medRxiv : serveur de preprint pour les sciences médicales

Objective: Clear criteria to individualize glycemic targets are lacking. In this post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD), we evaluate whether the kidney failure risk equation (KFRE) can identify patients who disproportionately benefit from intensive glycemic control on kidney microvascular outcomes. Research design and methods: We divided the ACCORD trial population in quartiles based on 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them to the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted-mean-survival-time (RMST) differences between intensive and standard glycemic control arms on (1) time-to-first development of severely elevated albuminuria or kidney failure and (2) all-cause mortality. Results: We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure benefitted the most from intensive glycemic control on kidney microvascular outcomes (7-year RMST difference of 115 v. 48 days in the entire trial population) However, this same patient group also experienced shorter times to death (7-year RMST difference of -57 v. -24 days). Conclusions: We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced benefits of treatment on kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.

Objective: Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. Methods: In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. Results: In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-{gamma} response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Conclusions: Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.

Objective: Mycobacterium tuberculosis (Mtb) primarily affects the lungs with involvement of other organs causing tuberculosis (TB) in humans. Since the lung-gut axis is bidirectional, and the gut microbiota contributes to metabolic and immune homeostasis, we looked at the gut microbiota and metabolites of TB patients and controls, and whether the perturbations, if any, resolve with anti-tuberculosis treatment. Methods: In this multicentric case-control study, a total of 107 fecal samples belonging to drug naive active tuberculosis (ATB) patients and controls (non-tuberculosis: NTB and healthy), were collected from two clinical sites in India. A group of drug-naive ATB patients (n=10) from one site was followed-up and monitored at 2, 4, 6, and 8 months of their anti-tuberculosis treatment. The fecal microbiome and metabolome of these study participants were characterized by 300 bp pair end sequencing of the V3-V4 region of 16S rRNA gene and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) respectively to identify disease and treatment-specific variations, if any. Results: Drug naive ATB and NTB patients showed a significant reduction of gut microbial diversity with respect to age matched healthy controls in both the clinical sites. ATB patients had underrepresentation of gut commensals such as Faecalibacterium prausnitzii, Prevotella copri DSM 18205, Coprococcus catus, and overrepresentation of Clostridium difficile ATCC 9689 = DSM 1296. Longitudinally followed-up ATB patients showed elimination of Alkalihalobacillus with treatment initiation, whereas harmful taxa such as Stenotrophomonas and Klebsiella pneumoniae appeared in treatment-completed subjects. Interestingly, the fecal metabolites also showed group-specific differences, clustering ATB patients away from the controls irrespective of the study sites. Consistently, fecal 2-piperidinone abundance was higher in ATB patients compared to healthy controls. The fecal metabolome of longitudinally followed-up ATB patients showed a gradual shift towards healthy during the course of treatment completion. Conclusion: Gut microbial dysbiosis observed in tuberculosis patients at case presentation is partially resolved with 6 months of treatment completion and also reflected in their metabolite level. The observed microbial and metabolite imbalance in these ATB patients could explain disease pathology which needs further exploration to exploit their translational potential for therapeutics development.

Background After initial COVID-19 disease, immune dysregulation may persist and drive post-acute sequelae of COVID-19 (PASC). We described longitudinal trajectories of cytokines in adults up to 6 months following SARS-CoV-2 infection and explored early predictors of PASC. Methods RECoVERED is a prospective cohort of individuals with laboratory-confirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24 of follow-up. Monthly symptom questionnaires were completed from month 2 after illness onset onwards; lung diffusion capacity (DLCO) was tested at 6 months. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We used a linear mixed-effects model to study log-concentrations of cytokines over time, assessing their association with socio-demographic and clinical characteristics that were included in the model as fixed effects. Results 186/349 (53%) participants had [≥]2 serum samples and were included. Of these, 101 (54%: 45/101[45%] female, median age 55 years [IQR=45-64]) reported PASC at 12 and 24 weeks after illness onset. We included 37 reference samples (17/37[46%] female, median age 49 years [IQR=40-56]). PASC was associated with raised CRP and abnormal diffusion capacity with raised IL10, IL17, IL6, IP10 and TNF at 24 weeks in the multivariate model. Early (0-4 week) IL-1{beta} and BMI at illness onset were predictive of PASC at 24 weeks. Conclusions Our findings indicate that immune dysregulation plays an important role in PASC pathogenesis, especially among those individuals with reduced pulmonary function. Early IL-1{beta} shows promise as predictors of PASC.

