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In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: SARS-CoV-2 antigen-detection rapid diagnostic tests (Ag-RDTs) have become widely utilized but longitudinal characterization of their community-based performance remains incompletely understood., Methods: This prospective longitudinal study at a large public university in Seattle, WA utilized remote enrollment, online surveys, and self-collected nasal swab specimens to evaluate Ag-RDT performance against real-time reverse transcription polymerase chain reaction (rRT-PCR) in the context of SARS-CoV-2 Omicron. Ag-RDT sensitivity and specificity within 1 day of rRT-PCR were evaluated by symptom status throughout the illness episode and Orf1b cycle threshold (Ct)., Results: From February to December 2022, 5757 participants reported 17 572 Ag-RDT results and completed 12 674 rRT-PCR tests, of which 995 (7.9%) were rRT-PCR positive. Overall sensitivity and specificity were 53.0% (95% confidence interval [CI], 49.6%-56.4%) and 98.8% (95% CI, 98.5%-99.0%), respectively. Sensitivity was comparatively higher for Ag-RDTs used 1 day after rRT-PCR (69.0%), 4-7 days after symptom onset (70.1%), and Orf1b Ct ≤20 (82.7%). Serial Ag-RDT sensitivity increased with repeat testing ≥2 (68.5%) and ≥4 (75.8%) days after an initial Ag-RDT-negative result., Conclusions: Ag-RDT performance varied by clinical characteristics and temporal testing patterns. Our findings support recommendations for serial testing following an initial Ag-RDT-negative result, especially among recently symptomatic persons or those at high risk for SARS-CoV-2 infection., Competing Interests: Potential conflicts of interest. H. Y. C. reports consulting for Ellume, Pfizer, the Bill and Melinda Gates Foundation, Glaxo Smith Kline, and Merck; research funding from Gates Ventures, Sanofi Pasteur; and support and reagents from Ellume and Cepheid, outside of the submitted work. J. A. E. reports research support from Gates Ventures, AstraZeneca, GlaxoSmithKline, Merck, and Pfizer; and consulting for Sanofi Pasteur, AstraZeneca, Teva Pharmaceuticals, and Meissa Vaccines, outside of the submitted work. M. B. reports research support from Vir Biotechnology, GSK, Regeneron, Gilead Sciences, Janssen Pharmaceutica, Ridgeback, Merck, and Gates Ventures; and consulting for Vir Biotechnology, Moderna, Helocyte, and Merck, outside of the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Individualizing treatment assignment can improve outcomes for diseases with patient-to-patient variability in comparative treatment effects. When a clinical trial demonstrates that some patients improve on treatment while others do not, it is tempting to assume that treatment effect heterogeneity exists. However, if outcome variability is mainly driven by factors other than variability in the treatment effect, investigating the extent to which covariate data can predict differential treatment response is a potential waste of resources. Motivated by recent meta-analyses assessing the potential of individualizing treatment for major depressive disorder using only summary statistics, we provide a method that uses summary statistics widely available in published clinical trial results to bound the benefit of optimally assigning treatment to each patient. We also offer alternate bounds for settings in which trial results are stratified by another covariate. Our upper bounds can be especially informative when they are small, as there is then little benefit to collecting additional covariate data. We demonstrate our approach using summary statistics from a depression treatment trial. Our methods are implemented in the rct2otrbounds R package., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca 2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, the systems regulating cellular Ca 2+ are compromised, leading to Ca 2+ -dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca 2+ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca 2+ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca 2+ . Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca 2+ metabolism is believed to contribute to the disease's pathophysiology. The Na+-Ca 2+ exchanger (NCX) is considered an important key regulator of Ca 2+ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca 2+ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration.

