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Background: Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes.Objective: This meta-analysis reports the effects on newborn size and duration of gestation of multiple micronutrient supplementation mainly compared with iron plus folic acid during pregnancy in recent randomized, controlled trials.Methods: Original data from 12 randomized, controlled trials in Bangladesh, Burkina Faso, China, Guinea-Bissau, Indonesia, Mexico, Nepal, Niger, Pakistan, and Zimbabwe, all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients to presumed HIV-negative women, were included. Outcomes included birthweight, other birth measurements, gestation, and incidence of low birthweight (LBW) (< 2500 g), small-for-gestational age birth (SGA, birthweight below the within-each-population 10th percentile), large-for-gestational age birth (LGA, birthweight above the within-each-population 90th percentile), and preterm delivery (< 37 weeks).Results: Compared with control supplementation (mainly with iron-folic acid), multiple micronutrient supplementation was associated with an increase in mean birthweight (pooled estimate: +22.4 g [95% CI, 8.3 to 36.4 g]; p = .002), a reduction in the prevalence of LBW (pooled OR = 0.89 [95% CI, 0.81 to 0.97]; p = .01) and SGA birth (pooled OR = 0.90 [95% CI, 0.82 to 0.99]; p = .03), and an increase in the prevalence of LGA birth (pooled OR = 1.13 [95% CI, 1.00 to 1.28]; p = .04). In most studies, the effects on birthweight were greater in mothers with higher body mass index (BMI). In the pooled analysis, the positive effect of multiple micronutrients on birthweight increased by 7.6 g (95% CI, 1.9 to 13.3 g) per unit increase in maternal BMI (p for interaction = .009). The intervention effect relative to the control group was + 39.0 g (95% CI, +22.0 to +56.1 g) in mothers with BMI of 20 kg/m2 or higher compared with -6.0 g (95% CI, -8.8 to +16.8 g) in mothers with BMI under 20 kg/m2. There were no significant effects of multiple micronutrient supplementation on birth length or head circumference nor on the duration of gestation (pooled effect: +0.17 day [95% CI, -0.35 to +0.70 day]; p = .51) or the incidence of preterm birth (pooled OR = 1.00 [95% CI, 0.93 to 1.09]; p = .92).Conclusions: Compared with iron-folic acid supplementation alone, maternal supplementation with multiple micronutrients during pregnancy in low-income countries resulted in a small increase in birthweight and a reduction in the prevalence of LBW of about 10%. The effect was greater among women with higher BMI. [ABSTRACT FROM AUTHOR]

Background: Multiple micronutrient deficiencies are common among women in low-income countries and may adversely affect pregnancy outcomes.Objective: To conduct a meta-analysis of the effects on stillbirths and on early and late neonatal mortality of supplementation during pregnancy with multiple micronutrients compared with iron-folic acid in recent randomized, controlled trials.Methods: Twelve randomized, controlled trials were included in the analysis (Bangladesh; Burkina Faso; China; Guinea-Bissau; Indramayu and Lombok, Indonesia; Mexico; Sarlahi and Janakur, Nepal; Niger; Pakistan; and Zimbabwe), all providing approximately 1 recommended dietary allowance (RDA) of multiple micronutrients or iron-folic acid to presumed HIV-negative women.Results: Supplementation providing approximately I RDA of multiple micronutrients did not decrease the risk of stillbirth (OR = 1.01; 95% CI, 0.88 to 1.16), early neonatal mortality (OR = 1.23; 95% CI, 0.95 to 1.59), late neonatal mortality (OR = 0.94; 95% CI, 0.73 to 1.23), or perinatal mortality (OR = 1.11; 95% CI, 0.93 to 1.33).Conclusions: Our meta-analysis provides consistent evidence that supplementation providing approximately 1 RDA of multiple micronutrients during pregnancy does not result in any reduction in stillbirths or in early or late neonatal deaths compared with iron-folic acid alone. [ABSTRACT FROM AUTHOR]

This paper reports on the methods and characteristics of 12 studies from developing countries included in a meta-analysis of the impact of antenatal supplements of multiple micronutrients compared with iron-folic acid on micronutrient status, maternal nutritional status, birth outcomes, and neonatal survival. [ABSTRACT FROM AUTHOR]

Chlamydia is an obligate intracellular bacterium that undergoes a complex biphasic developmental cycle, alternating between the smaller, infectious, non-dividing elementary body (EB) and the larger, non-infectious but dividing reticulate body. Due to the differences between these functionally and morphologically distinct forms, we hypothesize protein degradation is essential to chlamydial differentiation. The bacterial Clp system, consisting of an ATPase unfoldase (e.g., ClpX or ClpC) and a proteolytic component (e.g., ClpP), is critical for the physiology of bacteria through its recognition, and usually degradation, of specific substrates. We observed by transmission electron microscopy that overexpression of wild-type ClpC, but not an ATPase mutant isoform, in Chlamydia increased glycogen accumulation within the vacuolar niche of the bacteria earlier in the developmental cycle than typically observed. This suggested ClpC activity may increase the expression of EB-associated genes. Consistent with this, targeted RT-qPCR analyses demonstrated a significant increase in several EB-associated gene transcripts earlier in development. These effects were not observed with overexpression of the ATPase mutant of ClpC, providing strong evidence that the activity of ClpC drives secondary differentiation. By analyzing the global transcriptional response to ClpC overexpression using RNA sequencing, we observed a shift to earlier expression of canonical late developmental cycle genes and other EB-associated genes. Finally, we directly linked overexpression of ClpC with earlier production of infectious chlamydiae. Conversely, disrupting normal ClpC function with an ATPase mutant caused a delay in developmental cycle progression. Overall, these findings provide the first mechanistic insight for initiation of secondary differentiation in Chlamydia .IMPORTANCE Chlamydia species are obligate intracellular bacteria that require a host cell in which to complete their unique developmental cycle. Chlamydia differentiates between an infectious but non-replicating form, the elementary body, and a non-infectious but replicating form, the reticulate body. The signals that drive differentiation events are not characterized. We hypothesize that proteases are essential for mediating differentiation by allowing remodeling of the proteome as the organism transitions from one functional form to another. We previously reported that the C aseino l ytic p rotease (Clp) system is essential for chlamydial growth. Here, we reveal a surprising function for ClpC, an unfoldase, in driving production of infectious chlamydiae during the chlamydial developmental cycle.

