Curating retrospective multimodal and longitudinal data for community cohorts at risk for lung cancer.

BACKGROUND: Large community cohorts are useful for lung cancer research, allowing for the analysis of risk factors and development of predictive models. OBJECTIVE: A robust methodology for (1) identifying lung cancer and pulmonary nodules diagnoses as well as (2) associating multimodal longitudinal data with these events from electronic health record (EHRs) is needed to optimally curate cohorts at scale. METHODS: In this study, we leveraged (1) SNOMED concepts to develop ICD-based decision rules for building a cohort that captured lung cancer and pulmonary nodules and (2) clinical knowledge to define time windows for collecting longitudinal imaging and clinical concepts. We curated three cohorts with clinical data and repeated imaging for subjects with pulmonary nodules from our Vanderbilt University Medical Center. RESULTS: Our approach achieved an estimated sensitivity 0.930 (95% CI: [0.879, 0.969]), specificity of 0.996 (95% CI: [0.989, 1.00]), positive predictive value of 0.979 (95% CI: [0.959, 1.000]), and negative predictive value of 0.987 (95% CI: [0.976, 0.994]) for distinguishing lung cancer from subjects with SPNs. CONCLUSION: This work represents a general strategy for high-throughput curation of multi-modal longitudinal cohorts at risk for lung cancer from routinely collected EHRs.

A review of dairy food intake for improving health among black geriatrics in the US.

The transition to older adulthood is generally marked by progressive declines in body composition, metabolism, cognitive function, and immunity. For socially disadvantaged geriatric populations such as Black Americans, this life stage may also include additional stressors, including dealing with discrimination, poor access to healthcare, and food insecurity. These types of chronic stressors are linked to a higher allostatic load, which is associated with accelerated biological aging, higher rates of adverse health outcomes, and an overall lower quality of life. Of the numerous factors involved in healthy aging, a growing body of research indicates that consuming a higher quality diet that is rich in fruits, vegetables, whole grains, protein foods, and dairy foods, is one of the most potent factors for helping to protect against age-related disease progression. Among the food groups listed above that are recommended by the 2020-2025 Dietary Guidelines for Americans dairy foods are unique in their ability to provide several of the essential nutrients (e.g., high-quality protein, calcium, potassium, vitamin B12, and vitamin D in fortified products) that are most often inadequately consumed by older Black Americans. However, dairy is the most inadequately consumed food group in the US, with older Black adults consuming fewer than half of the 3 daily recommended servings. Therefore, this review examines the current body of evidence exploring the links between dairy intake and age-related disease risk, with a special focus on health and disparities among older Black Americans. Overall, the evidence from most systematic reviews and/or meta-analyses focused on dairy intake and musculoskeletal health suggest that higher dairy intake across the life span, and especially from fermented and fortified products, is associated with better bone and muscle health outcomes in older adults. The evidence on dairy intake and neurocognitive and immune outcomes among older adults holds significant promise for potential benefits, but most of these results are sourced from individual studies or narrative reviews and are not currently corroborated in systematic reviews or meta-analyses. Additionally, most of the research on dairy intake and age-related disease risk has been performed in White populations and can only be extrapolated to Black populations. Nonetheless, older Black populations who do not meet the DGA recommended 3 servings of dairy per day due to lactose intolerance, restrictive dietary patterns, or for other reasons, are likely falling short of several of the nutritional requirements necessary to support healthy aging.

Executive summary: The role of dairy food intake for improving health among Black Americans across the life continuum.