Introduction: Patients with chronic obstructive pulmonary disease (COPD) frequently have cardiovascular comorbidities, increasing the risk of hospitalised COPD exacerbations (H-ECOPDs) or death. This pragmatic study examined the effects of adding an inhaled corticosteroid (ICS) to long-acting bronchodilator(s) (LABDs) in patients with COPD and cardiac comorbidities who had a recent H-ECOPD., Methods: Patients >60 years of age with COPD and ≥1 cardiac comorbidity, within 6 months after discharge following an H-ECOPD, were randomised to receive LABD(s) with or without ICS, and were followed for 1 year. The primary outcome was the time to first rehospitalisation and/or all-cause death., Results: The planned number of patients was not recruited (803/1032), limiting the strength of the conclusions. In the intention-to-treat population, 89/403 patients (22.1 %) were rehospitalised or died in the LABD group (probability 0.257 [95 % confidence interval 0.206, 0.318]), vs 85/400 (21.3 %) in the LABD+ICS group (0.249 [0.198, 0.310]), with no difference between groups in time-to-event (hazard ratio 1.116 [0.827, 1.504]; p = 0.473). All-cause and cardiovascular mortality were lower in patients receiving LABD(s)+ICS, with relative reductions of 19.7 % and 27.4 %, respectively (9.8 % vs 12.2 % and 4.5 % vs 6.2 %), although the groups were not formally statistically compared for these endpoints. Fewer patients had adverse events in the LABD+ICS group (43.0 % vs 50.4 %; p = 0.013), with 4.9 % vs 5.4 % reporting pneumonia adverse events., Conclusions: Results suggest addition of ICS to LABDs did not reduce the time-to-combined rehospitalisation/death, although it decreased all-cause and cardiovascular mortality. ICS use was not associated with an increased risk of adverse events, particularly pneumonia., Competing Interests: Declaration of competing interest In addition to the medical writing support disclosed below, the authors have the following conflicts of interest. Alberto Papi reports grants to his institution from Chiesi, AstraZeneca, GlaxoSmithKline and Sanofi, consulting fees from Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals, Moderna, and Roche, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi, AstraZeneca, GlaxoSmithKline, Menarini, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion, Sanofi, and Regeneron, and participation on advisory boards for Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals, and Moderna. All are outside the scope of the current manuscript. Giacomo Forini has no other conflicts to disclose. Mauro Maniscalco declares grants or contracts (with payments to Istituti Clinici Scientifici Maugeri IRCCS) from GlaxoSmithKline and AstraZeneca, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GlaxoSmithKline, AstraZeneca, and Chiesi. All are outside the scope of the current manuscript. Elena Bargagli has no other conflicts to disclose. Claudia Crimi received honoraria for lectures from Fisher & Paykel, ResMed, AstraZeneca, Sanofi, GlaxoSmithKline, and Vitalaire. All are outside the scope of the current manuscript. Pierachille Santus declares research grants from AstraZeneca, Edmondpharma, GlaxoSmithKline, and Novartis (payments were made to the Department of Biomedical and Clinical Sciences of University of Milan), consulting fees from GlaxoSmithKline, Sanofi, Edmondpharma, Dompè, Valeas, and Neopharmed, and honoraria for lectures from AstraZeneca, Sanofi, GlaxoSmithKline, Berlin Chemie, Edmondpharma, and Zambon Brasil. All are outside the scope of the current manuscript. Antonio Molino has no other conflicts to disclose. Valeria Bandiera is an employee of Alira Health SrI, which received funding from the Università degli Studi di Ferrara to provide biometrics services to the study. Federico Baraldi received a short-term research fellowship from the European Respiratory Society, outside the scope of the current manuscript Silvestro Ennio D'Anna has no other conflicts to disclose. Mauro Carone received honoraria as speaker from GlaxoSmithKline and AstraZeneca, and honoraria for participation in speaker bureaus from Boehringer Ingelheim, support for attending meetings and travel from the Associazione Italiana Pneumologi Ospedalieri – Italian Thoracic Society (AIPO-ITS/ETS), and an unpaid role as the National President of the AIPO-ITS/ETS. All are outside the scope of the current manuscript. Maurizio Marvisi has no other conflicts to disclose. Corrado Pelaia received honoraria for lectures from AstraZeneca, GlaxoSmithKline, and Sanofi, all outside the scope of the current manuscript. Giulia Scioscia has no other conflicts to disclose. Vincenzo Patella has no other conflicts to disclose. Maria Aliani has no other conflicts to disclose. Leonardo M Fabbri received consulting fees from Alfasigma, AstraZeneca, Chiesi, GlaxoSmithKline, ICON, Menarini, Novartis, and Verona Pharma, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi, GlaxoSmithKline, Glenmark, Lusofama, and Novartis, support for attending meetings and/or travel from the Italian Society of Allergy, Asthma and Clinical Immunology and the Menarini Foundation, and participated in a data safety monitoring board or advisory board for Novartis, Chiesi, and ICON. All are outside the scope of the current manuscript., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Due to its chronic nature and complex pathophysiology, inflammatory bowel disease (IBD) poses significant challenges for treatment. The long-term therapies for patients, often diagnosed between the ages of 20 and 40, call for innovative strategies to target inflammation, minimize systemic drug exposure, and improve patients' therapeutic outcomes. Among the plethora of strategies currently pursued, bioinspired and bioderived nano-based formulations have garnered interest for their safety and versatility in the management of IBD. Bioinspired nanomedicine can host and deliver not only small drug molecules but also biotherapeutics, be made gastroresistant and mucoadhesive or mucopenetrating and, for these reasons, are largely investigated for oral administration, while surprisingly less for rectal delivery, recommended first-line treatment approach for several IBD patients. The use of bioderived nanocarriers, mostly extracellular vesicles (EVs), endowed with unique homing abilities, is still in its infancy with respect to the arsenal of nanomedicine under investigation for IBD treatment. An emerging source of EVs suited for oral administration is ingesta, that is, plants or milk, thanks to their remarkable ability to resist the harsh environment of the upper gastrointestinal tract. Inspired by the unparalleled properties of natural biomaterials, sophisticated avenues for enhancing therapeutic efficacy and advancing precision medicine approaches in IBD care are taking shape, although bottlenecks arising either from the complexity of the nanomedicine designed or from the lack of a clear regulatory pathway still hinder a smooth and efficient translation to the clinics. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2024 The Author(s). WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Objective: We aimed to evaluate the feasibility and utility of an unsupervised testing mechanism, in which participants pick up a swab kit, self-test (unsupervised) and return the kit to an on-campus drop box, as compared with supervised self-testing at staffed locations., Design: University SARS-CoV-2 testing cohort., Setting: Husky Coronavirus Testing provided voluntary SARS-CoV-2 testing at a university in Seattle, USA., Outcome Measures: We computed descriptive statistics to describe the characteristics of the study sample. Adjusted logistic regression implemented via generalised estimating equations was used to estimate the odds of a self-swab being conducted through unsupervised versus supervised testing mechanisms by participant characteristics, including year of study enrolment, pre-Omicron versus post-Omicron time period, age, sex, race, ethnicity, affiliation and symptom status., Results: From September 2021 to July 2022, we received 92 499 supervised and 26 800 unsupervised self-swabs. Among swabs received by the laboratory, the overall error rate for supervised versus unsupervised swabs was 0.3% vs 4%, although this declined to 2% for unsupervised swabs by the spring of the academic year. Results were returned for 92 407 supervised (5% positive) and 25 836 unsupervised (4%) swabs from 26 359 participants. The majority were students (79%), 61% were female and most identified as white (49%) or Asian (34%). The use of unsupervised testing increased during the Omicron wave when testing demand was high and stayed constant in spring 2022 even when testing demand fell. We estimated the odds of using unsupervised versus supervised testing to be significantly greater among those <25 years of age (p<0.001), for Hispanic versus non-Hispanic individuals (OR 1.2, 95% CI 1.0 to 1.3, p=0.01) and lower among individuals symptomatic versus asymptomatic or presymptomatic (0.9, 95% CI 0.8 to 0.9, p<0.001)., Conclusions: Unsupervised swab collection permitted increased testing when demand was high, allowed for access to a broader proportion of the university community and was not associated with a substantial increase in testing errors., Competing Interests: Competing interests: HYC reports consulting with Ellume, Pfizer, The Bill & Melinda Gates Foundation, Glaxo Smith Kline and Merck. HYC received research funding from Gates Ventures, Sanofi Pasteur and support and reagents from Ellume and Cepheid outside of the submitted work. GG received research grants and research support from the US National Institutes of Health, the University of Washington, the Bill & Melinda Gates Foundation, Gilead Sciences, Alere Technologies, Merck & Co., Janssen Pharmaceutica, Cerus Corporation, ViiV Healthcare, Bristol-Myers Squibb, Roche Molecular Systems, Abbott Molecular Diagnostics and THERA Technologies/TaiMed Biologics, all outside of the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cannabis sativa is the most used recreational drug worldwide. In recent years, there has been a growing interest in the potential therapeutic benefits of medicinal cannabis to treat a variety of psychiatric and neurological conditions. In particular, cannabidiol (CBD), a nonpsychoactive cannabis constituent, has been investigated for its potential prosocial effects on behavior, although the molecular mechanisms underlying this effect are still largely unknown. The aim of this study was to investigate the effect of a C. sativa oil CBD rich (CS oil) on social interaction and ultrasonic communication in mice. Study Design: Twenty-seven adult male mice (B6; 129P F2) were treated daily with vehicle or CS oil for 2 weeks. At Day 14, mice were tested for behavior (social interaction test and ultrasonic communication). Forty minutes before the behavioral tests, mice were exposed to intranasal treatment with vehicle or the oxytocin receptor antagonist, L-371,257. After behavioral tests, VH- and CS oil-treated mice were sacrificed, RNA was extracted from the hypothalamus and used for quantitative Real Time-PCR experiments. Results: We found that a 2-week treatment with the CS oil on mice exerted a prosocial effect associated with an increase in ultrasonic vocalizations. These effects were inhibited by pretreating mice with an oxytocin receptor antagonist. In addition, at the molecular level, we found that CS oil treatment caused a significant increase in oxytocin and a decrease in oxytocin receptor expression levels in the brain hypothalamus. Conclusion: Our results suggest that CS oil promotes social behavior by acting on oxytocin pathway.

