Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation.

Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. High-affinity cells are proposed to preferentially select into this compartment, potentiating the immune response. We used single-cell RNA-seq to track the germinal center (GC) development of Ighg2A10 B cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites, we identified 3 populations of cells in the GC light zone (LZ). One LZ population expressed a gene signature associated with the initiation of PC differentiation and readily formed PCs in vitro. The estimated affinity of these pre-PC B cells was indistinguishable from that of LZ cells that remained in the GC. This remained true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. These findings suggest that the initiation of PC development occurs via an affinity-independent process.

Abnormal higher-order network interactions in Parkinson's disease visual hallucinations.

Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby dysfunctional communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between-functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques-diffusion-map embedding and t-distributed stochastic neighbour embedding (t-SNE)-to resting state functional MRI data, in order to characterize the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy control subjects. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions, suggesting an additional layer of complexity in the functional brain network abnormalities implicated in hallucinations, which was not apparent in traditional functional connectivity analyses. Together, the results confirm abnormal brain organization associated with the hallucinating phenotype in Parkinson's disease and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.

Possibly pathogenic bacteria in aerosols and foams as a result of aeration remediation in a polluted urban waterway.

Newtown Creek is a tributary of the Hudson River Estuary. It has a legacy of both industrial pollution and sewage pollution and has been designated a Superfund site. To ameliorate the chronically low levels of dissolved oxygen detected in the Creek, the New York City Department of Environmental Protection has been installing aerators. The abundance of various bacteria in the aerosols, foams, and water, at two sites in the Creek, was studied before, during, and after the aeration process. Additionally, aerosols and dispersed foams created by the aeration process were sampled and cultured to determine what unique taxa of bacteria could be grown and identified. Taxa including Actinobacteria and Firmicutes were prevalent in cultures taken from aerosols, whereas Gammaproteobacteria were prevalent in cultures taken from foam. Campylobacteria was found to have a significant presence in both samples taken after the aerators were turned off. These taxa include potentially pathogenic bacteria and are therefore of particular concern.

Sleep spindle architecture associated with distinct clinical phenotypes in older adults at risk for dementia.

Sleep spindles are a hallmark of non-REM sleep and play a fundamental role in memory consolidation. Alterations in these spindles are emerging as sensitive biomarkers for neurodegenerative diseases of ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate the functional role of these distinct electroencephalographic oscillations and the pathophysiology of sleep and neurodegenerative disorders. Here, we use a data-driven approach to examine the sleep, memory and default mode network connectivity phenotypes associated with sleep spindle architecture in older adults (mean age = 66 years). Participants were recruited from a specialist clinic for early diagnosis and intervention for cognitive decline, with a proportion showing mild cognitive deficits on neuropsychological testing. In a sample of 88 people who underwent memory assessment, overnight polysomnography and resting-state fMRI, a k-means cluster analysis was applied to spindle measures of interest: fast spindle density, spindle duration and spindle amplitude. This resulted in three clusters, characterised by preserved spindle architecture with higher fast spindle density and longer spindle duration (Cluster 1), and alterations in spindle architecture (Clusters 2 and 3). These clusters were further characterised by reduced memory (Clusters 2 and 3) and nocturnal hypoxemia, associated with sleep apnea (Cluster 3). Resting-state fMRI analysis confirmed that default mode connectivity was related to spindle architecture, although directionality of this relationship differed across the cluster groups. Together, these results confirm a diversity in spindle architecture in older adults, associated with clinically meaningful phenotypes, including memory function and sleep apnea. They suggest that resting-state default mode connectivity during the awake state can be associated with sleep spindle architecture; however, this is highly dependent on clinical phenotype. Establishing relationships between clinical and neuroimaging features and sleep spindle alterations will advance our understanding of the bidirectional relationships between sleep changes and neurodegenerative diseases of ageing.

Development and validation of an artificial intelligence based screening tool for detection of retinopathy of prematurity in a South Indian population.