Given the complex relationships that many Black individuals have with dairy foods, due to issues with lactose intolerance or other cultural factors, the National Medical Association has made considerable efforts to examine the role that dairy foods play in the health and well-being of Black Americans. Over the last two decades, the National Medical Association and its partners have produced multiple reports on the value of including adequate milk and dairy foods in the diets of Black Americans. These publications have highlighted the impact that inadequate consumption of dairy foods and nutrients have on chronic disease risks. Past publications have also provided evidence-based recommendations for the proper diagnosis and management of lactose intolerance. This new series of evidence reviews focuses on dairy's role in improving nutrition and health among Black Americans across the life course and covers an extensive amount of new research that highlights additional health disparities and provides further evidence-based strategies for the management of lactose intolerance. Much like the 2020-2025 Dietary Guidelines for Americans, this work utilizes a life course approach to better address dairy intake on health outcomes for different ages and life stages: 1) pregnancy, fetal development, and lactation, 2) infants, toddlers, and young children, 3) older children and adolescents, 4) adults, and 5) geriatric populations. Overall, the findings and conclusions from this series of evidence reviews continue to indicate that higher dairy intake is associated with reduced risk for many of the most commonly occurring deficiencies and diseases impacting each life stage, and that Black Americans would receive significantly greater health benefits by increasing their daily dairy intake levels to meet the national dietary recommendations than they would from continuing to fall short of these recommendations. However, these recommendations must be considered with appropriate context and nuance as the intake of different dairy products can have different impacts on health outcomes. For instance, vitamin D fortified dairy products and fermented dairy products like yogurt - which are low in lactose and rich in live and active cultures - tend to show the greatest impacts for reducing disease risk across the life continuum, while whole-fat dairy foods may be most beneficial in early life for optimal brain development, and more protein-rich options may be most beneficial in later life to help maintain muscle mass and function.

A review of dairy food intake for improving health among black adults in the US.

The adult life stage encompasses a range of new experiences, opportunities, and responsibilities that impact health and well-being. During this life stage, health disparities continue to increase for Black Americans, with Black adults having a disproportionate burden of obesity, chronic diseases, comorbidities, and worse treatment outcomes compared to their White peers. While many of the underlying factors for these disparities can be linked to longstanding sociopolitical factors such as systemic racism, food insecurity, and poor access to healthcare, there are also several modifiable risk factors that are known to significantly impact health outcomes, such as improving diet quality, increasing physical activity, and not smoking. Of all the modifiable risk factors known to impact health, improving dietary habits is the factor most consistently associated with better outcomes for body weight and chronic disease. Of the major food groups recommended by the 2020-2025 Dietary Guidelines for Americans (DGA) for achieving healthier dietary patterns, dairy foods have a nutrient profile which matches most closely to what Black Americans are inadequately consuming (e.g., vitamin A, vitamin D, calcium, magnesium). However, Black adults tend to consume less than half the recommended daily servings of dairy foods, in part, due to issues with lactose intolerance, making higher intake of dairy foods an ideal target for improving diet quality and health in this population. This review examines the current body of evidence exploring the links between dairy intake, obesity, cardiometabolic disease risk, chronic kidney disease, and the most common types of cancer, with a special focus on health and disparities among Black adults. Overall, the evidence from most systematic reviews and/or meta-analyses published in the last decade on dairy intake and health outcomes has been conducted on White populations and largely excluded research on Black populations. The findings from this extensive body of research indicate that when teamed with an energy-restricted diet, meeting or exceeding the DGA recommended 3 daily servings of dairy foods is associated with better body weight and composition outcomes and lower rates of most common chronic diseases than lower intake (<2 servings per day). In addition to the number of daily servings consumed, the specific types (e.g., milk, yogurt, cheese) and subtypes (e.g., low-fat, fermented, fortified) consumed have also been shown to play major roles in how these foods impact health. For example, higher intake of fermented dairy foods (e.g., yogurt) and vitamin D fortified dairy products appear to have the most protective effects for reducing chronic disease risk. Along with lactose-free milk and cheese, yogurt is also generally low in lactose, making it an excellent option for individuals with lactose intolerance, who are trying to meet the DGA recommendations for dairy food intake.

The role of dairy food intake for improving health among black Americans across the life continuum: A summary of the evidence.