A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause. Moreover, the multitude of statistical methods garnered for CoP evaluation in phase 3 trials renders the comparison, interpretation, and synthesis of CoP results challenging. Toward promoting broader harmonization and standardization of CoP evaluation, this article summarizes four complementary statistical frameworks for evaluating CoPs in a phase 3 trial, focusing on the frameworks' distinct scientific objectives as measured and communicated by distinct causal vaccine efficacy parameters. Advantages and disadvantages of the frameworks are considered, dependent on phase 3 trial context, and perspectives are offered on how the frameworks can be applied and their results synthesized., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.

Vaccine effectiveness (VE) studies utilizing the test-negative design are typically conducted in clinical settings, rather than community populations, leading to bias in VE estimates against mild disease and limited information on VE in healthy young adults. In a community-based university population, we utilized data from a large SARS-CoV-2 testing program to estimate relative VE of COVID-19 mRNA vaccine primary series and monovalent booster dose versus primary series only against symptomatic SARS-CoV-2 infection from September 2021 to July 2022. We used the test-negative design and logistic regression implemented via generalized estimating equations adjusted for age, calendar time, prior SARS-CoV-2 infection, and testing frequency (proxy for test-seeking behavior) to estimate relative VE. Analyses included 2,218 test-positive cases (59 % received monovalent booster dose) and 9,615 test-negative controls (62 %) from 9,066 individuals, with median age of 21 years, mostly students (71 %), White (56 %) or Asian (28 %), and with few comorbidities (3 %). More cases (23 %) than controls (6 %) had COVID-19-like illness. Estimated adjusted relative VE of primary series and monovalent booster dose versus primary series only against symptomatic SARS-CoV-2 infection was 40 % (95 % CI: 33-47 %) during the overall analysis period and 46 % (39-52 %) during the period of Omicron circulation. Relative VE was greater for those without versus those with prior SARS-CoV-2 infection (41 %, 34-48 % versus 33 %, 9 %-52 %, P < 0.001). Relative VE was also greater in the six months after receiving a booster dose (41 %, 33-47 %) compared to more than six months (27 %, 8-42 %), but this difference was not statistically significant (P = 0.06). In this relatively young and healthy adult population, an mRNA monovalent booster dose provided increased protection against symptomatic SARS-CoV-2 infection, overall and with the Omicron variant. University testing programs may be utilized for estimating VE in healthy young adults, a population that is not well-represented by routine VE studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Helen Y. Chu reports a relationship with Ellume that includes: consulting or advisory. Helen Y. Chu reports a relationship with Pfizer that includes: consulting or advisory. Helen Y. Chu reports a relationship with The Bill and Melinda Gates Foundation that includes: consulting or advisory. Helen Y. Chu reports a relationship with Glaxo Smith Kline Eesti OÜ that includes: consulting or advisory. Helen Y. Chu reports a relationship with Merck & Co Inc that includes: consulting or advisory. Helen Y. Chu reports a relationship with Gates Ventures that includes: funding grants. Helen Y. Chu reports a relationship with Sanofi Pasteur that includes: funding grants. Helen Y. Chu reports a relationship with Ellume that includes: funding grants. Helen Y. Chu reports a relationship with Cepheid that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with US National Institutes of Health that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with University of Washington that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with The Bill and Melinda Gates Foundation that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Gilead Sciences that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Alere Technologies that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Merck & Co Inc that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Janssen Pharmaceutica that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Cerus Corporation that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with ViiV Healthcare that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Bristol-Myers Squibb that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Roche Molecular Systems that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Abbott Molecular Diagnostics that includes: funding grants. Geoffrey S. Gottlieb reports a relationship with Theratechnologies Inc that includes: funding grants. Janet A. Englund reports a relationship with AstraZeneca that includes: funding grants. Janet A. Englund reports a relationship with GlaxoSmithKline that includes: funding grants. Janet A. Englund reports a relationship with Merck & Co Inc that includes: funding grants. Janet A. Englund reports a relationship with Pfizer that includes: funding grants. Janet A. Englund reports a relationship with Abbvie that includes: consulting or advisory. Janet A. Englund reports a relationship with AstraZeneca that includes: consulting or advisory. Janet A. Englund reports a relationship with Ark Biopharma that includes: consulting or advisory. Janet A. Englund reports a relationship with GlaxoSmithKline that includes: consulting or advisory. Janet A. Englund reports a relationship with Meissa Vaccines that includes: consulting or advisory. Janet A. Englund reports a relationship with Moderna that includes: consulting or advisory. Janet A. Englund reports a relationship with Pfizer that includes: consulting or advisory. Janet A. Englund reports a relationship with Sanofi Pasteur that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the absence of data from a randomized trial, researchers may aim to use observational data to draw causal inference about the effect of a treatment on a time-to-event outcome. In this context, interest often focuses on the treatment-specific survival curves, that is, the survival curves were the population under study to be assigned to receive the treatment or not. Under certain conditions, including that all confounders of the treatment-outcome relationship are observed, the treatment-specific survival curve can be identified with a covariate-adjusted survival curve. In this article, we propose a novel cross-fitted doubly-robust estimator that incorporates data-adaptive (e.g. machine learning) estimators of the conditional survival functions. We establish conditions on the nuisance estimators under which our estimator is consistent and asymptotically linear, both pointwise and uniformly in time. We also propose a novel ensemble learner for combining multiple candidate estimators of the conditional survival estimators. Notably, our methods and results accommodate events occurring in discrete or continuous time, or an arbitrary mix of the two. We investigate the practical performance of our methods using numerical studies and an application to the effect of a surgical treatment to prevent metastases of parotid carcinoma on mortality., Competing Interests: Conflicts of Interest The authors report there are no competing interests to declare.