Background ChatGPT(Chat Generative Pre-trained Transformer) is an artificial intelligence (AI) based on a natural language processing tool developed by OpenAI (California, USA). This systematic review examines the potential of Chat GPT in diagnosing and treating patients and its contributions to medical research. Methods In order to locate articles on ChatGPT's use in clinical practise and medical research, this systematic review used PRISMA standards and conducted database searches across several sources. Selected records were analysed using ChatGPT, which also produced a summary for each article. The resultant word document was transformed to a PDF and handled using ChatPDF. The review looked at topics pertaining to scholarly publishing, clinical practise, and medical research. Results We reviewed 118 publications. There are difficulties and moral conundrums associated with using ChatGPT in therapeutic settings and medical research. Patient inquiries, note writing, decision-making, trial enrolment, data management, decision support, research support, and patient education are all things that ChatGPT can help with. However, the solutions it provides are frequently inadequate and inconsistent, presenting issues with its originality, privacy, accuracy, bias, and legality. When utilising ChatGPT for academic writings, there are issues with prejudice and plagiarism, and because it lacks human-like characteristics, its authority as an author is called into question. Conclusions ChatGPT has limitations when used in research and healthcare. Even while it aids in patient treatment, concerns regarding accuracy, authorship, and bias arise. Currently, ChatGPT can serve as a "clinical assistant" and be a huge assistance with research and scholarly writing.

Twinning is a partnership method that focuses on mutual transfer of knowledge and skills between two parties, including organisations, clinical practices, universities, or individual health professionals. In midwifery, twinning is a particularly important tool that can help countries with high maternal and infant morbidity and mortality rates to make connections with countries where sickness and death rates related to birth are lower and the role of midwives is better developed. The aim of this rapid evidence summary is to explore the literature for midwifery twinning initiatives and the facilitators and challenges of twinning partnerships. Sixteen research reports and textual evidence were identified. Facilitators of successful implementation of twinning initiatives include having a clear vision and mission statement along with investing time and promoting a co-creational approach. Reciprocity along with the building of personal relationships. Strong leadership, commitment, values, mutual respect and personal rapport between the projects. Clear communication plans, workshops, peer exchange visits alongside regular virtual contact. Building on existing relationships, previous experience of international and cross-cultural work and being prepared to overcome cultural differences. Having a local project team and careful; matching and selection of twins and having an adaptable personality. Having funding available. Challenges include communication issues, cultural differences in communication, technological issues and economic considerations. Additionally misplaced expectations, such as difference in social expectations, or one twin partner expecting opportunities that are not agreed upon by the other poses challenges to the successful implementation of twinning initiatives

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated. Co-expression network analysis of the endothelial genes yielded three gene set modules as significantly associated with arteriolar hyalinosis. Pathway analysis of these modules showed enrichment of transforming growth factor beta / Bone morphogenetic protein (TGF{beta} / BMP) and vascular endothelial growth factor (VEGF) signaling pathways in the endothelial cell signatures. Ligand-receptor analysis identified multiple integrins and cell adhesion receptors as over-expressed in arteriolar hyalinosis, suggesting a potential role of integrin-mediated TGF{beta} signaling in arteriolar hyalinosis. Further analysis of arteriolar hyalinosis associated endothelial module genes identified focal segmental glomerular sclerosis as an enriched term. On validation in gene expression profiles from the Nephrotic Syndrome Study Network cohort, one of the three modules was significantly associated with the composite endpoint (> 40% reduction in estimated glomerular filtration rate (eGFR) or kidney failure) independent of age, sex, race and baseline eGFR, suggesting poor prognosis with elevated expression of genes in this module. Thus, integration of structural and single cell molecular features yielded biologically relevant gene sets, signaling pathways and ligand-receptor interactions, underlying arteriolar hyalinosis and putative targets for therapeutic intervention.

Mutational analyses of tumor DNA guide the use of targeted therapies and checkpoint inhibitors in management of solid tumors. Reducing false positive mutation calls without compromising sensitivity as gene panels increase in size, and whole exome and genome sequencing enters clinical use, remains a major challenge. Aiming for robust somatic mutation analyses in the clinical setting, we have developed VARify, an integrated, accurate and computationally efficient software for cancer genome analyses encompassing all steps from pre-processing of sequencing reads to mutation identification. Benchmarking to two state-of-the-art open-source somatic mutation analysis pipelines demonstrated accurate detection of clinically actionable point mutations, all while strongly reducing the number of false positive mutations reported, at comparable or faster speed. Further, the VARify output classified microsatellite unstable colorectal cancers by tumor mutation burden better than the other pipelines. In comparisons where the same tumors were subjected to different panel enrichment and sequencing technologies, VARify had the most consistent intersection of consensus mutations. False positive calls were produced when the same data was used as tumor and reference by the other pipelines, while VARify did not produce such calls. The calling uniformity across sequencing technologies of VARify and its tumor-only analysis derivative pipeline ALTOmate was also demonstrated. Taken together, these two novel pipelines can improve clinical mutation analysis to the benefit of cancer patients.