Partner switching mechanisms (PSMs) are signal transduction systems comprised of a sensor phosphatase (RsbU), an anti-sigma factor (RsbW, kinase), an anti-anti-sigma factor (RsbV, the RsbW substrate), and a target sigma factor. Chlamydia spp. are obligate intracellular bacterial pathogens of animals that undergo a developmental cycle transitioning between the infectious elementary body (EB) and replicative reticulate body (RB) within a host cell-derived vacuole (inclusion). Secondary differentiation events (RB to EB) are transcriptionally regulated, in part, by the housekeeping sigma factor (σ 66 ) and two late-gene sigma factors (σ 54 and σ 28 ). Prior research supports that the PSM in Chlamydia trachomatis regulates availability of σ 66 . Pan-genome analysis revealed that PSM components are conserved across the phylum Chlamydiota, with Chlamydia spp. possessing an atypical arrangement of two anti-anti-sigma factors, RsbV1 and RsbV2. Bioinformatic analyses support RsbV2 as the homolog to the pan-genome-conserved RsbV with RsbV1 as an outlier. This, combined with in vitro data, indicates that RsbV1 and RsbV2 are structurally and biochemically distinct. Reduced levels or overexpression of RsbV1/RsbV2 did not significantly impact C. trachomatis growth or development. In contrast, overexpression of a non-phosphorylatable RsbV2 S55A mutant, but not overexpression of an RsbV1 S56A mutant, resulted in a 3 log reduction in infectious EB production without reduction in genomic DNA (total bacteria) or inclusion size, suggesting a block in secondary differentiation. The block was corroborated by reduced production of σ 54/28 -regulated late proteins and via transmission electron microscopy.IMPORTANCE Chlamydia trachomatis is the leading cause of reportable bacterial sexually transmitted infections (STIs) and causes the eye infection trachoma, a neglected tropical disease. Broad-spectrum antibiotics used for treatment can lead to microbiome dysbiosis and increased antibiotic resistance development in other bacteria, and treatment failure for chlamydial STIs is a recognized clinical problem. Here, we show that disruption of a partner switching mechanism (PSM) significantly reduces infectious progeny production via blockage of reticulate body to elementary body differentiation. We also reveal a novel PSM expansion largely restricted to the species infecting animals, suggesting a role in pathogen evolution. Collectively, our results highlight the chlamydial PSM as a key regulator of development that could be a potential target for novel therapeutics.

Schizotypal traits include abnormalities in cognition, behavior, and interpersonal relationships that are similar, yet less severe than psychotic symptomology. It is estimated that approximately 5% of the general population displays psychotic symptoms and experiences that can be considered schizotypal in nature, but there is little research examining the neurological correlates of these traits. The mismatch negativity (MMN) event-related potential is an objective measure of auditory change detection derived from electroencephalography. The current study contributes to the limited body of evidence examining the neurobiological underpinnings of schizotypy in a non-clinical sample using the MMN. Participants were recruited from the general population and divided into high and low-schizotypy groups for comparison. Individuals with high schizotypal traits displayed reduced MMN amplitudes in response to frequency and location deviants, and longer MMN latencies in response to location deviants. Specific sub-traits of schizotypy were uniquely related to frequency and location amplitudes, suggesting the previously reported inconsistencies in the literature may be due to diverse samples and differing deviant tone types. Finally, impulsivity and sensation-seeking likely contributed to the slower processing seen in location deviance detection. Ultimately, the current results provide evidence that the neurobiological abnormalities seen in clinical populations of schizotypal personality disorder and psychosis also extend to non-clinical populations., Competing Interests: All of the authors have no conflicts of interest to disclose., (© The Author(s) 2024.)