The conditional survival function of a time-to-event outcome subject to censoring and truncation is a common target of estimation in survival analysis. This parameter may be of scientific interest and also often appears as a nuisance in nonparametric and semiparametric problems. In addition to classical parametric and semiparametric methods (e.g., based on the Cox proportional hazards model), flexible machine learning approaches have been developed to estimate the conditional survival function. However, many of these methods are either implicitly or explicitly targeted toward risk stratification rather than overall survival function estimation. Others apply only to discrete-time settings or require inverse probability of censoring weights, which can be as difficult to estimate as the outcome survival function itself. Here, we employ a decomposition of the conditional survival function in terms of observable regression models in which censoring and truncation play no role. This allows application of an array of flexible regression and classification methods rather than only approaches that explicitly handle the complexities inherent to survival data. We outline estimation procedures based on this decomposition, empirically assess their performance, and demonstrate their use on data from an HIV vaccine trial. Supplementary materials for this article are available online., Competing Interests: Conflict of interest statement The authors report there are no competing interests to declare.

Background: While epidemiologic evidence links higher levels of exposure to fine particulate matter (PM 2.5 ) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence., Objective: To evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO 2 ]) and late-life dementia incidence., Methods: We ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM 2.5 , and APOE genotype. We ran sensitivity analyses where we did not adjust for PM 2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others., Results: We identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92-1.05) for every 2000 pt/cm 3 increment in UFP, 0.95 (0.89-1.01) for every 100 ng/m 3 increment in BC, and 0.96 (0.91-1.02) for every 2 ppb increment in NO 2 . These findings were consistent across sensitivity and secondary analyses., Discussion: We did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two chronic diseases that afflict many individuals worldwide with negative effects on health that may overlap in Overlap Syndrome (OS). The aim of our study was to investigate the differences in mortality between OSAS alone and OS and the risk factors involved., Methods: The study was conducted on patients with OSAS or OS diagnosis that completed 15-year follow-up between 2005 and 2023. Of these, the clinical, functional, sleep and survival data were registered and analysed. Risk factors were found by regression analysis., Results: 501 patients (428 OSAS and 73 OS) were enrolled. Patients with OS had higher mortality than OSAS (p < 0,001). The morality risk factors for the overall population found were age >65 years (odds ratio (OR) = 10.69 (95%CI 3,85-29,69), p < 0,001) and low forced-expiratory volume in 1-s (FEV 1 ) (OR = 10.18 (95%CI 2,32-44,68), p = 0,002). In patients with OSAS, age and nocturnal hypoxemia (NH) (OR = 2.41 (95%CI 1,07-5,41), p = 0,03) were risk factors, while adherence to nighttime positive airway pressure (PAP) reduced mortality (OR = 0,36 (95%CI 0,15-0,83), p = 0,017). Multivariate analysis confirmed age and FEV 1 as risk factors in OS. Conversely, the risk factors for the overall population under 65 years were NH, which is confirmed in patients with OSAS alone (OR = 4,72 (95%CI 1,07-20,77), p = 0,04) in whom, on the other hand, PAP compliance reduced the mortality risk., Conclusions: The study suggests that NH is a risk factor for all-cause mortality in sleep disorders by excluding the age; conversely, nighttime PAP improves the survival., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation., (© The Author 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Severe asthma (SA) is a chronic inflammatory disease of the airways. Due to the extreme heterogeneity of symptoms, new biomarkers are currently needed. MiRNAs are non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In biological fluids, miRNAs are contained within exosomes, vesicles capable of giving miRNAs considerable stability and resistance to degradation by RNAses. The main function attributed to the exosomes is intercellular communication. The goal of our study was to analyze intracellular and exosomal miRNAs in order to demonstrate their potential use as non-invasive biomarkers of asthma by showing, in particular, their role in SA. We detected miRNAs by qRT-PCR in both serum and serum-derived-exosomes of asthmatic patients and healthy controls. The levels of almost all analyzed intracellular miRNAs (miR-21, miR-223, and let-7a) were greater in asthmatic patients vs. healthy control, except for miR-223. In detail, miR-21 was greater in SA, while let-7a increased in mild-to-moderate asthma. On the other hand, in exosomes, all analyzed miRNAs were higher in SA. This study identified a series of miRNAs involved in SA, highlighting their potential role in asthma development and progression. These results need validation on a larger cohort.