Purpose: Severe SARS-CoV-2 pneumonia remains incompletely understood. We aimed to summarize current evidence regarding clinical features, laboratory findings, and treatment of severe SARS-CoV-2 pneumonia. Methods: Online databases were searched from December 1, 2019, to April 15, 2020. Studies performed in adults, with the definition of severe SARS-CoV-2 pneumonia, enough case number (>10), and data on clinical features or laboratory findings were included. Data were extracted independently by two reviewers. Results: Eighteen articles of 2,435 severe cases were eligible for analysis, with the average ages ranging from 49 to 70 years old, hypertension as the most common comorbidity, fever as the most common manifestation, and acute respiratory distress syndrome (ARDS) as the most common complication. As compared to non-severe cases, severe pneumonia was featured with the lower counts of lymphocytes, CD8+ and CD4+ T cells, and higher levels of D-dimer, lactate dehydrogenase (LDH), IL-6 and IL-10. Antiviral therapy was the mainstay of treatment for severe SARS-CoV-2 pneumonia, and oseltamivir was the most commonly used antiviral reagent. Ventilation therapy, especially mechanical ventilation, was the primary and effective treatment. Conclusions: This study represents the first systematic summarization of the aspects of severe SARS-CoV-2 pneumonia, and its comparison with non-severe cases in symptoms and laboratory findings. Research including elder cases and from regions outside China, especially western countries, would generate benefits in a full understanding of severe SARS-CoV-2 pneumonia. High-quality studies are urgently required to confirm or exclude the possibility of a treatment benefit.

Introduction An appropriately staffed midwifery workforce is essential for the provision of safe and high-quality maternity care. However, there is a global and national shortage of midwives. Understaffed maternity services are frequently identified as contributing to unsafe care provision and adverse outcomes for mothers and babies. While there is a need to recruit midwives through pre-registration midwifery programmes, this is associated with cost and resource implications, and is counteracted to a large extent by the high number of midwives leaving the workforce. It is increasingly recognised that there is a critical need to attend to retention in midwifery in order to develop and maintain safe staffing levels. The objective of this review is to collate and map factors that have been found to influence attrition and retention in midwifery. Methods and analysis Joanna Briggs Institute guidance for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews will be used to guide the review process and reporting of the review. CINAHL, MEDLINE, PsycINFO, and Scopus databases will be used to carry out the search for relevant literature. Results will be screened against inclusion criteria. Data will be extracted using a pre-formed data extraction tool and findings will be presented in narrative, tabular, and graphical formats. Ethics and dissemination The review will collate data from existing research, therefore ethics approval is not required. Findings will be published in journals, presented at conferences, and will be translated into infographics and other formats for online dissemination. Strengths and limitations of this study This will be the first review to systematically map the factors found to influence midwives decision to stay in or leave their role as a midwife Scoping reviews provide a rigorous and structured method through which to collate and map evidence on a given topic This protocol and the full review will follow Joanna Briggs Institute guidance for scoping reviews and will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews The review will be of relevance to other high income countries but is unlikely be relevant for low and middle income countries

Wastewater-based testing (WBT) for SARS-CoV-2 has rapidly expanded over the past three years due to its ability to provide a comprehensive measurement of disease prevalence independent of clinical testing. The development and simultaneous application of the field blurred the boundary between measuring biomarkers for research activities and for pursuit of public health goals, both areas with well-established ethical frameworks. Currently, WBT practitioners do not employ a standardized ethical review process (or associated data management safeguards), introducing the potential for adverse outcomes for WBT professionals and community members. To address this deficiency, an interdisciplinary group developed a framework for a structured ethical review of WBT. The workshop employed a consensus approach to create this framework as a set of 11-questions derived from primarily public health guidance because of the common exemption of wastewater samples to human subject research considerations. This study retrospectively applied the set of questions to peer-reviewed published reports on SARS-CoV-2 monitoring campaigns covering the emergent phase of the pandemic from March 2020 to February 2022 (n=53). Overall, 43% of the responses to the questions were unable to be assessed because of lack of reported information. It is therefore hypothesized that a systematic framework would at a minimum improve the communication of key ethical considerations for the application of WBT. Consistent application of a standardized ethical review will also assist in developing an engaged practice of critically applying and updating approaches and techniques to reflect the concerns held by both those practicing and being monitored by WBT supported campaigns.