Decades of health data show major health disparities occurring at every life stage between Black and White Americans. These disparities include greater mortality rates among Black mothers and their offspring, higher levels of malnutrition and obesity among Black children and adolescents, and a higher burden of chronic disease and lower life expectancy for Black adults. Although nutrition is only one of many factors that influence human health and well-being across the life continuum, a growing body of research continues to demonstrate that consuming a healthy dietary pattern is one of the most dominant factors associated with increased longevity, improved mental health, improved immunity, and decreased risk for obesity and chronic disease. Unfortunately, large percentages of Black Americans tend to consume inadequate amounts of several essential nutrients such as vitamin A, vitamin D, calcium, and magnesium; and simultaneously consume excessive amounts of fast foods and sugar-sweetened beverages to a greater degree than other racial/ethnic groups. Therefore, strategies that can help improve dietary patterns for Black Americans could make up a major public health opportunity for reducing nutrition-related diseases and health disparities across the life course. A key intervention strategy to improve diet quality among Black Americans is to focus on increasing the intake of nutrient-rich dairy foods, which are significantly underconsumed by most Black Americans. Compared to other food group, dairy foods are some of the most accessible and affordable sources of essential nutrients like vitamin A, D, and B12, calcium, magnesium, potassium, selenium, and zinc in the food supply, as well as being some of the primary sources of several health-promoting bioactive compounds, including polar lipids, bioactive proteins and peptides, oligosaccharides, and live and active cultures in fermented products. Given the complex relationships that many Black Americans have with dairy foods, due to issues with lactose intolerance, and/or negative perceptions about the health effects of dairy foods, there is still a need to examine the role that dairy foods play in the health and well-being of Black Americans of all ages and life stages. Therefore, the National Medical Association and its partners have produced multiple reports on the value of including adequate dairy in the diet of Black Americans. This present summary paper and its associated series of evidence reviews provide an examination of an immense amount of research focused on dairy intake and health outcomes, with an emphasis on evidence-based strategies for improving the health of Black Americans. Overall, the findings and conclusions from this body of research continue to indicate that higher dairy intake is associated with reduced risk for many of the most commonly occurring deficiencies and diseases impacting each life stage, and that Black Americans would receive significantly greater health benefits by increasing their daily dairy intake levels to meet the national recommendations than they would from continuing to fall short of these recommendations. However, these recommendations must be considered with appropriate context and nuance as the intake of different dairy products can have different impacts on health outcomes. For instance, vitamin D fortified dairy products and fermented dairy products like yogurt - which are low in lactose and rich in live and active cultures - tend to show the greatest benefits for improved health. Importantly, there are significant limitations to these research findings for Black Americans, especially as they relate to reproductive and child health, since most of the research on dairy intake and health has failed to include adequate representation of Black populations or to sufficiently address the role of dairy intake during the most vulnerable life stages, such as pregancy, lactation, fetal development, early childhood, and older age. This population and these life stages require considerably more research and policy attention if health equity is ever to be achieved for Black Americans. Sharing and applying the learnings from this summary paper and its associated series of evidence reviews will help inform and empower nutrition and health practitioners to provide more evidence-based dietary recommendations for improving the health and well-being of Black Americans across the life course.

Longitudinal lung cancer prediction convolutional neural network model improves the classification of indeterminate pulmonary nodules.

A deep learning model (LCP CNN) for the stratification of indeterminate pulmonary nodules (IPNs) demonstrated better discrimination than commonly used clinical prediction models. However, the LCP CNN score is based on a single timepoint that ignores longitudinal information when prior imaging studies are available. Clinically, IPNs are often followed over time and temporal trends in nodule size or morphology inform management. In this study we investigated whether the change in LCP CNN scores over time was different between benign and malignant nodules. This study used a prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) design. Subjects with incidentally or screening detected IPNs 6-30 mm in diameter with at least 3 consecutive CT scans prior to diagnosis (slice thickness ≤ 1.5 mm) with the same nodule present were included. Disease outcome was adjudicated by biopsy-proven malignancy, biopsy-proven benign disease and absence of growth on at least 2-year imaging follow-up. Lung nodules were analyzed using the Optellum LCP CNN model. Investigators performing image analysis were blinded to all clinical data. The LCP CNN score was determined for 48 benign and 32 malignant nodules. There was no significant difference in the initial LCP CNN score between benign and malignant nodules. Overall, the LCP CNN scores of benign nodules remained relatively stable over time while that of malignant nodules continued to increase over time. The difference in these two trends was statistically significant. We also developed a joint model that incorporates longitudinal LCP CNN scores to predict future probability of cancer. Malignant and benign nodules appear to have distinctive trends in LCP CNN score over time. This suggests that longitudinal modeling may improve radiomic prediction of lung cancer over current models. Additional studies are needed to validate these early findings.

Psychosocial Peer Support to Address Mental Health and Burnout of Health Care Workers Affected by COVID-19: A Qualitative Evaluation.