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

Summary: Background. Asthma affects millions of people worldwide, with a subgroup suffering from severe asthma (SA). Biologics have revolutionized SA treatment, but challenges remain in managing different patient traits. This study analyzed data from the Italian Registry on Severe Asthma (IRSA) to investigate changes in SA characteristics and effectiveness of treatments after one year of follow-up, and to identify factors associated with response to treatments in a real-world setting. Methods. Data on SA patients with one year of follow-up were extracted from IRSA. Asthma control, exacerbations, lung function, and treatments, were assessed at follow-up and analyzed against baseline characteristics. Results. After one year of follow-up, notable improvements were observed in all the outcomes of SA of the included patients (n = 570). The effectiveness of biologic therapies was particularly evident, as they contributed significantly to these positive outcomes. Additionally, certain factors were found to be associated with improvement, namely T2 phenotype, baseline eosinophil count (BEC), and area of residence. On the other hand, comorbidities (obesity, gastro-esophageal reflux disease) and poor lung function were risk factors. Notably, poor-responders to biologics exhibited lower level of education, BEC, and exacerbations, and higher frequency of atopy and ACT score ≥ 20. Conclusions. The findings demonstrate the effectiveness of biologics in asthma management, when implemented as part of a planned follow-up strategy aimed at optimizing and fine-tuning the therapy. Moreover, the study highlights the importance of considering key traits such as the T2 phenotype, BEC, education, and comorbidities when tailoring SA treatment. Overall, this study contributes to enhancing our understanding of SA management and guiding the development of personalized treatment approaches for patients with SA.

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Although SARS-CoV-2 vaccines were first approved under Emergency Use Authorization by the Food and Drug Administration in late 2020 for adults, authorisation for young children 6 months to <5 years of age did not occur until 2022. These authorisations were based on clinical trials, understanding real-world vaccine effectiveness (VE) in the setting of emerging variants is critical. The primary goal of this study is to evaluate SARS-CoV-2 VE against infection among children aged >6 months and adults aged <50 years., Methods: CASCADIA is a 4-year community-based prospective study of SARS-CoV-2 VE among 3500 adults and paediatric populations aged 6 months to 49 years in Oregon and Washington, USA. At enrolment and regular intervals, participants complete a sociodemographic questionnaire. Individuals provide a blood sample at enrolment and annually thereafter, with optional blood draws every 6 months and after infection and vaccination. Participants complete weekly self-collection of anterior nasal swabs and symptom questionnaires. Swabs are tested for SARS-CoV-2 and other respiratory pathogens by reverse transcription-PCR, with results of selected pathogens returned to participants; nasal swabs with SARS-CoV-2 detected will undergo whole genome sequencing. Participants who test positive for SARS-CoV-2 undergo serial swab collection every 3 days for 21 days. Serum samples are tested for SARS-CoV-2 antibody by binding and neutralisation assays., Analysis: The primary outcome is SARS-CoV-2 infection. Cox regression models will be used to estimate the incidence rate ratio associated with SARS-CoV-2 vaccination among the paediatric and adult population, controlling for demographic factors and other potential confounders., Ethics and Dissemination: All study materials including the protocol, consent forms, data collection instruments, participant communication and recruitment materials, were approved by the Kaiser Permanente Interregional Institutional Review Board, the IRB of record for the study. Results will be disseminated through peer-reviewed publications, presentations, participant newsletters and appropriate general news media., Competing Interests: Competing interests: HYC reports consulting with Ellume, Pfizer, The Bill and Melinda Gates Foundation, Glaxo Smith Kline, and Merck. HYC received research funding from Gates Ventures, Sanofi Pasteur, and support and reagents from Ellume and Cepheid outside of the submitted work. JAE reports research support from Gates Ventures, AstraZeneca, GlaxoSmithKline, Merck, and Pfizer, and consulting with Sanofi Pasteur, AstraZeneca, Teva Pharmaceuticals, and Meissa Vaccines, outside of the submitted work. ALN reports research funding from Pfizer and Vir Biotechnology, outside of the submitted work. JLK reports research funding from Vir Biotechnology, outside of the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We propose causal isotonic calibration, a novel nonparametric method for calibrating predictors of heterogeneous treatment effects. In addition, we introduce a novel data-efficient variant of calibration that avoids the need for hold-out calibration sets, which we refer to as cross-calibration. Causal isotonic cross-calibration takes cross-fitted predictors and outputs a single calibrated predictor obtained using all available data. We establish under weak conditions that causal isotonic calibration and cross-calibration both achieve fast doubly-robust calibration rates so long as either the propensity score or outcome regression is estimated well in an appropriate sense. The proposed causal isotonic calibrator can be wrapped around any black-box learning algorithm to provide strong distribution-free calibration guarantees while preserving predictive performance.

Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments., (© 2023. The Author(s).)

Background: People experiencing homelessness (PEH) are at increased risk for acquiring SARS-CoV-2, but the burden of long COVID in this population is unknown., Methods: We conducted a matched prospective cohort study to assess the prevalence, characteristics, and impact of long COVID among sheltered PEH in Seattle, WA between September 2020-April 2022. Adults ≥ 18 years, residing across nine homeless shelters with active respiratory virus surveillance, were eligible to complete in-person baseline surveys and interval follow-up phone surveys. We included a subset of 22 COVID-19-positive cases who tested positive or inconclusive for SARS-CoV-2 and 44 COVID-19-negative controls who tested negative for SARS-CoV-2, frequency matched on age and sex. Among controls, 22 were positive and 22 were negative for one of 27 other respiratory virus pathogens. To assess the impact of COVID-19 on the risk of symptom presence at follow-up (day 30-225 post-enrollment test), we performed log-linear regression with robust standard errors, adjusting for confounding by shelter site and demographic variables determined a priori., Results: Of 53 eligible COVID-19 cases, 22 (42%) completed ≥ 1 follow-up survey. While five (23%) cases reported ≥ 1 symptom at baseline, this increased to 77% (10/13) between day 30-59 and 33% (4/12) day 90 + . The most commonly reported symptoms day 30 + were fatigue (27%) and rhinorrhea (27%), with 8 (36%) reporting symptoms that interfered with or prevented daily activities. Four (33%) symptomatic cases reported receiving medical care outside of a medical provider at an isolation facility. Of 44 controls, 12 (27%) reported any symptoms day 90 + . Risk of any symptoms at follow-up was 5.4 times higher among COVID-19 cases compared to controls (95% CI: 2.7-10.5)., Conclusions: Shelter residents reported a high prevalence of symptoms 30 + days after their SARS-CoV-2 detection, though few accessed medical care for persistent illness. The impact of COVID-19 extends beyond acute illness and may exacerbate existing challenges that marginalized populations face in maintaining their health and wellbeing., (© 2023. The Author(s).)