Purpose: The primary objective of this study was to develop and validate an AI algorithm as a screening tool for the detection of retinopathy of prematurity (ROP). Participants: Images were collected from infants enrolled in the KIDROP tele-ROP screening program. Methods: We developed a deep learning (DL) algorithm with 227,326 wide-field images from multiple camera systems obtained from the KIDROP tele-ROP screening program in India over an 11-year period. 37,477 temporal retina images were utilized with the dataset split into train (n = 25,982, 69.33%), validation (n = 4,006, 10.69%), and an independent test set (n = 7,489, 19.98%). The algorithm consists of a binary classifier that distinguishes between the presence of ROP (Stages 1-3) and the absence of ROP. The image labels were retrieved from the daily registers of the tele-ROP program. They consist of per-eye diagnoses provided by trained ROP graders based on all images captured during the screening session. Infants requiring treatment and a proportion of those not requiring urgent referral had an additional confirmatory diagnosis from an ROP specialist. Results: Of the 7,489 temporal images analyzed in the test set, 2,249 (30.0%) images showed the presence of ROP. The sensitivity and specificity to detect ROP was 91.46% (95% CI: 90.23%-92.59%) and 91.22% (95% CI: 90.42%-91.97%), respectively, while the positive predictive value (PPV) was 81.72% (95% CI: 80.37%-83.00%), negative predictive value (NPV) was 96.14% (95% CI: 95.60%-96.61%) and the AUROC was 0.970. Conclusion: The novel ROP screening algorithm demonstrated high sensitivity and specificity in detecting the presence of ROP. A prospective clinical validation in a real-world tele-ROP platform is under consideration. It has the potential to lower the number of screening sessions required to be conducted by a specialist for a high-risk preterm infant thus significantly improving workflow efficiency.

Parallel processing relies on a distributed, low-dimensional cortico-cerebellar architecture.

A characteristic feature of human cognition is our ability to 'multi-task'-performing two or more tasks in parallel-particularly when one task is well learned. How the brain supports this capacity remains poorly understood. Most past studies have focussed on identifying the areas of the brain-typically the dorsolateral prefrontal cortex-that are required to navigate information-processing bottlenecks. In contrast, we take a systems neuroscience approach to test the hypothesis that the capacity to conduct effective parallel processing relies on a distributed architecture that interconnects the cerebral cortex with the cerebellum. The latter structure contains over half of the neurons in the adult human brain and is well suited to support the fast, effective, dynamic sequences required to perform tasks relatively automatically. By delegating stereotyped within-task computations to the cerebellum, the cerebral cortex can be freed up to focus on the more challenging aspects of performing the tasks in parallel. To test this hypothesis, we analysed task-based fMRI data from 50 participants who performed a task in which they either balanced an avatar on a screen (balance), performed serial-7 subtractions (calculation) or performed both in parallel (dual task). Using a set of approaches that include dimensionality reduction, structure-function coupling, and time-varying functional connectivity, we provide robust evidence in support of our hypothesis. We conclude that distributed interactions between the cerebral cortex and cerebellum are crucially involved in parallel processing in the human brain.

Knowledge, attitudes, and perceptions of hidradenitis suppurativa among young adults in Singapore.

Background: The prevalence of hidradenitis suppurativa (HS) is 0.00033% to 4.10% globally. Few epidemiological studies derive from Asia, with social stigmatization postulated to result in under-diagnosis. Objective: This study aimed to assess the self-reported prevalence of HS, and the knowledge, attitudes, and perceptions towards HS among Singaporean young-adults. Methods: A cross-sectional study (n = 158) was conducted by anonymous online questionnaire. The association between demographic factors and risk of potentially undiagnosed HS was evaluated using multivariable logistic regression. Differences between attitude-perception scores by demographic factors and knowledge of HS were tested using two-sample t-tests. Results: The prevalence of diagnosed and potentially undiagnosed HS was 0.63% and 8.9%, respectively. Non-Chinese had significantly higher social attitude-perception scores than Chinese (P = .029). Females had significantly higher social (P = .048) as well as economic and work (P = .037) attitude-perception scores than males. Those with knowledge of HS had significantly higher attitude-perception scores for interpersonal (P = .031) and social (P = .0052) subsections. Limitations: Small sample size, low frequency of HS cases, and self-reported prevalence may not generalize to the broader population in Singapore. Conclusion: Our results suggest a potential underdiagnosis of HS. Non-Chinese stigmatize HS less than Chinese, and females less than males. Individuals with knowledge of HS might be more open to interpersonal and social interactions with HS sufferers.

Digital game-based interventions for cognitive training in healthy adults and adults with cognitive impairment: protocol for a two-part systematic review and meta-analysis.