Electric stimulation via a Cochlear Implant (CI) enables people with severe to profound sensorineural hearing loss to regain speech understanding and music appreciation and thus allowing them to actively engage in social life. Three main manufacturers (Cochlear, MED-EL and Advanced Bionics) have been offering CI systems, thus challenging CI recipients and Otolaryngologists with a difficult decision, as currently no comprehensive overview or meta-analyses on performance outcome following CI implantation is available. The main goal of this scoping review is to provide evidence that data and standardized speech and music performance tests are available for performing such comparisons. To this end, a literature search was conducted to find studies that address speech and music outcomes in CI recipients. From a total of 1592 papers, 188 paper abstracts were analyzed and 147 articles were found suitable for examination of full text. From which, 42 studies were included for synthesis. A total of 16 studies used the consonant-nucleus-consonant (CNC) word recognition test in quiet at 60db SPL. We found that aside from technical comparisons, only very few publications compare speech outcomes across manufacturers of CI systems. Evidence suggests though, that these data are available in large CI centers in Germany and US. Future studies should therefore leverage large data cohorts to perform such comparisons that could provide critical evaluation criteria and assist both CI recipients and Otolaryngologists to make informed performance-based decisions.

Objective: Magnetomyography (MMG) is currently a rather unexplored neurophysiological modality and it is not known to which extent the number of motor units have an influence on the amplitude and the direction of the MMG-signal. Methods: A simultaneous invasive electromyography (iEMG), surface EMG (sEMG) and MMG using optically pumped magnetometer (OPM-MMG) of the right abductor digiti minimi muscle (ADM) of two healthy participants was recorded during a stepwise increasing electrical stimulation of the ADM innervating ulnar nerve. Then, the number of electrically evoked motor units was estimated (MUNE), the magnetic field vectors were reconstructed and aligned to the muscular anatomy. In addition, a finite element simulation of the ADM muscle was performed and compared to the experimental data. Results: The more motor units were activated by increasing electrical stimulation, the stronger the MMG signal became, which was the same for iEMG&sEMG (r>0.96). The finite element simulation showed the same relation between the magnetic and electric signal. Further, based on the simulation the number of activated muscular fibers and neuromuscular units could be estimated the ratio of signal to fibers determined. In addition, the precise vector direction of the magnetomyography (MMG) signal can reliably be recorded following the electric stimulation of the ulnar nerve and followed the muscle fiber direction. Conclusion: The MMG signal can be used to determine the amount of activated motor units, but also analysis of the magnetic field vector corresponds to the muscle fiber direction, offering a functional as well as structural characterization of muscles. The modelling and simulation is especially helpful to understand the magnetic muscular signal in detail. Significance: Next to establishing MUNE in MMG, our results provide the first quantitative comparison between MMG vs. iEMG&sEMG and highlight the possibilities of the vector component analysis in MMG.

It is important to monitor of antibiotic susceptibility patterns of bacteria in clinical settings periodically to ascertain the current trends as well as re-establish empirical therapy. This study aimed to determine bacterial contaminants and their antimicrobial susceptibility patterns from medical equipment, inanimate surfaces and clinical samples isolated from Thika Level V Hospital (TLVH). Three hundred and five samples were collected and comprised of urine, pus swabs, catheter swabs, stool and environmental samples. Bacterial identification and antimicrobial susceptibility testing were done on VITEK 2 and disc diffusion respectively. Coagulase negative Staphylococci (28 /160, 17.5%) were the most isolated species from patients followed by E. coli (22 /160 13.8%) and S. aureus (22/160, 13.8%). The bed rail was the most contaminated surface with S. aureus at (6/42)14.2%. The clinical sample that yielded the highest number of pathogens was pus (92/160). Trauma patients had the largest proportion of isolates (67/160, 41.8%). Bacteria recovered from this study demonstrated high levels of resistance especially enteric bacteria. Extended Spectrum Beta Lactamase phenotype was noted in 29/44 (65.9%) enteric isolates. Although ESBL genetic confirmatory studies are needed, this study shows that there is an urgent need for actions that mitigate the spread of antibiotics resistant bacteria.