Using electroencephalography (EEG) to examine the simple mismatch negativity (MMN), a marker of auditory cortex function, has been of great interest in the exploration of biomarkers for psychotic illness. Despite many studies reporting MMN deficits in chronic schizophrenia, there are inconsistent reports of MMN reductions in the early phases of psychotic illness, suggesting the MMN elicited by traditional paradigms may not be a sensitive enough measure of vulnerability to be used as a biomarker. Recently, a more computationally complex measure of auditory cortex function (the complex mismatch negativity; cMMN) has been hypothesized to provide a more sensitive marker of illness vulnerability. The current study employed a novel dual rule paradigm, in which two pattern rules are established and violated, to examine the cMMN in 14 individuals with early phase psychosis (EPP, < 5 years illness) and 15 healthy controls (HC). Relationships between cMMN waveforms, symptom severity, and measures of functioning were explored. We found reductions of cMMN amplitudes at the site of maximal amplitude in EPP ( p  = .017) with large effect sizes ( Hedges' g  = 0.96). This study is an early step in the exploration of the cMMN as a biomarker for psychosis. Our results provide evidence that the dual rule cMMN paradigm shows promise as a method for cMMN elicitation that captures more subtle neurofunctional changes in the early stages of illness., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Over the past decade, there has been extensive research on the mismatch negativity (MMN) and its promise as a biomarker of illness in people with schizophrenia (SZ). Nevertheless, when attempting to assess the early stages of illness progression, the utility of MMN has been inconsistent. Recently, researchers have been investigating a more advanced MMN paradigm (the complex MMN [cMMN]) which is believed to index higher-order cognitive processing and has been suggested to be a more effective indicator of the early phases of SZ. The cMMN is defined as a paradigm that relies on alterations within a pre-established pattern of stimuli. In this meta-analysis, we investigated cMMN deficits in individuals with SZ, including an analysis involving those in the first 5 years of illness. Our search also included individuals with bipolar disorder who experience psychosis; however, no related papers were found and thus, no findings are reported. Our findings indicate a small/moderate effect (d = 0.47), suggesting that individuals with SZ exhibit reduced cMMN amplitudes compared to individuals without SZ. Interestingly, this effect seems to be more pronounced in individuals within the first 5 years of their illness (d = 0.58), suggesting that cMMN might be a more sensitive biomarker in the early phases of SZ compared to traditional paradigms., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators., Methods: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954., Findings: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ 2 =103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ 2 =0·03) for each unit increase in pre-treatment post-traumatic stress symptoms., Interpretation: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress., Funding: Swiss National Science Foundation., Competing Interests: Declaration of interests RM-S received personal payment for teaching on the delivery of cognitive therapy for post-traumatic stress disorder for children and young people at various UK universities and training bodies, and he is an unpaid council member of the UK Trauma Council. EBF received payment for contributing to a post-traumatic stress disorder manual and workbook and for post-traumatic stress disorder workshops, lectures, and meetings. JDF served as a consultant for Advanced Trauma Solutions Professionals. SK received minor side income from lecturing in a clinical training program for Narrative Exposure Therapy (University of Turku, Turku, Finland). PS received a share of royalties from Routledge publishers from publication of a cognitive therapy for post-traumatic stress disorder manual for young people; he was an unpaid member of the research committee of the Children and War Foundation (a non-profit based in Norway) and an unpaid trustee of the Children and War UK (a non-profit based in the UK). CHi received personal payment for writing an article regarding treatment of therapy for post-traumatic stress disorder in preschool-aged children from the Aeon Media Group. TD received personal payment for teaching on the delivery of cognitive therapy for post-traumatic stress disorder for children and young people at various UK universities and training bodies. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Individual participant data (IPD) meta-analyses of randomised trials are considered a reliable way to assess participant-level treatment effect modifiers but may not make the best use of the available data. Traditionally, effect modifiers are explored one covariate at a time, which gives rise to the possibility that evidence of treatment-covariate interaction may be due to confounding from a different, related covariate. We aimed to evaluate current practice when estimating treatment-covariate interactions in IPD meta-analysis, specifically focusing on involvement of additional covariates in the models. We reviewed 100 IPD meta-analyses of randomised trials, published between 2015 and 2020, that assessed at least one treatment-covariate interaction. We identified four approaches to handling additional covariates: (1) Single interaction model (unadjusted): No additional covariates included (57/100 IPD meta-analyses); (2) Single interaction model (adjusted): Adjustment for the main effect of at least one additional covariate (35/100); (3) Multiple interactions model: Adjustment for at least one two-way interaction between treatment and an additional covariate (3/100); and (4) Three-way interaction model: Three-way interaction formed between treatment, the additional covariate and the potential effect modifier (5/100). IPD is not being utilised to its fullest extent. In an exemplar dataset, we demonstrate how these approaches lead to different conclusions. Researchers should adjust for additional covariates when estimating interactions in IPD meta-analysis providing they adjust their main effects, which is already widely recommended. Further, they should consider whether more complex approaches could provide better information on who might benefit most from treatments, improving patient choice and treatment policy and practice., (© 2023 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

In network meta-analysis, studies evaluating multiple treatment comparisons are modeled simultaneously, and estimation is informed by a combination of direct and indirect evidence. Network meta-analysis relies on an assumption of consistency, meaning that direct and indirect evidence should agree for each treatment comparison. Here we propose new local and global tests for inconsistency and demonstrate their application to three example networks. Because inconsistency is a property of a loop of treatments in the network meta-analysis, we locate the local test in a loop. We define a model with one inconsistency parameter that can be interpreted as loop inconsistency. The model builds on the existing ideas of node-splitting and side-splitting in network meta-analysis. To provide a global test for inconsistency, we extend the model across multiple independent loops with one degree of freedom per loop. We develop a new algorithm for identifying independent loops within a network meta-analysis. Our proposed models handle treatments symmetrically, locate inconsistency in loops rather than in nodes or treatment comparisons, and are invariant to choice of reference treatment, making the results less dependent on model parameterization. For testing global inconsistency in network meta-analysis, our global model uses fewer degrees of freedom than the existing design-by-treatment interaction approach and has the potential to increase power. To illustrate our methods, we fit the models to three network meta-analyses varying in size and complexity. Local and global tests for inconsistency are performed and we demonstrate that the global model is invariant to choice of independent loops., (© 2023 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

The continued emergence and spread of antimicrobial resistance among pathogenic bacteria are ever-growing threats to health and economy. Here, we report the draft genomes for 45 Enterobacterales clinical isolates, including historical and contemporary drug-resistant organisms, obtained in Pakistan between 1998 and 2016: 5 Serratia , 3 Salmonella , 3 Enterobacter , and 34 Klebsiella ., Competing Interests: The authors declare no conflict of interest.