Competing Interests: The authors have no conflicts of interest to disclose.

In Bayesian data analysis, it is often important to evaluate quantiles of the posterior distribution of a parameter of interest (e.g., to form posterior intervals). In multi-dimensional problems, when non-conjugate priors are used, this is often difficult generally requiring either an analytic or sampling-based approximation, such as Markov chain Monte-Carlo (MCMC), Approximate Bayesian computation (ABC) or variational inference. We discuss a general approach that reframes this as a multi-task learning problem and uses recurrent deep neural networks (RNNs) to approximately evaluate posterior quantiles. As RNNs carry information along a sequence, this application is particularly useful in time-series. An advantage of this risk-minimization approach is that we do not need to sample from the posterior or calculate the likelihood. We illustrate the proposed approach in several examples.

Introduction: Overall, resilient health systems build upon sufficient, qualified, well-distributed, and motivated health workers; however, this precious resource is limited in numbers to meet people's demands, particularly in LMICs. Understanding the subnational distribution of health workers from different lens is critical to ensure quality healthcare and improving health outcomes., Methods: Using data from Health Personnel Information System, facility-level Service Availability and Readiness Assessment, and other sources, we performed a district-level longitudinal analysis to assess health workforce density and the ratio of male to female health workers between January 2016 and June 2020 across all districts in Mozambique., Results: 22 011 health workers were sampled, of whom 10 405 (47.3%) were male. The average age was 35 years (SD: 9.4). Physicians (1025, 4.7%), maternal and child health nurses (4808, 21.8%), and nurses (6402, 29.1%) represented about 55% of the sample. In January 2016, the average district-level workforce density was 75.8 per 100 000 population (95% CI 65.9, 87.1), and was increasing at an annual rate of 8.0% (95% CI 6.00, 9.00) through January 2018. The annual growth rate declined to 3.0% (95% CI 2.00, 4.00) after January 2018. Two provinces, Maputo City and Maputo Province, with 268.3 (95% CI 186.10, 387.00) and 104.6 (95% CI 84.20, 130.00) health workers per 100 000 population, respectively, had the highest workforce density at baseline (2016). There were 3122 community health workers (CHW), of whom 72.8% were male, in January 2016. The average number of CHWs per 10 000 population was 1.33 (95% CI 1.11, 1.59) in 2016 and increased by 18% annually between January 2016 and January 2018. This trend reduced to 11% (95% CI 0.00, 13.00) after January 2018. The sex ratio was twice as high for all provinces in the central and northern regions relative to Maputo Province. Maputo City (OR: 0.34; 95% CI 0.32, 0.34) and Maputo Province (OR: 0.56; 95% CI 0.49, 0.65) reported the lowest sex ratio at the baseline. Encouragingly, important sex ratio improvements were observed after January 2018, particularly in the northern and central regions., Conclusion: Mozambique made substantial progress in health workers' availability during the study period; however, with a critical slowdown after 2018. Despite the progress, meaningful shortages and distribution disparities persist., (© 2023. The Author(s).)

The best assay or marker to define mRNA-1273 vaccine-induced antibodies as a correlate of protection (CoP) is unclear. In the COVE trial, participants received two doses of the mRNA-1273 COVID-19 vaccine or placebo. We previously assessed IgG binding antibodies to the spike protein (spike IgG) or receptor binding domain (RBD IgG) and pseudovirus neutralizing antibody 50 or 80% inhibitory dilution titer measured on day 29 or day 57, as correlates of risk (CoRs) and CoPs against symptomatic COVID-19 over 4 months after dose. Here, we assessed a new marker, live virus 50% microneutralization titer (LV-MN 50 ), and compared and combined markers in multivariable analyses. LV-MN 50 was an inverse CoR, with a hazard ratio of 0.39 (95% confidence interval, 0.19 to 0.83) at day 29 and 0.51 (95% confidence interval, 0.25 to 1.04) at day 57 per 10-fold increase. In multivariable analyses, pseudovirus neutralization titers and anti-spike binding antibodies performed best as CoRs; combining antibody markers did not improve correlates. Pseudovirus neutralization titer was the strongest independent correlate in a multivariable model. Overall, these results supported pseudovirus neutralizing and binding antibody assays as CoRs and CoPs, with the live virus assay as a weaker correlate in this sample set. Day 29 markers performed as well as day 57 markers as CoPs, which could accelerate immunogenicity and immunobridging studies.

Aims: To provide the overall rate for all types of neurologic iatrogenic injuries during urogynaecologic surgery from textual data., Methods: Systematic research focused on complications of gynaecologic surgery and neurologic injuries in abstracts. Keywords concerning complications (cluster A), unspecific; neurologic issues (cluster B); surgery (generic words) (cluster C); specific gynaecologic operations (cluster D); and specific gynaecologic operations for pelvic organ prolapse and urinary incontinence (cluster E) were extracted. Associations among clusters of keywords were assessed by using multiple runs of text-mining software Semantic Brand Score (SBS, https://semanticbrandscore.com/#primary). Association scores were converted into probabilities. The rate of neurologic complications in urogynaecologic surgery was calculated ("a priori" probability) by applying Bayes' theorem. Textual estimates of neurological injuries in urogynaecologic surgery are 0.035554 (95% confidence intervals 0.019607-0.0515001; no quantitative data were found). To test if the probability calculated on textual information was the same as quantitative data reports ("a posteriori" probability), the rate of neurologic complication of all gynaecologic surgery was calculated using a meta-analytics approach and was compared with the textual analysis value., Results: The rate of neurologic complications in gynaecologic surgery after meta-analytic data synthesis has been 0.016489 (95% confidence intervals 0.012163-0.022320), which is equal to the textual estimate (0.016889, 95% confidence intervals 0.019607-0.051501). Therefore, 0.035554 is a reliable likelihood to observe a neurologic complication in urogynaecologic surgery., Conclusion: Iatrogenic nerve injuries in urogynaecologic surgery are higher than whole gynaecologic surgery. Text-mining software SBS and probability conversion can provide reliable answers from overall scholars' opinions on unsolved clinical questions when better evidence is lacking., (© 2023 Wiley Periodicals LLC.)