Background: Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. Aims: To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3+CD152+, FoxP3+GARP+, and FoxP3+CB1+ cells. Methods: We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20+CB2+ B cells, in 30 MDD patients and 20 healthy controls. Results: A larger part of the variance in the depression phenome (40.8%) was explained by increased CD20+CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20+CB2+, CD3+CD71+, CD3+CD40L+, CD4+CD71+, CD4+CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8+CD40L+ numbers. The sum of ACEs was significantly associated with CD20+CB2+, CD3+CD40L+, CD4+40L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8% of its variance was explained by ACEs. Conclusions: ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses.

While the identification of autoantigens remains a critical challenge in understanding and treating autoimmune diseases, the role of autoantibodies in the pathophysiology of autoimmune hepatitis (AIH) is uncertain. To better characterize the antigenic landscape of AIH, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies specific to patients. Using these results, a logistic regression classifier was able to predict which patients had AIH, relative to healthy controls indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified with >98% specificity relative to a broad array of controls (298 patients with NAFLD, PBV, or healthy controls). Top ranked autoreactive targets included anti-SLA, a well-recognized autoantibody in AIH, and a second hit to disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a nearly identical 8 amino acid stretch with the U27 protein of HHV-6, a virus known to reside in the liver. Finally, peptides derived from the LRRNT domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, required for RXFP1 signaling. RXFP1 is a G-protein coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in THP1 cells relative to anti-RXFP1 negative control serum, while depletion of IgG abrogated this effect. These data demonstrate that PhIP-Seq is a powerful discovery tool, capable of identifying known and novel autoantibody targets in AIH, lending additional supporting evidence that HHV6 may play a role in the development of AIH, and pointing to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention.

Identifying novel mechanisms underlying dementia is critical to improving prevention and treatment. As an approach to mechanistic discovery, we investigated whether MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), a consistent risk factor for dementia, is correlated with a specific profile of cortical gene expression, and whether such a transcriptomic profile is associated with dementia, in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). RNA sequencing (RNA-Seq) was conducted in postmortem dorsolateral prefrontal cortex tissue from 1,204 deceased participants; neuropsychological assessments were performed annually prior to death. In a subset of 482 participants, diet was assessed ~6 years before death using a validated food-frequency questionnaire; in these participants, using elastic net regression, we identified a transcriptomic profile, consisting of 50 genes, significantly correlated with MIND diet score (P=0.001). In multivariable analysis of the remaining 722 individuals, higher transcriptomic score of MIND diet was associated with slower annual rate of decline in global cognition ({beta}=0.011 per standard deviation increment in transcriptomic profile score, P=0.003) and lower odds of dementia (odds ratio [OR] =0.76, P=0.0002). Cortical expression of several genes appeared to mediate the association between MIND diet and dementia, including TCIM, whose expression in inhibitory neurons and oligodendrocytes was associated with dementia in a subset of 424 individuals with single-nuclei RNA-seq data. In a secondary Mendelian randomization analysis, genetically predicted transcriptomic profile score was associated with dementia (OR=0.93, P=0.04). Our study suggests that associations between diet and cognitive health may involve brain molecular alterations at the transcriptomic level. Investigating brain molecular alterations related to diet may inform the identification of novel pathways underlying dementia.

Gastric Bypass surgery (GBS) represents a well-established approach to counteract human morbid obesity and its related comorbidities in modern countries. Beside its beneficial effect on weight loss and glucose homeostasis, emerging evidence suggests that GBS impacts on the circulating levels of phospho- and sphingolipids. However, long-term effects of GBS on lipid metabolism have not been explored. Thereby, we aimed to unveil to what extent GBS improves lipid homeostasis in serum and tissues from morbid obese individuals. To investigate alterations in lipidomic signatures associated with massive weight loss following GBS in morbid obese patients, we employed direct infusion tandem mass spectrometry (MS) allowing to quantify a wide range of lipid metabolites in serum and subcutaneous adipose tissue (SAT) samples. Systematic lipidomic analyses were conducted in samples collected in a longitudinal cohort of patients (cohort 1, n = 11) prior to GBS, and one year following the surgery. These novel data (cohort 1) were cross compared with our recent lipidomic analyses conducted by the same approach in an independent cohort of morbid obese patients and lean controls, where serum (n = 7 lean and n = 16 obese individuals) and visceral adipose tissue (VAT) (n = 5 control and n = 11 obese individuals) lipids were analysed (cohort 2). Over 400 phospholipid and sphingolipid species have been quantified in serum and SAT (cohort 1), allowing to establish detailed lipidomic signatures associated with morbid obesity in a tissue-specific manner. Concomitant with weight loss and improvement of metabolic parameters, a massive rearrangement of lipid metabolites was observed one year following GBS. Strikingly, a substantial reduction of ceramide levels and increased amount of hexosylceramides were detected in both serum and SAT. The comparison of these new lipidomic profiles with the serum and VAT lipidomes established from lean and morbid obese subjects (cohort 2) revealed that GBS partly restored the lipid alterations associated with morbid obesity. Our study provides the first systematic analysis of the long-term lipid homeostasis modifications upon GBS in humans SAT and serum and demonstrates that lipid metabolism alterations associated with morbid obesity might be partly reversed by GBS. The research protocols were registered with the Protocol Registration and Results System at ClinicalTrial.gov [NCT 02384148] [NCT03029572].