INTRODUCTION: Digital game-based training interventions are scalable solutions that may improve cognitive function for many populations. This protocol for a two-part review aims to synthesise the effectiveness and key features of digital game-based interventions for cognitive training in healthy adults across the life span and adults with cognitive impairment, to update current knowledge and impact the development of future interventions for different adult subpopulations. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. A systematic search was performed in PubMed, Embase, CINAHL, Cochrane Library, Web of Science, PsycINFO and IEEE Explore on 31 July 2022 for relevant literature published in English from the previous 5 years. Experimental, observational, exploratory, correlational, qualitative and mixed methods studies will be eligible if they report at least one cognitive function outcome and include a digital game-based intervention intended to improve cognitive function. Reviews will be excluded but retained to search their reference lists for other relevant studies. All screening will be done by at least two independent reviewers. The appropriate Joanna Briggs Institute Critical Appraisal Tool, according to the study design, will be applied to perform the risk of bias assessment. Outcomes related to cognitive function and digital game-based intervention features will be extracted. Results will be categorised by adult life span stages in the healthy adult population for part 1 and by neurological disorder in part 2. Extracted data will be analysed quantitatively and qualitatively, according to study type. If a group of sufficiently comparable studies is identified, we will perform a meta-analysis applying the random effects model with consideration of the I2 statistic. ETHICS AND DISSEMINATION: Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022351265.

Short exposure to photo-oxidative damage triggers molecular signals indicative of early retinal degeneration.

Introduction: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, currently affecting over 350 billion people globally. For the most prevalent late-stage form of this disease, atrophic AMD, there are no available prevention strategies or treatments, in part due to inherent difficulties in early-stage diagnosis. Photo-oxidative damage is a well-established model for studying inflammatory and cell death features that occur in late-stage atrophic AMD, however to date has not been investigated as a potential model for studying early features of disease onset. Therefore, in this study we aimed to determine if short exposure to photo-oxidative damage could be used to induce early retinal molecular changes and advance this as a potential model for studying early-stage AMD. Methods: C57BL/6J mice were exposed to 1, 3, 6, 12, or 24h photo-oxidative damage (PD) using 100k lux bright white light. Mice were compared to dim-reared (DR) healthy controls as well as mice which had undergone long periods of photo-oxidative damage (3d and 5d-PD) as known timepoints for inducing late-stage retinal degeneration pathologies. Cell death and retinal inflammation were measured using immunohistochemistry and qRT-PCR. To identify retinal molecular changes, retinal lysates were sent for RNA sequencing, following which bioinformatics analyses including differential expression and pathway analyses were performed. Finally, to investigate modulations in gene regulation as a consequence of degeneration, microRNA (miRNA) expression patterns were quantified using qRT-PCR and visualized using in situ hybridization. Results: Short exposure to photo-oxidative damage (1-24h-PD) induced early molecular changes in the retina, with progressive downregulation of homeostatic pathways including metabolism, transport and phototransduction observed across this time-course. Inflammatory pathway upregulation was observed from 3h-PD, preceding observable levels of microglia/macrophage activation which was noted from 6h-PD, as well as significant photoreceptor row loss from 24h-PD. Further rapid and dynamic movement of inflammatory regulator miRNA, miR-124-3p and miR-155-5p, was visualized in the retina in response to degeneration. Conclusion: These results support the use of short exposure to photo-oxidative damage as a model of early AMD and suggest that early inflammatory changes in the retina may contribute to pathological features of AMD progression including immune cell activation and photoreceptor cell death. We suggest that early intervention of these inflammatory pathways by targeting miRNA such as miR-124-3p and miR-155-5p or their target genes may prevent progression into late-stage pathology.

A Phase I, First-in-Human Study of PRL3-zumab in Advanced, Refractory Solid Tumors and Hematological Malignancies.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival. OBJECTIVE: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies. METHODS: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682. RESULTS: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody. CONCLUSIONS: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies.

Using the Johns Hopkins ACG Case-Mix System for population segmentation in a hospital-based adult patient population in Singapore.

