Neutralization, effector function and immune imprinting of Omicron variants

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain$^{1}$ (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development

Applying systems thinking to identify enablers and challenges to scale-up interventions for hypertension and diabetes in low-income and middle-income countries: protocol for a longitudinal mixed-methods study.

INTRODUCTION: There is an urgent need to reduce the burden of non-communicable diseases (NCDs), particularly in low-and middle-income countries, where the greatest burden lies. Yet, there is little research concerning the specific issues involved in scaling up NCD interventions targeting low-resource settings. We propose to examine this gap in up to 27 collaborative projects, which were funded by the Global Alliance for Chronic Diseases (GACD) 2019 Scale Up Call, reflecting a total funding investment of approximately US$50 million. These projects represent diverse countries, contexts and adopt varied approaches and study designs to scale-up complex, evidence-based interventions to improve hypertension and diabetes outcomes. A systematic inquiry of these projects will provide necessary scientific insights into the enablers and challenges in the scale up of complex NCD interventions. METHODS AND ANALYSIS: We will apply systems thinking (a holistic approach to analyse the inter-relationship between constituent parts of scaleup interventions and the context in which the interventions are implemented) and adopt a longitudinal mixed-methods study design to explore the planning and early implementation phases of scale up projects. Data will be gathered at three time periods, namely, at planning (TP), initiation of implementation (T0) and 1-year postinitiation (T1). We will extract project-related data from secondary documents at TP and conduct multistakeholder qualitative interviews to gather data at T0 and T1. We will undertake descriptive statistical analysis of TP data and analyse T0 and T1 data using inductive thematic coding. The data extraction tool and interview guides were developed based on a literature review of scale-up frameworks. ETHICS AND DISSEMINATION: The current protocol was approved by the Monash University Human Research Ethics Committee (HREC number 23482). Informed consent will be obtained from all participants. The study findings will be disseminated through peer-reviewed publications and more broadly through the GACD network

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland

Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care

Gestalt Processing in Autistic Adolescents

Previous research has documented that individuals with autism preferentially attend to local rather than global elements of a visual scene. We tested another pre-attentive phenomenon - gestalt processing - to investigate whether the global processing deficits seen in autism extend to gestalt processing. We asked 5 individuals with low functioning autism and 13 typically developing individuals to point to the odd item in a four-item display to test ability and speed in using gestalt principles of proximity, similarity and closure. As expected, the control group was significantly faster at responding to gestalt-grouped targets than targets differing in only a single feature. However, individuals with autism did not show a significant difference in reaction time between conditions, implying that parsing gestalt relationships is as taxing as processing single features. Both groups were generally more accurate in the gestalt condition. Taken together, these findings suggest that although the ability to process gestalt relationships appears to be intact in autism, gestalt processing may not be a pre-attentive process for this sample. Implications and future directions are discussed

Study on Crop Diversification through Area Status of Crops in Kharif Season of Chhattisgarh

In the State of Chhattisgarh, nicknamed the Rice Bowl of India, about 80% of the population is engaged in agriculture. It has been mostly engaged in the paddy-based mono-cropping system for a long period. So, crop diversification (a shift of area away from a less profitable crop toward more profitable ones) is one of the measures, expected to enhance the economic growth of the farmers in this State. Therefore, the present study attempts to assess the status of the area under different crops in the Kharif season in Chhattisgarh, based on secondary data for the period of 19 years, i.e., 2000-01 to 2018-19. For the Kharif season, the area is under crops such as pigeon pea and maize have, in general, increased over the period 2001-19. while the area under moong and sesamum over the period has decreased

Effect of Different Thermal Regimes and Moisture Levels on the Growth Parameters of Wheat (Triticum aestivum L.) Crop Grown under Agro-climatic Conditions of Eastern Uttar Pradesh, India

A field experiment was carried out at Agrometeorological Research Farm, Acharya Narendra Deva University of Agriculture & Technology, Kumarganj, Ayodhya (U.P.) during rabi season of 2022-23 and 2023-24 to investigate the influence of different thermal regimes and moisture levels on wheat growth parameters, including phenophases occurrence, leaf area index (LAI), plant height, and dry matter accumulation at various stages of crop development.  The experiment comprised twelve treatment combinations and conducted in split plot design and replicated four times. Treatment consisted of three thermal regimes viz. 15th November, 25th November and 5th December with four moisture levels viz, I1 at CRI (crown root initiation) , I2- CRI+tillering, I3- CRI+ jointing and milking, I4- CRI+ jointing +anthesis and dough stage. Results reveal that Plant height (cm), dry matter accumulation (gm-2) and leaf area index increased significantly at all the stages of crop growth . Highest values are recorded with the crop thermal regime on 15th November followed by 25th November. Lowest values of all were recorded in 5th December thermal regime. Among the moisture levels, I4- (CRI+ jointing +anthesis and dough stage) took relatively longer duration for maturirty compared to levels I3, I2 and I1.. These findings underscore the importance of carefully managing both temperature and moisture conditions to optimize wheat growth and development. This research contributes to the broader understanding of crop responses to thermal regimes/date of sowing and provides valuable insights for moisture management strategies aimed at improving crop yield and resilience in the face of changing climate conditions

Improving the completeness of public metadata accompanying omics studies

Over the last decade there has been tremendous progress to improve the sharing of genomics data, which allows researchers to easily access the various types of data across a wide range of phenotypes. Some of the most well known public repositories are Gene Expression Omnibus, Sequence Read Archive and ArrayExpress. However, despite the availability of raw data, metadata accompanying the raw data is often unavailable. Incomplete and improperly annotated metadata on repositories proves to be a hindrance to reusing and reproducing existing data, especially for making novel discoveries. Leveraging previously published data for novel biological discoveries is only possible to its maximum extent if the metadata that accompanies raw omics data is complete and present in a standardized format. Existing literature has explored how sharing of data should be FAIR - Findable, Accessible, Interoperable and Reusable, and considered accuracy, completeness and consistency as three vital parameters to assess the quality of available metadata, although not many have examined it exclusively as an appendage to omics studies. In our study, we perform a systematic assessment of completeness of public metadata accompanying omics data. We have performed our analysis on sepsis cohorts and are currently extending the same to tuberculosis and cystic fibrosis cohorts. On comparing the data available on both platforms, we observed discrepancies between omics data and the corresponding metadata on public repositories. The results we have for the sepsis cohorts are intriguing and advocate the need to have a standardized "checklist" for researchers to submit their study results and data to public repositories. Our study opens a wide discussion about this being a potential solution to bridge the gap between omics data and metadata on repositories

Protocol for process evaluation of SMART Mental Health cluster randomised control trial:an intervention for management of common mental disorders in India

INTRODUCTION: In India about 95% of individuals who need treatment for common mental disorders like depression, stress and anxiety and substance use are unable to access care. Stigma associated with help seeking and lack of trained mental health professionals are important barriers in accessing mental healthcare. Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health integrates a community-level stigma reduction campaign and task sharing with the help of a mobile-enabled electronic decision support system (EDSS)—to reduce psychiatric morbidity due to stress, depression and self-harm in high-risk individuals. This paper presents and discusses the protocol for process evaluation of SMART Mental Health. METHODS AND ANALYSIS: The process evaluation will use mixed quantitative and qualitative methods to evaluate implementation fidelity and identify facilitators of and barriers to implementation of the intervention. Case studies of six intervention and two control clusters will be used. Quantitative data sources will include usage analytics extracted from the mHealth platform for the trial. Qualitative data sources will include focus group discussions and interviews with recruited participants, primary health centre doctors, community health workers (Accredited Social Health Activits) who participated in the project and local community leaders. The design and analysis will be guided by Medical Research Council framework for process evaluations, the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework, and the normalisation process theory. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the George Institute for Global Health, India and the Institutional Ethics Committee, All India Institute of Medical Sciences (AIIMS), New Delhi. Findings of the study will be disseminated through peer-reviewed publications, stakeholder meetings, digital and social media platforms. TRIAL REGISTRATION NUMBER: CTRI/2018/08/015355