16% –56. Thesrelapse) . As the While pre-clinical evidence supports a role for HMAs in enhancing the GVL effect, the potential impact of BCL-2 inhibition on the GVL effect is unclear, but the remarkable efficacy of the BCL-2 inhibitor venetoclax in combination with HMAs for newly diagnosed AML in the elderly suggests that this could be a viable strategy for the treatment of post-transplant relapse. In a murine transplant model, pre-transplant NK cell depletion through BCL-2 inhibition/knock-out leads to improved engraftment, and also improves survival without worsening GVHD in mice inoculated with an MLL-rearranged AML that is insensitive to BCL-2 inhibition . HoweverIn practice the rates of serious and fatal infectious complications have proven much higher in post-transplant and relapsed/refractory than newly diagnosed AML patients treated with HMAs and venetoclax, but the regimen consistently induces remissions post-transplant, even in the absence of DLI. When used in the post-transplant setting, the incidence of fatal infectious complications in patients treated with HMAs and venetoclax is 16%, while the incidence of invasive fungal infections with such regimens more broadly in the relapsed/refractory setting is 19% , 62. Thu+ T cells and regulatory T cells, leading to reduced IL-2 and IFN-gamma production, which can be reversed by treatment with azacitidine and lenalidomide , FLT3 (28%), DNMT3A (26%), and IDH1/IDH2 (20%) with roughly 7% being IDH1 and 13% being IDH2 , which is defined as leukemia that has progressed from an antecedent hematologic disorder or is related to prior therapy with cytotoxic agents or radiation  of 41.6% without any differences in response noted based on most baseline clinical characteristics, which included prior allo-HCT . FurtherMutations in the tumor suppressor gene TP53 are frequent in AML patients with adverse cytogenetics and confer an extremely poor prognosis even with allo-HCT with subsequent relapse rates of 60% . Howeverin vitro and in vivo.  and represent a promising modality for the treatment of post-transplant, relapsed AML. Among patients with ALL, response rates to CD19-targeted CAR T cells and 12-month overall survival are similar regardless of prior receipt of allo-HCT . ImportaThe importance of KIR mismatching in preventing AML relapse was initially reported in patients undergoing haploidentical allo-HCT , but mornd transplant over DLI as consolidation therapy in certain patients. However, there is a lack of compelling data to guide the choice between these two options as consolidative cellular immunotherapy in most AML patients with post-transplant relapse. A retrospective study of 418 patients from the EBMT attempted to compare outcomes with second transplant versus DLI for AML and demonstrated similar 5-year overall survival (19% for 2nd transplant vs. 15% for DLI), although patients receiving 2nd transplant were significantly younger (median age 43 vs. 49), more likely to have achieved remission prior to cellular therapy (38.7% vs. 18.1%), and had a significantly longer interval from 1st transplant to relapse (median 348 days vs. 211 days). Notably, the incidence of NRM at 2 years was significantly higher among patients who received second transplant (26% vs. 9%) as was the incidence of grade 2-4 aGVHD at day +100 after intervention (37% vs. 20%), but there were no differences in the incidence of cGVHD  following second transplant were transplant with active disease versus CR  and duration of remission >13.2 months following the first transplant  without appreciable differences based on donor type . Unsurprof cGVHD . Based ond allogeneic transplant should be considered. However, this must be approached with caution, as a history of grade 2-4 acute GVHD prior to a second transplant or DLI has been shown to lead to significantly increased NRM and poorer survival compared to patients without such a history  are detected. . Another history .In patients without active or unresolved complications of GVHD who suffer a post-transplant relapse, treatment begins with the withdrawal of immunosuppression. However, this is rarely an effective strategy in isolation, so additional treatment is indicated. Given the lack of a standard-of-care approach in patients with post-allo-HCT relapse, enrollment on a clinical trial is preferred. nd transplant is indicated, as there is not currently any data to suggest that such responses are durable in the absence of cellular immunotherapy. For patients with persistent leukemia despite treatment of post-transplant relapse and reasonable fitness, DLI or a second transplant with active disease still may be an option given a 5-year survival of 11% with either therapy in this scenario (If a response is achieved following intensive; lower-intensity; or targeted therapy, then subsequent cellular immunotherapy with DLI or a 2scenario . Howevernd transplant with haplotype switch for patients who have relapsed after haploidentical transplant with leukemic blasts demonstrating loss of the mismatched haplotype. Thus advancements in the laboratory may help to guide our use of the expanding options for the treatment of post-allo-HCT relapse of AML.Ultimately, the recent proliferation of novel agents for the treatment of AML including both targeted therapies and immunotherapies, which may both enhance the GVL effect, is altering the landscape for treatment of post-allo-HCT AML relapse. This review highlights the unmet need for further studies in this area, especially as increases in the frequency of allo-HCT for AML coupled with decreases in NRM due to improvements in supportive care and the use of reduced-intensity conditioning place more patients at risk for post-transplant relapse. As we continue to better understand the immunologic mechanisms underlying the GVL effect, some of these novel therapies may serve to enhance it without exacerbating GVHD. Furthermore, a better understanding of the immunologic mechanisms underlying post-transplant relapse may facilitate the rational selection of treatment strategies to overcome those mechanisms such as 2JW and IG contributed equally to the conception of the manuscript. JW drafted the initial manuscript. IG and LL revised the initial draft. JW, LL, and IG agreed upon the final contents of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by NIH grant P30 CA06973.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.