Objective: To summarise and critically appraise systematic review (SR) evidence on the effects of timing of complementary feeding (CF) on the occurrence of allergic sensitisation and disease. Design: Overview of SRs. AMSTAR-2 and ROBIS were used to assess methodological quality and risk of bias (RoB) of SRs. RoB Tool 2.0 was used to assess RoB of primary randomised controlled trials (RCTs) (or extracted). The Certainty of Evidence (CoE) was assessed using GRADE. Findings were synthesised narratively. Data sources: MEDLINE (via PubMed and Ovid), the Cochrane Library and Web of Science Core Collection. Eligibility criteria: SRs investigating the effects of timing of CF on risk of developing food allergy (FA), allergic sensitisation, asthma, allergic rhinitis, atopic eczema, and adverse events in infants or young children (0-3 years), based on RCT evidence. Results: Eleven SRs were included, with predominantly low methodological quality and high RoB. Primary study overlap was very high for specific FA and slight to moderate for FA in general and other primary outcomes. Introducing specific foods (peanut, cooked egg) early probably reduces the risk of specific FA based on evidence across most SRs. The evidence for other allergic outcomes was mostly very uncertain and based on single primary studies. SRs varied regarding the timing of CF, the nature of complementary foods and the population risk, which limited comparability between SRs. Conclusions: The overlap of primary studies within SRs was high to very high for many outcomes, overemphasising single trials. Future research should focus on producing high quality trials and SRs that allow drawing more trustworthy conclusions. For developing guidelines to support decision-making on the timing of CF as a preventive strategy, the early introduction of specific foods (i.e., egg and peanut) seems promising and safe whereas more extensive research is required regarding other allergic outcomes and potential adverse events. Registration: PROSPERO (CRD42021240160); Open Science Forum (https://doi.org/10.17605/OSF.IO/HJKUN)

Introduction: Targeted temperature management (TTM) has been associated with greater likelihood of neurological recovery among comatose survivors of cardiac arrest. However, the efficacy of TTM is not consistently observed, possibly due to heterogeneity of therapeutic response. The aim of this study is to determine if models leveraging multi-modal data available in the first 12 hours after ICU admission (hyperacute phase) can predict short-term outcome after TTM. Methods: Adult patients receiving TTM after cardiac arrest were selected from a multicenter ICU database. Predictive features were extracted from clinical, physiologic, and laboratory data available in the hyperacute phase. Primary endpoints were survival and favorable neurological outcome, determined as the ability to follow commands (motor Glasgow Coma Scale [mGCS] of 6) upon discharge. Three machine learning (ML) algorithms were trained: generalized linear models (GLM), random forest (RF), and gradient boosting (XG). Models with optimal features from forward selection were 10-fold cross-validated and resampled 10 times. Results: Data were available on 310 cardiac arrest patients who received TTM, of whom 183 survived and 123 had favorable neurological outcome. The GLM performed best, with an area under the receiver operating characteristic curve (AUROC) of 0.86 {+/-} 0.04, sensitivity 0.75 {+/-} 0.09, and specificity 0.77 {+/-} 0.07 for the prediction of survival and an AUROC of 0.85 {+/-} 0.03, sensitivity 0.71 {+/-} 0.10, and specificity 0.80 {+/-} 0.12 for the prediction of favorable neurological outcome. Features most predictive of both endpoints included lower serum chloride concentration, higher serum pH, and greater neutrophil counts. Conclusion: In patients receiving TTM after cardiac arrest, short-term outcomes can be accurately discriminated using ML applied to data routinely collected in the first 12 hours after ICU admission. With validation, hyperacute prediction could enable personalized approach to clinical decision-making in the post-cardiac arrest setting.