Health care workers in the U.S. are experiencing alarming rates of burnout. Furthermore, the COVID-19 pandemic has worsened this issue. Psychosocial peer-support programs that address general distress and are tailored to health care systems are needed. A Care for Caregivers (CFC) Program was developed at an American metropolitan university hospital and outpatient health care system. The CFC program trains "Peer Caregivers" and managers and has four components: the identification of colleagues in need of support; psychological first aid; linkage to resources; and the promotion of hope among colleagues experiencing demoralization. Qualitative interviews (n = 18) were conducted with Peer Caregivers and Managers participating in the initial piloting of the program. Results suggest that the CFC program shifts the organizational culture, teaches staff skills for recognizing and supporting others in distress, and supports those staff who are already providing these services informally. Findings suggest that staff distress resulted primarily from external factors and secondarily from internal organizational stressors. External stressors were exacerbated by the COVID-19 pandemic. Although the program has promise for addressing staff burnout, other organizational efforts are needed to simultaneously promote staff wellness. Ultimately, psychosocial peer support programs for health care workers are feasible and potentially impactful, but also require other systemic changes within a health care system to improve and sustain staff well-being.

Obesity among African American people in the United States: A review.

Obesity is a growing public health crisis in the United States and is associated with a substantial disease burden due to an increased risk for multiple complications, including cardiovascular and metabolic diseases. As highlighted in this review, obesity disproportionately affects the African American population, women in particular, regardless of socioeconomic status. Structural racism remains a major contributor to health disparities between African American people and the general population, and it limits access to healthy foods, safe spaces to exercise, adequate health insurance, and medication, all of which impact obesity prevalence and outcomes. Conscious and unconscious interpersonal racism also impacts obesity care and outcomes in African American people and may adversely affect interactions between health care practitioners and patients. To reduce health disparities, structural racism and racial bias must be addressed. Culturally relevant interventions for obesity management have been successfully implemented that have shown benefits in weight management and risk-factor reduction. Strategies to improve health care practitioner-patient engagement should also be implemented to improve health outcomes in African American people with obesity. When managing obesity in African American people, it is critical to take a holistic approach and to consider an individual's social and cultural context in order to implement a successful treatment strategy.

Computational modelling of diatom silicic acid transporters predicts a conserved fold with implications for their function and evolution.

Diatoms are an important group of algae that can produce intricate silicified cell walls (frustules). The complex process of silicification involves a set of enigmatic integral membrane proteins that are thought to actively transport the soluble precursor of biosilica, dissolved silicic acid. Full-length silicic acid transporters are found widely across the diatoms while homologous shorter proteins have now been identified in a range of other organisms. It has been suggested that modern silicic acid transporters arose from the union of such partial sequences. Here, we present a computational study of the silicic acid transporters and related transporter-like sequences to help understand the structure, function and evolution of this class of membrane protein. The AlphaFold software predicts that all of the protein sequences studied here share a common fold in the membrane domain which is entirely different from the predicted folds of non-homologous silicic acid transporters from plants. Substrate docking reveals how conserved polar residues could interact with silicic acid at a central solvent-accessible binding site, consistent with an alternating access mechanism of transport. The structural conservation between these proteins supports a model where modern silicon transporters evolved from smaller ancestral proteins by gene fusion.

Characterization of the molecular mechanisms of silicon uptake in coccolithophores.

Coccolithophores are an important group of calcifying marine phytoplankton. Although coccolithophores are not silicified, some species exhibit a requirement for Si in the calcification process. These species also possess a novel protein (SITL) that resembles the SIT family of Si transporters found in diatoms. However, the nature of Si transport in coccolithophores is not yet known, making it difficult to determine the wider role of Si in coccolithophore biology. Here, we show that coccolithophore SITLs act as Na+ -coupled Si transporters when expressed in heterologous systems and exhibit similar characteristics to diatom SITs. We find that CbSITL from Coccolithus braarudii is transcriptionally regulated by Si availability and is expressed in environmental coccolithophore populations. However, the Si requirement of C. braarudii and other coccolithophores is very low, with transport rates of exogenous Si below the level of detection in sensitive assays of Si transport. As coccoliths contain only low levels of Si, we propose that Si acts to support the calcification process, rather than forming a structural component of the coccolith itself. Si is therefore acting as a micronutrient in coccolithophores and natural populations are only likely to experience Si limitation in circumstances where dissolved silicon (DSi) is depleted to extreme levels.

The impact of forced degradation conditions on mAb dimer formation and subsequent influence on aggregation propensity.