OBJECTIVE: Population health management involves risk characterisation and patient segmentation. Almost all population segmentation tools require comprehensive health information spanning the full care continuum. We assessed the utility of applying the ACG System as a population risk segmentation tool using only hospital data. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in central Singapore. PARTICIPANTS: 100 000 randomly selected adult patients from 1 January to 31 December 2017. INTERVENTION: Hospital encounters, diagnoses codes and medications prescribed to the participants were used as input data to the ACG System. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospital costs, admission episodes and mortality of these patients in the subsequent year (2018) were used to assess the utility of ACG System outputs such as resource utilisation bands (RUBs) in stratifying patients and identifying high hospital care users. RESULTS: Patients placed in higher RUBs had higher prospective (2018) healthcare costs, and were more likely to have healthcare costs in the top five percentile, to have three or more hospital admissions, and to die in the subsequent year. A combination of RUBs and ACG System generated rank probability of high healthcare costs, age and gender that had good discriminatory ability for all three outcomes, with area under the receiver-operator characteristic curve (AUC) values of 0.827, 0.889 and 0.876, respectively. Application of machine learning methods improved AUCs marginally by about 0.02 in predicting the top five percentile of healthcare costs and death in the subsequent year. CONCLUSION: A population stratification and risk prediction tool can be used to appropriately segment populations in a hospital patient population even with incomplete clinical data.

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases.

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype.

Composing games into complex institutions.

Game theory is used by all behavioral sciences, but its development has long centered around the economic interpretation of equilibrium outcomes in relatively simple games and toy systems. But game theory has another potential use: the high-level design of large game compositions that express complex architectures and represent real-world institutions faithfully. Compositional game theory, grounded in the mathematics underlying programming languages, and introduced here as a general computational framework, increases the parsimony of game representations with abstraction and modularity, accelerates search and design, and helps theorists across disciplines express real-world institutional complexity in well-defined ways. Relative to existing approaches in game theory, compositional game theory is especially promising for solving game systems with long-range dependencies, for comparing large numbers of structurally related games, and for nesting games into the larger logical or strategic flows typical of real world policy or institutional systems.

Searching for common ground.

The conserved coronavirus fusion peptide is a target of broadly neutralizing antibodies.

Associations Between Mean HbA1c, HbA1c Variability, and Both Mortality and Macrovascular Complications in Patients with Diabetes Mellitus: A Registry-Based Cohort Study.

Background: We investigate the association between mean HbA1c, HbA1c variability, and all-cause mortality and diabetes-related macrovascular complications in patients with diabetes. Methods: We performed a retrospective cohort study using patients present in the Singapore Health Services diabetes registry (SDR) during 2013 to 2014. We assessed mean HbA1c using three models: a baseline mean HbA1c for 2013-14, the mean across the whole follow-up period, and a time-varying yearly updated mean. We assessed HbA1c variability at baseline using the patient's HbA1c variability score (HVS) for 2013-14. The association between mean HbA1c, HVS, and 6 outcomes were assessed using Cox proportional hazard models. Results: We included 43,837-53,934 individuals in the analysis; 99.3% had type 2 diabetes mellitus. The data showed a J-shaped distribution in adjusted hazard ratios (HRs) for all-cause mortality, ischemic heart disease, acute myocardial infarction, peripheral arterial disease, and ischemic stroke, with an increased risk of developing these outcomes at HbA1c <6% (42 mmol/mol) and ≥8% (64 mmol/mol). With the addition of HVS, the J-shaped distribution was maintained for the above outcomes, but HRs were greater at HbA1c <6.0% (42 mmol/mol) and reduced at HbA1c ≥8.0% (64 mmol/mol) when compared to models without HVS. The risk for all outcomes increased substantially with increasing glycaemic variability. Conclusion: Both low (<6.0% [42 mmol/mol]) and high (≥8.0% [64 mmol/mol]) levels of glycaemic control are associated with increased all-cause mortality and diabetes-related macrovascular complications. Glycaemic variability is independently associated with increased risk for these outcomes. Therefore, patients with stable glycaemic level of 6-8% (42-64mmol/mol) are at lowest risk of all-cause mortality and diabetes-related macrovascular complications.

Comparative Assessment of the Binding and Neutralisation Activity of Bispecific Antibodies Against SARS-CoV-2 Variants.

Background: Neutralising antibodies against SARS-CoV-2 are a vital component in the fight against COVID-19 pandemic, having the potential of both therapeutic and prophylactic applications. Bispecific antibodies (BsAbs) against SARS-CoV-2 are particularly promising, given their ability to bind simultaneously to two distinct sites of the receptor-binding domain (RBD) of the viral spike protein. Such antibodies are complex molecules associated with multi-faceted mechanisms of action that require appropriate bioassays to ensure product quality and manufacturing consistency. Methods: We developed procedures for biolayer interferometry (BLI) and a cell-based virus neutralisation assay, the focus reduction neutralisation test (FRNT). Using both assays, we tested a panel of five BsAbs against different spike variants (Ancestral, Delta and Omicron) to evaluate the use of these analytical methods in assessing binding and neutralisation activities of anti-SARS-CoV-2 therapeutics. Results: We found comparable trends between BLI-derived binding affinity and FRNT-based virus neutralisation activity. Antibodies that displayed high binding affinity against a variant were often followed by potent neutralisation at lower concentrations, whereas those with low binding affinity also demonstrated reduced neutralisation activity. Conclusion: The results support the utility of BLI and FRNT assays in measuring variant-specific binding and virus neutralisation activity of anti-SARS-CoV-2 antibodies.

Clinical informatics training in medical school education curricula: a scoping review.

OBJECTIVES: This scoping review evaluates the existing literature on clinical informatics (CI) training in medical schools. It aims to determine the essential components of a CI curriculum in medical schools, identify methods to evaluate the effectiveness of a CI-focused education, and understand its delivery modes. MATERIALS AND METHODS: This review was informed by the methodological guidance of the Joanna Briggs Institute. Three electronic databases including PubMed, Scopus, and Web of Science were searched for articles discussing CI between January 2010 and December 2021. RESULTS: Fifty-nine out of 3055 articles were included in our final analysis. Components of CI education include its utilization in clinical practice, ethical implications, key CI-related concepts, and digital health. Evaluation of educational effectiveness entails external evaluation by organizations external to the teaching institute, and internal evaluation from within the teaching institute. Finally, modes of delivery include various pedagogical strategies and teaching CI using a multidisciplinary approach. DISCUSSION: Given the broad discussion on the required competencies, we propose 4 recommendations in CI delivery. These include situating CI curriculum within specific contexts, developing evidence-based guidelines for a robust CI education, developing validated assessment techniques to evaluate curriculum effectiveness, and equipping educators with relevant CI training. CONCLUSION: The literature reveals that CI training in the core curricula will complement if not enhance clinical skills, reiterating the need to equip students with relevant CI competencies. Furthermore, future research needs to comprehensively address current gaps in CI training in different contexts, evaluation methodologies, and delivery modes to facilitate structured training.

Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses.

Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.

Trends in diabetes-related complications in Singapore, 2013-2020: A registry-based study.

BACKGROUND: Diabetes mellitus (DM) is a growing global health problem. In Singapore, the prevalence of Type 2 DM is rising, but comprehensive information about trends in DM-related complications is lacking. OBJECTIVES: We utilized the Singapore Health Services (SingHealth) diabetes registry (SDR) to assess trends in DM micro and macro-vascular complications at the population level, explore factors influencing these trends. METHODS: We studied trends for ten DM-related complications: ischemic heart disease (IHD), acute myocardial infarction (AMI), peripheral arterial disease (PAD) and strokes, diabetic eye complications, nephropathy, neuropathy, diabetic foot, major and minor lower extremity amputation (LEA). The complications were determined through clinical coding in hospital (inpatient and outpatient) and primary care settings within the SingHealth cluster. We described event rates for the complications in 4 age-bands. Joinpoint regression was used to identify significant changes in trends. RESULTS: Among 222,705 patients studied between 2013 and 2020. 48.6% were female, 70.7% Chinese, 14.7% Malay and 10.6% Indian with a mean (SD) age varying between 64.6 (12.5) years in 2013 and 65.7 (13.2) years in 2020. We observed an increase in event rates in IHD, PAD, stroke, diabetic eye complications nephropathy, and neuropathy. Joinpoints was observed for IHD and PAD between 2016 to 2018, with subsequent plateauing of event rates. Major and minor LEA event rates decreased through the study period. CONCLUSION: We found that DM and its complications represent an important challenge for healthcare in Singapore. Improvements in the trends of DM macrovascular complications were observed. However, trends in DM microvascular complications remain a cause for concern.