Given the association between major depressive disorder (MDD) and cortical inefficiency related to executive control, specifically in the sense that individuals with MDD may recruit more cognitive resources to complete tasks at the same capacity as those without MDD, the current study was interested in examining the attention networks and executive functioning of those with MDD. Past research has used the Attention Network Test (ANT) to measure changes of attention in clinical vs. healthy populations; however, theoretical concerns have been raised regarding the task. The Combined Attention Systems Task (CAST) was developed to address these concerns and was used in our study in combination with quantitative-electroencephalography (QEEG) to assess both behavioural and neurophysiological changes in participants with MDD (n = 18) compared to healthy controls (HCs; n = 22). We found no behavioural differences between MDD and HC groups suggesting individuals with MDD in our sample were not experiencing the executive functioning deficits previously reported in the literature. Neurophysiological measures of attention revealed that MDD participants had greater theta and alpha 1 activity relative to HCs, suggesting that although individuals with MDD do not show deficits in behavioural attention, they exhibit altered neural processing which underlies cognitive function., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours., Methods: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591., Findings: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (p interaction =0·0019), higher volume of metastases (p interaction =0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p interaction =0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival)., Interpretation: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes., Funding: UK Medical Research Council and Prostate Cancer UK., Competing Interests: Declaration of interests BT declares consulting fees from Amgen, Astellas, Bayer, Ferring, Novartis, and Janssen; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen, Astellas, Bayer, Ferring, Novartis, Janssen, and Myovant during the past 36 months. CJS declares grants or contracts from Bayer, Sanofi, Astellas/Pfizer, Dendreon, and Janssen, and personal consulting fees from Bayer, Astellas, Janssen, CellCentric, PointBiopharma, Pfizer, Novartis, Genentech/Roche, Bristol Myers Squibb (BMS), Lilly, Henguiu, and AstraZeneca during the past 36 months. GG declares institutional grants from BMS; institutional payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Amgen, BMS, IPSEN, AAA, Curium, AstraZeneca, Bayer, Pfizer/Merck, and Astellas; personal payment for expert testimony from BMS, Bayer, and Pfizer/Merck; and institutional support for attending meetings or travel from Janssen, BMS, AstraZeneca, Bayer, and Pfizer/Merck during the past 36 months. GL declares payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Sanofi-Genzyme; participation on a data safety monitoring board or advisory board from Janssen; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from ECOG-ACRIN (Prostate Cancer Subcommittee Chair) during the past 36 months. MRS declares grants or contracts from Astellas, Clovis Oncology, Janssen, Pfizer, Novartis, and Sanofi-Aventis (all on research that is independent of this manuscript); consulting fees from Eli Lilly; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Lilly Oncology and Janssen (speaker fees not relating to any particular medicinal product) during the past 36 months. KF declares institutional honoraria for participation on advisory boards and in talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, and personal honoraria for participation in advisory boards with Arvinas, CureVac and Orion during the past 36 months. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The study aim was to investigate multidrug-resistant (MDR) plasmids from a collection of 10 carbapenemase-producing Klebsiella pneumoniae clinical isolates identified within the same healthcare institution in Pakistan. Full characterization of the MDR plasmids including structure, typing characteristics, and AMR content as well as determination of their plasmid-based antimicrobial susceptibility profiles were carried out., Methods: Plasmids were isolated from 10 clinical isolates of Klebsiella pneumoniae , and from a corresponding set of Escherichia coli transconjugants, then sequenced using Nanopore/Illumina technology to generate plasmid hybrid assemblies. Full characterization of MDR plasmids, including determination of next generation sequencing (NGS)-based AMR profiles, plasmid incompatibility groups, and types, was carried out. The structure of MDR plasmids was analyzed using the Galileo AMR platform. For E. coli transconjugants, the NGS-based AMR profiles were compared to NGS-predicted AMR phenotypes and conventional broth microdilution (BMD) antimicrobial susceptibility testing (AST) results., Results: All carbapenemase-producing K. pneumoniae isolates (carrying either bla NDM-1 , or/and bla OXA-48 ) carried multiple AMR plasmids encoding 34 antimicrobial resistance genes (ARGs) conferring resistance to antimicrobials from 6 different classes. The plasmid incompatibility groups and types identified were: IncC (types 1 and 3), IncFIA (type 26) IncFIB, IncFII (types K1, K2, K7, and K9), IncHI1B, and IncL. None of the bla NDM-1 and bla ESBL -plasmids identified in this study were previously described. Most bla NDM-1- plasmids shared identical AMR regions suggesting potential genetic material/plasmid exchange between K. pneumoniae isolates of this collection. The majority of NGS-based AMR profiles from the E. coli transconjugants correlated well with both NGS-based predicted and conventional AST results., Conclusion: This study highlights the complexity and diversity of the plasmid-based genetic background of carbapenemase-producing clinical isolates from Pakistan. This study emphasizes the need for characterization of MDR plasmids to determine their complete molecular background and monitor AMR through plasmid transmission between multi-resistant bacterial pathogens., Competing Interests: 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 © 2023 Lascols, Cherney, Conley, Rishishwar, Crawford, Morse, Fisher, Anderson, Hodge, Pillai, Hughes, Khan and Sue.)

The ability to genetically manipulate a pathogen is fundamental to discovering factors governing host-pathogen interactions at the molecular level and is critical for devising treatment and prevention strategies. While the genetic "toolbox" for many important bacterial pathogens is extensive, approaches for modifying obligate intracellular bacterial pathogens were classically limited due in part to the uniqueness of their obligatory lifestyles. Many researchers have confronted these challenges over the past two and a half decades leading to the development of multiple approaches to construct plasmid-bearing recombinant strains and chromosomal gene inactivation and deletion mutants, along with gene-silencing methods enabling the study of essential genes. This review will highlight seminal genetic achievements and recent developments (past 5 years) for Anaplasma spp., Rickettsia spp., Chlamydia spp., and Coxiella burnetii including progress being made for the still intractable Orientia tsutsugamushi . Alongside commentary of the strengths and weaknesses of the various approaches, future research directions will be discussed to include methods for C . burnetii that should have utility in the other obligate intracellular bacteria. Collectively, the future appears bright for unraveling the molecular pathogenic mechanisms of these significant pathogens., Competing Interests: 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 © 2023 Fisher and Beare.)

The obligate intracellular human pathogen Chlamydia trachomatis (Ctr) undergoes a complex developmental cycle in which the bacterium differentiates between two functionally and morphologically distinct forms: the elementary body (EB) and the reticulate body (RB). The EB is the smaller, infectious, nondividing form which initiates infection of a susceptible host cell, whereas the RB is the larger, non-infectious form which replicates within a membrane-bound vesicle called an inclusion. The mechanism(s) which drives differentiation between these developmental forms is poorly understood. Bulk protein turnover is likely required for chlamydial differentiation given the significant differences in the protein repertoires and functions of the EB and RB. We hypothesize that periplasmic protein turnover is also critical for the reorganization of an RB into an EB, referred to as secondary differentiation. Ct441 is a periplasmic protease ortholog of tail-specific proteases (i.e., Tsp, Prc) and is expressed in Ctr during secondary differentiation. We investigated the effect of altering Tsp expression on developmental cycle progression. Through assessment of bacterial morphology and infectious progeny production, we found that both overexpression and CRISPR interference/dCas9 (CRISPRi)-mediated knockdown of Tsp negatively impacted chlamydial development through different mechanisms. We also confirmed that catalytic activity is required for the negative effect of overexpression and confirmed the effect of the mutation in in vitro assays. Electron microscopic assessments during knockdown experiments revealed a defect in EB morphology, directly linking Tsp function to secondary differentiation. These data implicate Ct441/Tsp as a critical factor in secondary differentiation. IMPORTANCE The human pathogen Chlamydia trachomatis is the leading cause of preventable infectious blindness and bacterial sexually transmitted infections worldwide. This pathogen has a unique developmental cycle that alternates between distinct forms. However, the key processes of chlamydial development remain obscure. Uncovering the mechanisms of differentiation between its metabolically and functionally distinct developmental forms may foster the discovery of novel Chlamydia-specific therapeutics and limit development of resistant bacterial populations derived from the clinical use of broad-spectrum antibiotics. In this study, we investigate chlamydial tail-specific protease (Tsp) and its function in chlamydial growth and development. Our work implicates Tsp as essential to chlamydial developmental cycle progression and indicates that Tsp is a potential drug target for Chlamydia infections., Competing Interests: The authors declare no conflict of interest.