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

(1) Background: We investigated the differences in the neuropsychological profile as well as the pneumological and motor functions in two groups of patients admitted to rehabilitation who received different respiratory support during their COVID-19 infection. (2) Methods: Group-1 ( n = 18; 15 male, median age 67.5) consisted of patients who received non-invasive mechanical ventilation; Group-2 ( n = 19; 16 male, median age 63) consisted of patients who received invasive mechanical ventilation. All patients underwent a neuropsychological assessment including Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and the Repeatable Battery for the Assessment of Neuropsychological Status (R-BANS) to evaluate the patients' cognition. Depression and anxiety were also measured at admission and discharge to rehabilitation. (3) Results: At admission, patients impaired at MMSE were 44% in Group-1 and 5% in Group-2, while patients impaired at FAB were 88% in Group-1 and 26% in Group-2. Wilcoxon's effect size revealed meaningful differences between groups for FAB, R-BANS global score, immediate and delayed memory, and attention-coding task, with Group-2 performing better than Group-1 across all measures. At discharge, 52% of the 25 patients re-assessed still had mild to moderate cognitive deficits, while 19% had depression and 35% had anxiety. (4) Conclusions: Patients who received oxygen therapy experienced higher levels of acute and chronic stress compared to those who benefitted from invasive mechanical ventilation. Despite patients showing a meaningful improvement at discharge, cognitive impairment persisted in a great number of patients; therefore, long-term neuropsychological follow-up and treatment for COVID-19 patients are recommended.

In many applications, it is of interest to assess the relative contribution of features (or subsets of features) toward the goal of predicting a response - in other words, to gauge the variable importance of features. Most recent work on variable importance assessment has focused on describing the importance of features within the confines of a given prediction algorithm. However, such assessment does not necessarily characterize the prediction potential of features, and may provide a misleading reflection of the intrinsic value of these features. To address this limitation, we propose a general framework for nonparametric inference on interpretable algorithm-agnostic variable importance. We define variable importance as a population-level contrast between the oracle predictiveness of all available features versus all features except those under consideration. We propose a nonparametric efficient estimation procedure that allows the construction of valid confidence intervals, even when machine learning techniques are used. We also outline a valid strategy for testing the null importance hypothesis. Through simulations, we show that our proposal has good operating characteristics, and we illustrate its use with data from a study of an antibody against HIV-1 infection.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID 50 ) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID 50 ; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID 50 (<2.7 IU 50  ml -1 ) and increased to 89% (78%, 96%) at ID 50  = 96.3 IU 50  ml -1 . Comparison of the vaccine efficacy by ID 50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID 50 titre as a correlate of protection across trials and vaccine types., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Microalgae-based biorefinery processes are gaining particular importance as a biotechnological tool for direct carbon dioxide fixation and production of high-quality biomass and energy feedstock for different industrial markets. However, despite the many technological advances in photobioreactor designs and operations, microalgae cultivation is still limited due to the low yields achieved in open systems and to the high investment and operation costs of closed photobioreactors. In this work, a new alveolar flat panel photobioreactor was designed and characterized with the aim of achieving high microalgae productivities and CO 2 bio-fixation rates. Moreover, the energy efficiency of the employed pump-assisted hydraulic circuit was evaluated. The 1.3 cm thick alveolar flat-panels enhance the light utilization, whereas the hydraulic design of the photobioreactor aims to improve the global CO 2 gas-liquid mass transfer coefficient (k L aCO 2 ). The mixing time, liquid flow velocity, and k L aCO 2 as well as the uniformity matrix of the artificial lighting source were experimentally calculated. The performance of the system was tested by cultivating the green microalga Acutodesmus obliquus. A volumetric biomass concentration equal to 1.9 g L -1 was achieved after 7 days under controlled indoor cultivation conditions with a CO 2 bio-fixation efficiency of 64% of total injected CO 2 . The (gross) energy consumption related to substrate handling was estimated to be between 27 and 46 Wh m -3 , without any cost associated to CO 2 injection and O 2 degassing. The data suggest that this pilot-scale cultivation system may constitute a relevant technology in the development of microalgae-based industrial scenario for CO 2 mitigation and biomass production., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation., (© The Author 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction Surgical site infections (SSIs) are common and carry a significant risk of morbidity and mortality and lead to increased healthcare costs. Perioperative antibiotic prophylaxis decreases the risk of SSIs. There are several guidelines on the use of perioperative antibiotic prophylaxis. The American College of Surgeons (ACS) recommends weight-based antibiotic administration within 60 minutes prior to (two hours for vancomycin/fluoroquinolones) incision and redosing by drug half-life. There are limited data regarding adherence to existing recommendations. Furthermore, there are scarce data on the relationship between adherence to recommendations and the risk of postoperative SSI. Objectives In this study, we aimed to assess the adherence to ACS guidelines for perioperative antimicrobial prophylaxis in the Seattle Children's Hospital (SCH) National Surgical Quality Improvement Program (NSQIP) pediatric cohort and to determine whether adherence to ACS guidelines is associated with a decreased risk of SSI. the secondary objective was to identify risk factors associated with SSI in our patient population. Materials and methods We conducted a secondary analysis of an institutional NSQIP pediatric data cohort between Jan 1, 2012, and Dec 31, 2017. We calculated summary statistics to assess adherence to ACS recommendations and fit a logistic regression model to identify factors associated with the risk of SSI. Patients who did not receive antibiotic prophylaxis were excluded. Results  A total of 6,072 surgeries among 5,532 patients met the inclusion criteria. Adherence was achieved for weight-based dosing in 35% of surgeries, administration prior to the incision in 91%, administration within 60 minutes (two hours for vancomycin/fluoroquinolones) in 86%, correct redosing in 97%, and to all recommendations in 29%. There were no significant associations between any adherence metrics and SSI, although confidence intervals were wide for some metrics. Factors associated with SSI when adherence was met included urgent case status, wound class 2 or 4, the American Society of Anesthesiologists (ASA) class 2-5, and surgery duration. Conclusion There was varying adherence to ACS recommendations on antibiotic prophylaxis in our cohort. More evidence is needed to better understand the effects of adherence to any or all components of the recommendations on SSI. We identified a group of pediatric patients at risk of SSI and a need for further research and targeted interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Berrondo et al.)

Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known., Objective: To evaluate whether DSI is associated with incident dementia in older adults., Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020., Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits., Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria., Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05)., Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

In 2020, COPD was the third leading cause of death worldwide. Lung function is central for the diagnosis of this disease, and COPD severity is still partially classified based on airflow obstruction, which can range from "mild" (GOLD 1 group, FEV1 ≥80% predicted) to "very severe" (GOLD 4, FEV1 <30% predicted). However, the term "mild COPD" needs to be carefully analyzed. Several studies have shown that even in the presence of a mild obstruction, patients can have significant symptoms, physiological deterioration, evidence of emphysema, and suffer from recurrent exacerbations. Small airways pathology significantly correlates with the presence of symptoms, and it has been demonstrated that the onset of bronchiolitis occurs earlier than that of emphysema. These damages have long been known to not be detectable with conventional tests, and exclusive reliance on spirometry is not enough to adequately study and stage a patient with "mild COPD." Therefore, early identification of COPD is of utmost importance in the light of modifying the natural course of the disease. However, patients with early lung damage are yet to be included and studied in interventional clinical trials., (© 2022 S. Karger AG, Basel.)

Estimation and evaluation of individualized treatment rules have been studied extensively, but real-world treatment resource constraints have received limited attention in existing methods. We investigate a setting in which treatment is intervened upon based on covariates to optimize the mean counterfactual outcome under treatment cost constraints when the treatment cost is random. In a particularly interesting special case, an instrumental variable corresponding to encouragement to treatment is intervened upon with constraints on the proportion receiving treatment. For such settings, we first develop a method to estimate optimal individualized treatment rules. We further construct an asymptotically efficient plug-in estimator of the corresponding average treatment effect relative to a given reference rule.

In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline. KEY MESSAGE Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients. The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung. The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.

Suppose that we wish to estimate a finite-dimensional summary of one or more function-valued features of an underlying data-generating mechanism under a nonparametric model. One approach to estimation is by plugging in flexible estimates of these features. Unfortunately, in general, such estimators may not be asymptotically efficient, which often makes these estimators difficult to use as a basis for inference. Though there are several existing methods to construct asymptotically efficient plug-in estimators, each such method either can only be derived using knowledge of efficiency theory or is only valid under stringent smoothness assumptions. Among existing methods, sieve estimators stand out as particularly convenient because efficiency theory is not required in their construction, their tuning parameters can be selected data adaptively, and they are universal in the sense that the same fits lead to efficient plug-in estimators for a rich class of estimands. Inspired by these desirable properties, we propose two novel universal approaches for estimating function-valued features that can be analyzed using sieve estimation theory. Compared to traditional sieve estimators, these approaches are valid under more general conditions on the smoothness of the function-valued features by utilizing flexible estimates that can be obtained, for example, using machine learning.

Background: Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory condition characterized by heterogeneous clinical presentations (phenotypes). The aim of this study was to assess the prevalence of the main COPD phenotypes and match of each phenotype to the most fitting clinical and lung function profile., Methods: the CLIMA (Clinical Phenotypes in Actual Clinical Practice) study was an observational, cross-sectional investigation involving twenty-four sites evenly distributed throughout Italy. Patients were tentatively grouped based on their history and claimed prevailing symptoms at recruitment: chronic cough (CB, suggesting chronic bronchitis); dyspnoea (possible emphysema components, E); recurrent wheezing (presuming asthma components, A). Variables collected were: anagraphics; smoking habit; history of asthma; claim of >1 exacerbations in the previous year; blood eosinophil count; total blood IgE and alpha 1 anti-trypsin (α 1 -AT) levels; complete lung function, and the chest X-ray report. mMRC, CAT, BCS, EQ5d-5L were also used. The association between variables and phenotypes were checked by Chi-square test and multinomial logistic regression., Results: The CB phenotype was prevalent (48.3%), followed by the E and the A phenotypes (38.8% and 12.8%, respectively). When dyspnoea was the prevailing symptom, the probability of belonging to the COPD-E phenotype was 3.40 times higher. Recurrent wheezing was mostly related to the COPD-A phenotype. Lung function proved more preserved in the COPD-CB phenotype. Smoke; n. exacerbations/year; VR, and BODE index were positively correlated with the COPD-E phenotype, while SpO 2 , FEV 1 /FVC, FEV 1 /VC, and FEV 1 reversibility were negatively correlated. Lower DLco values were highly probative for the COPD-E phenotype (p<0.001). Conversely, smoke, wheezing, plasma eosinophils, FEV 1 reversibility, and DLco were positively correlated with the COPD-A phenotype. The probability of belonging to the COPD-A phenotype raised by 2.71 times for any increase of one unit in % plasma eosinophils (p<0.001). Also multiparametrical scores contributed to discriminate the three phenotypes., Conclusion: The recognition of the main phenotypes of COPD can be effectively pursued by means of a few clinical and instrumental parameters, easy to obtain also in current daily practice. The phenotypical approach is crucial in the management of COPD as it allows to individualize the therapeutic strategy and to obtain more effective clinical outcomes., (©Copyright: the Author(s).)