Monoclonal antibody (mAb) aggregation can present major challenges for the development of biotherapeutics. An understanding of the molecular mechanisms of mAb aggregation is highly desirable both because it allows the performance of informed risk assessments regarding the criticality of mAb aggregates and because it may facilitate rational stabilization of aggregation prone regions. Here, we report the generation and isolation of dimer species of an IgG4 mAb (mAb1) that were present in stressed material under differing levels of temperature stress. We demonstrate the power of combining established higher order techniques with non-routine analysis, such as small-angle X-ray scattering, hydrogen/deuterium exchange mass spectrometry (HDX-MS), and protein conformational array enzyme-linked immunosorbent assay (PCA ELISA), and show that dimer species formed under temperature stress are structurally distinct from those present in unstressed mAb1. Specifically, stress-induced dimers are shown to adopt a more elongated conformation with a greater degree of unfolding when compared to native dimers. Analysis by HDX-MS and PCA ELISA, supported by in silico shape and charge molecular docking, enabled the identification of residues in both the variable and constant domains that appear to play a significant role in the dimerization of mAb1. Furthermore, we show that dimers formed under temperature stress are significantly more long-lived than those present in unstressed mAb1. We also present evidence that mAb1 dimers can behave as aggregation nuclei, and that dimers produced under high-temperature stress do so to a greater extent. This work presents an advancement in our understanding of the molecular mechanisms of mAb aggregation and highlights the importance of structural characterization of dimer species during the development of mAb biotherapeutics.Abbreviations: 2DSA: 2-Dimensional Spectrum Analysis; CD: Circular Dichroism; CDR: Complementarity-Determining Region; CQA: Critical Quality Attribute; DSC: Differential Scanning Calorimetry; FTIR: Fourier Transform Infrared spectroscopy; HDX-MS: Hydrogen/Deuterium Exchange Mass Spectrometry; HIC: Hydrophobic interaction chromatography; HMWS: High Molecular Weight Species; HOS: Higher Order Structure; mAb: Monoclonal Antibody; MD: Molecular Dynamics PCA; ELISA: Protein Conformational Array Enzyme-Linked Immunosorbent Assay; Rg: Radius of Gyration; SAXS: Small Angle X-ray Scattering; SE-HPLC: Size Exclusion High Performance Liquid Chromatography; SV-AUC: Sedimentation Velocity-Analytical Ultracentrifugation.

Rotavirus RNA chaperone mediates global transcriptome-wide increase in RNA backbone flexibility.

Due to genome segmentation, rotaviruses must co-package eleven distinct genomic RNAs. The packaging is mediated by virus-encoded RNA chaperones, such as the rotavirus NSP2 protein. While the activities of distinct RNA chaperones are well studied on smaller RNAs, little is known about their global effect on the entire viral transcriptome. Here, we used Selective 2'-hydroxyl Acylation Analyzed by Primer Extension and Mutational Profiling (SHAPE-MaP) to examine the secondary structure of the rotavirus transcriptome in the presence of increasing amounts of NSP2. SHAPE-MaP data reveals that despite the well-documented helix-unwinding activity of NSP2 in vitro, its incubation with cognate rotavirus transcripts does not induce a significant change in the SHAPE reactivities. However, a quantitative analysis of mutation rates measured by mutational profiling reveals a global 5-fold rate increase in the presence of NSP2. We demonstrate that the normalization procedure used in deriving SHAPE reactivities from mutation rates can mask an important global effect of an RNA chaperone. Analysis of the mutation rates reveals a larger effect on stems rather than loops. Together, these data provide the first experimentally derived secondary structure model of the rotavirus transcriptome and reveal that NSP2 acts by globally increasing RNA backbone flexibility in a concentration-dependent manner.

The proximity of the N- and C- termini of bovine knob domains enable engineering of target specificity into polypeptide chains.

Cysteine-rich knob domains can be isolated from the ultralong heavy-chain complementarity-determining region (CDR) 3, which are unique to a subset of bovine antibodies, to create antibody fragments of ~4 kDa. Advantageously, the N- and C- termini of these small binding domains are in close proximity, and we propose that this may offer a practical route to engineer extrinsic binding specificity into proteins. To test this, we transplanted knob domains into various loops of rat serum albumin, targeting sites that were distal to the interface with the neonatal Fc receptor. Using knob domains raised against the clinically validated drug target complement component C5, we produced potent inhibitors, which exhibit an extended plasma half-life in vivo via attenuated renal clearance and neonatal Fc receptor-mediated avoidance of lysosomal catabolism. The same approach was also used to modify a Camelid VHH, targeting a framework loop situated at the opposing end of the domain to the CDRs, to produce a small, single-chain bispecific antibody and a dual inhibitor of Complement C3 and C5. This study presents new protein inhibitors of the complement cascade and demonstrates a broadly applicable method to engineer target specificity within polypeptide chains, using bovine knob domains.