Background: MMN and P3a are EEG-derived event related potentials that are thought to be prospective biomarkers for schizophrenia and, potentially, early-phase psychosis (EPP)., Methods: EPP (n = 12) and healthy control (HC; n = 35) participants listened to a multi-feature optimal paradigm with five deviant types (gap, duration, location, intensity, and frequency)., Results: There was a significant amplitude difference between the EPP and HC group with duration MMN (p = .02). No significant amplitude differences between groups were found for the P3a waveform. There were several correlations for the EPP group with the BNSS, SOFAS, and PANSS-general questionnaires. Length of illness was not associated with MMN or P3a., Conclusions: The optimal paradigm is suitable for eliciting multiple deviant types within a short amount of time in both clinical and healthy populations. This study confirms duration MMN deficits within an EPP group and that MMN is related to functional outcomes and positive and negative symptomology., 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 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is one of the most common neurological diseases in North America and it is frequently associated with sensory processing difficulties, cognitive deficits, and psychiatric illness. While many studies have examined cognitive deficits in MS measured by behavioural responses and neuroimaging techniques, only a few studies have examined neurophysiological measures of auditory functioning in MS, such as the mismatch negativity (MMN). The MMN is an event-related potential that indicates automatic auditory change detection. This study examined whether MMN endpoints measured by electroencephalography (EEG) differ in individuals with relapsing-remitting MS compared to healthy controls and whether the symptomatology of MS, including symptoms of depression and fatigue, are related to MMN measures. A multi-feature MMN paradigm, which includes five distinct deviant tones, was used to assess auditory cortex function in MS. There were no significant differences in MMN amplitudes or latencies between the MS and control group (p < 0.05) and corresponding effect sizes were small. However, there was a correlation between reduced MMN amplitudes in response to an intensity deviant and physician-reported disability. The intensity MMN may be more sensitive to deterioration in this population. Ultimately, this study provides a comprehensive profile of early auditory processing abilities in MS and suggests that a reduction in the MMN response may be representative of disease severity in MS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of this study was to better understand the relation of schizotypy traits with sensory gating ability in a sample of community-dwelling individuals with high and low schizotypy traits. Sensory gating was assessed through the paired click paradigm and mid-latency evoked responses (i.e., P50, N100, P200), while schizotypy traits were assessed through the SPQ-BR which was used to classify participants into "high" and "low" schizotypy groups. Based on prior work, we hypothesized that those with the highest schizotypy scores would have reduced sensory gating ability. While this study does not show differences between relatively low and high schizotypy groups on sensory gating ability, it does suggest that our participants may have been experiencing deficits in attention allocation, a downstream cognitive processing measure. Scores on the SPQ-BR suggest that our sample was not close to the high end of the schizotypy traits which may help explain why no differences were found. This research shows the importance of including all levels of schizotypy ratings in clinical research as we can gain a clearer view of the impact of schizotypy on the brain and cognitive functioning in those with "high" levels of schizotypy. Additionally, this work highlights the importance of including measures of important factors such as impulsivity and sensation-seeking to better understand what aspects of schizotypy may be driving these sensory gating alterations reported in the literature., Competing Interests: All of the authors have no conflicts of interest to disclose., (© The Author(s) 2023.)

Bacterial AAA+ unfoldases are crucial for bacterial physiology by recognizing specific substrates and, typically, unfolding them for degradation by a proteolytic component. The c aseino l ytic p rotease (Clp) system is one example where a hexameric unfoldase (e.g., ClpC) interacts with the tetradecameric proteolytic core ClpP. Unfoldases can have both ClpP-dependent and ClpP-independent roles in protein homeostasis, development, virulence, and cell differentiation. ClpC is an unfoldase predominantly found in Gram-positive bacteria and mycobacteria. Intriguingly, the obligate intracellular Gram-negative pathogen Chlamydia, an organism with a highly reduced genome, also encodes a ClpC ortholog, implying an important function for ClpC in chlamydial physiology. Here, we used a combination of in vitro and cell culture approaches to gain insight into the function of chlamydial ClpC. ClpC exhibits intrinsic ATPase and chaperone activities, with a primary role for the Walker B motif in the first nucleotide binding domain (NBD1). Furthermore, ClpC binds ClpP1P2 complexes via ClpP2 to form the functional protease ClpCP2P1 in vitro , which degraded arginine-phosphorylated β-casein. Cell culture experiments confirmed that higher order complexes of ClpC are present in chlamydial cells. Importantly, these data further revealed severe negative effects of both overexpression and depletion of ClpC in Chlamydia as revealed by a significant reduction in chlamydial growth. Here, again, NBD1 was critical for ClpC function. Hence, we provide the first mechanistic insight into the molecular and cellular function of chlamydial ClpC, which supports its essentiality in Chlamydia. ClpC is, therefore, a potential novel target for the development of antichlamydial agents. IMPORTANCE Chlamydia trachomatis is an obligate intracellular pathogen and the world's leading cause of preventable infectious blindness and bacterial sexually transmitted infections. Due to the high prevalence of chlamydial infections along with negative effects of current broad-spectrum treatment strategies, new antichlamydial agents with novel targets are desperately needed. In this context, bacterial Clp proteases have emerged as promising new antibiotic targets, since they often play central roles in bacterial physiology and, for some bacterial species, are even essential for survival. Here, we report on the chlamydial AAA+ unfoldase ClpC, its functional reconstitution and characterization, individually and as part of the ClpCP2P1 protease, and establish an essential role for ClpC in chlamydial growth and intracellular development, thereby identifying ClpC as a potential target for antichlamydial compounds.

Chlamydia trachomatis (CT) causes the most prevalent sexually transmitted bacterial disease in the United States. The lack of drug selectivity is one of the main challenges of the current antichlamydial pharmacotherapy. The metabolic needs of CT are controlled, among others, by cylindrical proteases and their chaperones ( e.g. , ClpX). It has been shown that dihydrothiazepines can disrupt CT-ClpXP. Based on this precedent, we synthesized a dihydrothiazepine library and characterized its antichlamydial activity using a modified semi-high-throughput screening assay. Then, we demonstrated their ability to inhibit ClpX ATPase activity in vitro , supporting ClpX as a target. Further, our lead compound displayed a promising selectivity profile against CT, acceptable cytotoxicity, no mutagenic potential, and good in vitro stability. A two-dimensional quantitative structure-activity relationship (2D QSAR) model was generated as a support tool in the identification of more potent antichlamydial molecules. This study suggests dihydrothiazepines are a promising starting point for the development of new and selective antichlamydial drugs.

CXCL10 is a pro-inflammatory chemokine produced by the host in response to microbial infection. In addition to canonical, receptor-dependent actions affecting immune-cell migration and activation, CXCL10 has also been found to directly kill a broad range of pathogenic bacteria. Prior investigations suggest that the bactericidal effects of CXCL10 occur through two distinct pathways that compromise the cell envelope. These observations raise the intriguing notion that CXCL10 features a separable pair of antimicrobial domains. Herein, we affirm this possibility through peptide-based mapping and structure/function analyses, which demonstrate that discrete peptides derived from the N- and C-terminal regions of CXCL10 mediate bacterial killing. The N-terminal derivative, peptide P1, exhibited marked antimicrobial activity against Bacillus anthracis vegetative bacilli and spores, as well as antibiotic-resistant clinical isolates of Klebsiella pneumoniae , Acinetobacter baumannii , Enterococcus faecium , and Staphylococcus aureus , among others. At bactericidal concentrations, peptide P1 had a minimal degree of chemotactic activity, but did not cause red blood cell hemolysis or cytotoxic effects against primary human cells. The C-terminal derivative, peptide P9, exhibited antimicrobial effects, but only against Gram-negative bacteria in low-salt medium─conditions under which the peptide can adopt an α-helical conformation. The introduction of a hydrocarbon staple induced and stabilized α-helicity; accordingly, stapled peptide P9 displayed significantly improved bactericidal effects against both Gram-positive and Gram-negative bacteria in media containing physiologic levels of salt. Together, our findings identify and characterize the antimicrobial regions of CXCL10 and functionalize these novel determinants as discrete peptides with potential therapeutic utility against difficult-to-treat pathogens.

Estimation of within-trial interactions in meta-analysis is crucial for reliable assessment of how treatment effects vary across participant subgroups. However, current methods have various limitations. Patients, clinicians and policy-makers need reliable estimates of treatment effects within specific covariate subgroups, on relative and absolute scales, in order to target treatments appropriately-which estimation of an interaction effect does not in itself provide. Also, the focus has been on covariates with only two subgroups, and may exclude relevant data if only a single subgroup is reported. Therefore, in this article we further develop the "within-trial" framework by providing practical methods to (1) estimate within-trial interactions across two or more subgroups; (2) estimate subgroup-specific ("floating") treatment effects that are compatible with the within-trial interactions and make maximum use of available data; and (3) clearly present this data using novel implementation of forest plots. We described the steps involved and apply the methods to two examples taken from previously published meta-analyses, and demonstrate a straightforward implementation in Stata based upon existing code for multivariate meta-analysis. We discuss how the within-trial framework and plots can be utilised with aggregate (or "published") source data, as well as with individual participant data, to effectively demonstrate how treatment effects differ across participant subgroups., (© 2022 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Chlamydia trachomatis (ct) is the most reported bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Caseinolytic proteases (ClpP) from pathogenic bacteria are attractive antibiotic targets, particularly for bacterial species that form persister colonies with phenotypic resistance against common antibiotics. ClpP functions as a multisubunit proteolytic complex, and bacteria are eradicated when ClpP is disrupted. Although crucial for chlamydial development and the design of agents to treat chlamydia, the structures of ctClpP1 and ctClpP2 have yet to be solved. Here, we report the first crystal structure of full-length ClpP2 as an inactive homotetradecamer in a complex with a candidate antibiotic at 2.66 Å resolution. The structure details the functional domains of the ClpP2 protein subunit and includes the handle domain, which is integral to proteolytic activation. In addition, hydrogen-deuterium exchange mass spectroscopy probed the dynamics of ClpP2, and molecular modeling of ClpP1 predicted an assembly with ClpP2. By leveraging previous enzymatic experiments, we constructed a model of ClpP2 activation and its interaction with the protease subunits ClpP1 and ClpX. The structural information presented will be relevant for future rational drug design against these targets and will lead to a better understanding of ClpP complex formation and activation within this important human pathogen., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Research overlap and duplication is a recognised problem in the context of both pairwise and network systematic reviews and meta-analyses. As a case study, we carried out a scoping review to identify and examine duplicated network meta-analyses (NMAs) in a specific disease setting where several novel therapies have recently emerged: hormone-sensitive metastatic prostate cancer (mHSPC)., Methods: MEDLINE and EMBASE were systematically searched, in January 2020, for indirect or mixed treatment comparisons or network meta-analyses of the systemic treatments docetaxel and abiraterone acetate in the mHSPC setting, with a time-to-event outcome reported on the hazard-ratio scale. Eligibility decisions were made, and data extraction performed, by two independent reviewers., Results: A total of 13 eligible reviews were identified, analysing between 3 and 8 randomised comparisons, and comprising between 1773 and 7844 individual patients. Although the included trials and treatments showed a high degree of overlap, we observed considerable variation between identified reviews in terms of review aims, eligibility criteria and included data, statistical methodology, reporting and inference. Furthermore, crucial methodological details and specific source data were often unclear., Conclusions and Recommendations: Variation across duplicated NMAs, together with reporting inadequacies, may compromise identification of best-performing treatments. Particularly in fast-moving fields, review authors should be aware of all relevant studies, and of other reviews with potential for overlap or duplication. We recommend that review protocols be published in advance, with greater clarity regarding the specific aims or scope of the project, and that reports include information on how the work builds upon existing knowledge. Source data and results should be clearly and completely presented to allow unbiased interpretation., (© 2022. The Author(s).)

The obligate intracellular bacterial pathogen Chlamydia trachomatis is a leading cause of sexually transmitted infections and infectious blindness. Chlamydia undergo a biphasic developmental cycle alternating between the infectious elementary body (EB) and the replicative reticulate body (RB). The molecular mechanisms governing RB growth and RB-EB differentiation are unclear. We hypothesize that the bacterium senses host cell and bacterial energy levels and metabolites to ensure that development and growth coincide with nutrient availability. We predict that a partner switching mechanism (PSM) plays a key role in the sensing and response process acting as a molecular throttle sensitive to metabolite levels. Using purified wild type and mutant PSM proteins, we discovered that metal type impacts enzyme activity and the substrate specificity of RsbU and that RsbW prefers ATP over GTP as a phosphate donor. Immunoblotting analysis of RsbV1/V2 demonstrated the presence of both proteins beyond 20 hours post infection and we observed that an RsbV1-null strain has a developmental delay and exhibits differential growth attenuation in response to glucose levels. Collectively, our data support that the PSM regulates growth in response to metabolites and further defines biochemical features governing PSM-component interactions which could help in the development of novel PSM-targeted therapeutics., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Despite having a highly reduced genome, Chlamydia trachomatis undergoes a complex developmental cycle in which the bacteria differentiate between the following two functionally and morphologically distinct forms: the infectious, nonreplicative elementary body (EB) and the noninfectious, replicative reticulate body (RB). The transitions between EBs and RBs are not mediated by division events that redistribute intracellular proteins. Rather, both primary (EB to RB) and secondary (RB to EB) differentiation likely require bulk protein turnover. One system for targeted protein degradation is the trans -translation system for ribosomal rescue, where polypeptides stalled during translation are marked with an SsrA tag encoded by a hybrid tRNA-mRNA, tmRNA . ClpX recognizes the SsrA tag, leading to ClpXP-mediated degradation. We hypothesize that ClpX functions in chlamydial differentiation through targeted protein degradation. We found that mutation of a key residue (R230A) within the specific motif in ClpX associated with the recognition of SsrA-tagged substrates resulted in abrogated secondary differentiation while not reducing chlamydial replication or developmental cycle progression as measured by transcripts. Furthermore, inhibition of trans -translation through chemical and targeted genetic approaches also impeded chlamydial development. Knockdown of tmRNA and subsequent complementation with an allele mutated in the SsrA tag closely phenocopied the overexpression of ClpX R230A , thus suggesting that ClpX recognition of SsrA-tagged substrates plays a critical function in secondary differentiation. Taken together, these data provide mechanistic insight into the requirements for transitions between chlamydial developmental forms. IMPORTANCE Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections and preventable infectious blindness. This unique organism undergoes developmental transitions between infectious, nondividing forms and noninfectious, dividing forms. Therefore, the chlamydial developmental cycle is an attractive target for Chlamydia-specific antibiotics, which would minimize effects of broad-spectrum antibiotics on the spread of antibiotic resistance in other organisms. However, the lack of knowledge about chlamydial development on a molecular level impedes the identification of specific, druggable targets. This work describes a mechanism through which both the fundamental processes of trans -translation and proteomic turnover by ClpXP contribute to chlamydial differentiation, a critical facet of chlamydial growth and survival. Given the almost universal presence of trans -translation and ClpX in eubacteria, this mechanism may be conserved in developmental cycles of other bacterial species. Additionally, this study expands the fields of trans -translation and Clp proteases by emphasizing the functional diversity of these systems throughout bacterial evolution.

Rationale: Caffeine is the most consumed stimulant worldwide, and there is great interest in understanding its neurophysiological effects. Resting-state electroencephalography (EEG) studies suggest that caffeine enhances arousal, which suppresses the spectral power of alpha frequencies associated with reduced alertness. However, it is unclear whether caffeine's neurophysiological effects vary across the human menstrual cycle., Objective: The objective of our study was to test whether caffeine's effect on EEG activity differs across the human menstrual cycle., Methods: Fifty-six female participants were randomly assigned to complete the experiment while in either their menstrual (n = 21), follicular (n = 19), or luteal (n = 16) phase. Each participant completed two study sessions in the same menstrual phase, approximately 1 month apart, during which they were administered either a caffeine pill (200 mg, oral) or a placebo pill in a counterbalanced order using a randomized double-blinded procedure. We measured their eyes-closed resting-state EEG approximately 30 min after pill administration and conducted a spectral power analysis at different frequency bands., Results: Caffeine reduced EEG power in the alpha 1 frequency band (8-10 Hz), but only for participants who self-reported higher weekly caffeine consumption. Importantly, caffeine's effects did not differ by menstrual phase., Conclusions: We conclude that when studying caffeine's effects on resting-state EEG, participants' baseline caffeine consumption is more influential than their menstrual cycle phase. This study has important implications for the inclusion of menstruating individuals in neurophysiological studies of caffeine., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence., Methods: Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence., Findings: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28., Conclusions: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist., Competing Interests: LPGD is a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. ACG has received personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. JCM received personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Individuals with schizophrenia use on average twice as much caffeine than the healthy population, but the underlying cortical effects of caffeine in this population are still not well understood. Using resting electroencephalography (EEG) data, we can determine recurrent configurations of the electric field potential over the cortex. These configurations, referred to as microstates, are reported to be altered in schizophrenia and can give us insight into the functional dynamics of large-scale brain networks. In the current study, we use a placebo-controlled, randomized, double-blind, repeated-measures design to examine the effects of a moderate dose of caffeine (200mg) on microstate classes A, B, C, and D in a sample of individuals within the first five years of psychosis onset compared to healthy controls. The results support the reduction of microstate class C and D, as well as the increase of microstate class A and B in schizophrenia. Further, acute caffeine administration appears to exacerbate these group differences by reducing class D, and increasing occurrences of class A and B states in the patient group only. The current results support the hypothesis of a microstate class D reduction as an endophenotypic marker for psychosis and provide the first descriptive account of how caffeine is affecting these microstate classes in an early phase psychosis sample.

Individuals with schizophrenia use twice as much caffeine on average when compared to healthy controls. Knowing the high rates of consumption, and the potential negative effects of such, it is important we understand the cortical mechanisms that underlie caffeine use, and the consequences of caffeine use on neural circuits in this population. Using a randomized, placebo controlled, double-blind, repeated measures design, the current study examines caffeine's effects on resting electroencephalography (EEG) power in those who have been recently diagnosed with schizophrenia (SZ) compared to regular-using healthy controls (HC). Correlations between average caffeine consumption, withdrawal symptoms, drug related symptoms and clinical psychosis symptoms were measured and significant correlations with neurophysiological data were examined. Results showed caffeine had no effect on alpha asymmetry in the SZ group, although caffeine produced a more global effect on the reduction of alpha 2 power in the SZ group. Further, those with more positive symptoms were found to have a greater reduction in alpha 2 power following caffeine administration. Caffeine also reduced beta power during eyes closed and eyes open resting in HC, but only during eyes closed resting conditions in the SZ group. These findings provide a descriptive profile of the resting EEG state following caffeine administration in individuals with schizophrenia. The findings ultimately suggest caffeine does not affect alpha or beta power as readily in this population and a higher dose may be needed to achieve the desired effects, which may elucidate motivational factors for high caffeine use.

The mismatch negativity (MMN) and P3a waveforms are both markers of auditory change detection. MMN indicates deficits in performing auditory change-detection tasks, while the P3a reflects the evaluative and conscious aspect of orienting to the sound. Understanding the role biological sex has concerning these waveforms would provide insight into overall brain-based differences, but whether sex differences exist to such a degree that it can moderate the effect of auditory change detection is not certain. Thus, the purpose of this study was to examine potential sex differences in MMN and P3a elicited by a novelty paradigm in a healthy population. The results showed no significant differences between males and females. This study proves to be useful by adding to the limited literature on the topic and by providing a foundation of knowledge regarding sex differences in auditory change detection mechanisms within the population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Long-term cannabis use has been associated with the appearance of psychotic symptoms and schizophrenia-like cognitive impairments; however these studies may be confounded by concomitant use of tobacco by cannabis users. We aimed to determine if previously observed cannabis-associated deficits in sensory gating would be seen in cannabis users with no history of tobacco use, as evidenced by changes in the P50, N100, and P200 event-related potentials. A secondary objective of this study was to examine the effects of acute nicotine administration on cannabis users with no tobacco use history., Methods: Three components (P50, N100, P200) of the mid-latency auditory-evoked response (MLAER) were elicited by a paired-stimulus paradigm in 43 healthy, non-tobacco smoking male volunteers between the ages of 18-30. Cannabis users (CU, n = 20) were administered nicotine (6 mg) and placebo gum within a randomized, double-blind design. Non-cannabis users (NU, n = 23) did not receive nicotine., Results: Between-group sensory gating effects were only observed for the N100, with CUs exhibiting a smaller N100 to S 1 of the paired stimulus paradigm, in addition to reduced dN100 (indicating poorer gating). Results revealed no significant sensory gating differences with acute administration of nicotine compared to placebo cannabis conditions., Conclusions: These findings suggest a relationship between gating impairment and cannabis use; however, acute nicotine administration nicotine does not appear to impact sensory gating function., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glutamate and N-acetylaspartate have been investigated in the neuropathology of chronic schizophrenia, with fewer studies focusing on early phase psychosis. Additionally, there has been little review and synthesis of the literature focused on multiple brain regions. This systematic review aims to provide a clear report of the current state of research on glutamate and n-acetylaspartate concentrations in early phase psychosis (defined as the first five years following psychosis onset) in multiple brain regions. Existing literature was searched systematically to compile reports of glutamate/glutamate+glutamine (Glx) and n-acetylaspartate absolute levels and ratios in both male and female individuals with early phase psychosis. Reports on glutamate/Glx concentrations in the medial prefrontal region and thalamus were varied, but the majority of reports suggested no alterations in EPP. No studies reported glutamate alterations in the hippocampus or cerebellum. There was no evidence for n-acetylaspartate alterations in the caudate, basal ganglia, and medial prefrontal cortex, and minimal evidence for NAA reductions in the thalamus, anterior cingulate cortex, and hippocampus. Future research should focus on the regions that are less commonly reported, and should aim to explore possible confounds, such as medication status and substance use., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cannabis has been shown to cause structural and functional neurocognitive changes in heavy users. Cannabis use initiation aligns with brain development trajectories; therefore, it is imperative that the potential neurological implications of cannabis use are understood. Males and females reach neurodevelopmental milestones at different rates making it necessary to consider biological sex in all cannabis and brain-based research. Through use of a systamatic review in accordance with PRISMA guidelines, we aimed to understand the interaction between biological sex and cannabis use on brain-based markers. In total, 18 articles containing a sex-based analysis of cannabis users were identified. While the majority of studies ( n  = 11) reported no sex by cannabis use interactions on brain-based markers, those that reported findings ( n  = 8) suggest females may be more susceptible to cannabis' neurotoxic effects. Unfortunately, a large portion of the literature was excluded due to no sex-based analysis. In addition, studies that reported no sex differences often contained a reduced number of females which may result in some studies being underpowered for sex-based analyses, making it difficult to draw firm conclusions. Suggestions to improve cannabis and sex-based reseach are proposed., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)