The SARS-CoV-2 RNA polymerase is a viral RNA capping enzyme.

SARS-CoV-2 is a positive-sense RNA virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, which continues to cause significant morbidity, mortality and economic strain. SARS-CoV-2 can cause severe respiratory disease and death in humans, highlighting the need for effective antiviral therapies. The RNA synthesis machinery of SARS-CoV-2 is an ideal drug target and consists of non-structural protein 12 (nsp12), which is directly responsible for RNA synthesis, and numerous co-factors involved in RNA proofreading and 5' capping of viral RNAs. The formation of the 5' 7-methylguanosine (m7G) cap structure is known to require a guanylyltransferase (GTase) as well as a 5' triphosphatase and methyltransferases; however, the mechanism of SARS-CoV-2 RNA capping remains poorly understood. Here we find that SARS-CoV-2 nsp12 is involved in viral RNA capping as a GTase, carrying out the addition of a GTP nucleotide to the 5' end of viral RNA via a 5' to 5' triphosphate linkage. We further show that the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase) domain performs this reaction, and can be inhibited by remdesivir triphosphate, the active form of the antiviral drug remdesivir. These findings improve understanding of coronavirus RNA synthesis and highlight a new target for novel or repurposed antiviral drugs against SARS-CoV-2.

Correction: Breadth and function of antibody response to acute SARS-CoV-2 infection in humans.

[This corrects the article DOI: 10.1371/journal.ppat.1009352.].

Detection of Isopeptide Bonds in Monoclonal Antibody Aggregates.

PURPOSE: A major difficulty in monoclonal antibody (mAb) therapeutic development is product aggregation. In this study, intermolecular isopeptide bonds in mAb aggregates were characterized for the first time. We aim to propose a mechanism of covalent aggregation in a model antibody using stressed studies at raised temperatures to aid in the understanding of mAb aggregation pathways. METHODS: Aggregate fractions were generated using raised temperature and were purified using size-exclusion chromatography (SEC). The fractions were tryptically digested and characterized using liquid chromatography hyphenated to tandem mass-spectrometry (LC-MS/MS). RESULTS: An increased amount of clipping between aspartic acid and proline in a solvent accessible loop in the constant heavy 2 (CH2) domain of the mAb was observed under these conditions. Detailed peptide mapping revealed 14 isopeptide bonds between aspartic acid at that cleavage site and lysine residues on adjacent antibodies. Two additional isopeptide bonds were identified between the mAb HC N-terminal glutamic acid or a separate aspartic acid to lysine residues on adjacent antibodies. CONCLUSIONS: Inter-protein isopeptide bonds between the side chains of acidic amino acids (aspartate and glutamate) and lysine were characterized for the first time in mAb aggregates. A chemical mechanism was presented whereby spontaneous isopeptide bond formation could be facilitated via either the aspartic acid side chain or C-terminus.

Pharmacotherapeutic options for weight regain after bariatric surgery.

PURPOSE OF REVIEW: We sought to critically evaluate the recent literature published over the past 3 years on the topic of weight regain after bariatric surgery in children, adolescents, and adults, with an emphasis on clinically- relevant information for pharmacologic treatment of weight regain after metabolic and bariatric surgery. FINDINGS: There are multiple pharmacotherapeutic agents available to treat obesity in children, adolescents, and adults; these agents have varying efficacy and indications for use and have been studied in a variety of clinical and research scenarios. We present an overview of these findings. SUMMARY: This review represents a comprehensive compilation of the recently published data on efficacy of anti-obesity pharmacotherapy in the treatment of weight regain after bariatric surgery for children, adolescents, and adults.

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern.

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress.

Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate cytopathic events induced by SARS-CoV-2 with virus replication processes in frozen-hydrated cells, we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. Here we report critical SARS-CoV-2 structural events - e.g. viral RNA transport portals, virus assembly intermediates, virus egress pathway, and native virus spike structures, in the context of whole-cell volumes revealing drastic cytppathic changes. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules.