Gesture encoding in human left precentral gyrus neuronal ensembles.

Understanding the cortical activity patterns driving dexterous upper limb motion has the potential to benefit a broad clinical population living with limited mobility through the development of novel brain-computer interface (BCI) technology. The present study examines the activity of ensembles of motor cortical neurons recorded using microelectrode arrays in the dominant hemisphere of two BrainGate clinical trial participants with cervical spinal cord injury as they attempted to perform a set of 48 different hand gestures. Although each participant displayed a unique organization of their respective neural latent spaces, it was possible to achieve classification accuracies of ~70% for all 48 gestures (and ~90% for sets of 10). Our results show that single unit ensemble activity recorded in a single hemisphere of human precentral gyrus has the potential to generate a wide range of gesture-related signals across both hands, providing an intuitive and diverse set of potential command signals for intracortical BCI use.

Low food security is associated with frailty status and frailty components among people with HIV.

BACKGROUND: Low food security is common among people with HIV (PWH) and is associated with poorer health outcomes. Frailty, an aging-related outcome that is increasingly prevalent among PWH, may be stimulated by low food security. We assessed associations between food security and frailty among PWH. METHODS: The Impact of Physical Activity Routines and Dietary Intake on the Longitudinal Symptom Experience of People Living with HIV (PROSPER-HIV) study follows PWH to evaluate how diet and physical activity impact symptoms. We utilized food security and frailty data from PROSPER-HIV Year 1 visits (January 2019 to July 2022) to estimate associations. Food security was measured via the validated two-item Food Security Questionnaire and categorized as Food Secure, Low Food Security, or Very Low Food Security. Frailty was measured with the Fried frailty phenotype, and categorized as robust, prefrail, and frail. We used relative risk regression to estimate associations between food security and frailty status, adjusted for demographic characteristics. RESULTS: Among 574 PWH, nearly one-quarter were women (22%), mean age was 52 years old, 8% were frail, and 46% prefrail. Low food security was reported among nearly one-third of PWH: 13% Low Food Security and 18% Very Low Food Security. Compared with being Food Secure, we found Low Food Security was associated with frailty [prevalence ratio: 4.06 (95% confidence interval (CI) 2.16-7.62] and Very Low Food Security was associated with both prefrailty [1.48 (1.23-1.78)] and frailty [5.61 (3.14-10.0)], as compared with robust status. CONCLUSION: Low food security was associated with increased frailty among PWH in this study, suggesting a potential intervention point to promote healthy aging.

A practical guide for combining functional regions of interest and white matter bundles.

Diffusion-weighted imaging (DWI) is the primary method to investigate macro- and microstructure of neural white matter in vivo. DWI can be used to identify and characterize individual-specific white matter bundles, enabling precise analyses on hypothesis-driven connections in the brain and bridging the relationships between brain structure, function, and behavior. However, cortical endpoints of bundles may span larger areas than what a researcher is interested in, challenging presumptions that bundles are specifically tied to certain brain functions. Functional MRI (fMRI) can be integrated to further refine bundles such that they are restricted to functionally-defined cortical regions. Analyzing properties of these Functional Sub-Bundles (FSuB) increases precision and interpretability of results when studying neural connections supporting specific tasks. Several parameters of DWI and fMRI analyses, ranging from data acquisition to processing, can impact the efficacy of integrating functional and diffusion MRI. Here, we discuss the applications of the FSuB approach, suggest best practices for acquiring and processing neuroimaging data towards this end, and introduce the FSuB-Extractor, a flexible open-source software for creating FSuBs. We demonstrate our processing code and the FSuB-Extractor on an openly-available dataset, the Natural Scenes Dataset.

Psychiatric Comorbidity Does Not Enhance Prescription Opioid Use in Inflammatory Bowel Disease as It Does in the General Population.

INTRODUCTION: Little is known about patterns of opioid prescribing in inflammatory bowel disease (IBD), but pain is common in persons with IBD. We estimated the incidence and prevalence of opioid use in adults with IBD and an unaffected reference cohort and assessed factors that modified opioid use. METHODS: Using population-based health administrative data from Manitoba, Canada, we identified 5233 persons with incident IBD and 26 150 persons without IBD matched 5:1 on sex, birth year, and region from 1997 to 2016. New and prevalent opioid prescription dispensations were quantified, and patterns related to duration of use were identified. Generalized linear models were used to test the association between IBD, psychiatric comorbidity, and opioid use adjusting for sociodemographic characteristics, physical comorbidities, and healthcare use. RESULTS: Opioids were dispensed to 27% of persons with IBD and to 12.9% of the unaffected reference cohort. The unadjusted crude incidence per 1000 person-years of opioid use was nearly twice as high for the IBD cohort (88.63; 95% CI, 82.73-91.99) vs the reference cohort (45.02; 95% CI, 43.49-45.82; relative risk 1.97; 95% CI, 1.86-2.08). The incidence rate per 1000 person-years was highest in those 18-44 years at diagnosis (98.01; 95% CI, 91.45-104.57). The relative increase in opioid use by persons with IBD compared to reference cohort was lower among persons with psychiatric comorbidity relative to the increased opioid use among persons with IBD and reference cohort without psychiatric comorbidity. DISCUSSION: The use of opioids is more common in people with IBD than in people without IBD. This does not appear to be driven by psychiatric comorbidity.

The use of opioids is more common in people with inflammatory bowel disease (IBD) than in people without IBD. Psychiatric comorbidity does not significantly impact chronic opioid use in persons with IBD as it does in unaffected controls.

Structure Activity of ß-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic ß-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of 1a that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole (1o) and 4-cyanopyrazole (8d) analogs exhibited kinact/Ki ratios >9000 M-1 s-1. 3-Arylisoxazole (10) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like 1a. A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.

Fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease in the Democratic Republic of the Congo: a case report study.

BACKGROUND: During the 2018-20 Ebola virus disease outbreak in the Democratic Republic of the Congo, thousands of patients received unprecedented vaccination, monoclonal antibody (mAb) therapy, or both, leading to a large number of survivors. We aimed to report the clinical, virological, viral genomic, and immunological features of two previously vaccinated and mAb-treated survivors of Ebola virus disease in the Democratic Republic of the Congo who developed second episodes of disease months after initial discharge, ultimately complicated by fatal meningoencephalitis associated with viral persistence. METHODS: In this case report study, we describe the presentation, management, and subsequent investigations of two patients who developed recrudescent Ebola virus disease and subsequent fatal meningoencephalitis. We obtained data from epidemiological databases, Ebola treatment units, survivor programme databases, laboratory datasets, and hospital records. Following national protocols established during the 2018-20 outbreak in the Democratic Republic of the Congo, blood, plasma, and cerebrospinal fluid (CSF) samples were collected during the first and second episodes of Ebola virus disease from both individuals and were analysed by molecular (quantitative RT-PCR and next-generation sequencing) and serological (IgG and IgM ELISA and Luminex assays) techniques. FINDINGS: The total time between the end of the first Ebola virus episode and the onset of the second episode was 342 days for patient 1 and 137 days for patient 2. In both patients, Ebola virus RNA was detected in blood and CSF samples during the second episode of disease. Complete genomes from CSF samples from this relapse episode showed phylogenetic relatedness to the genome sequenced from blood samples collected from the initial infection, confirming in-host persistence of Ebola virus. Serological analysis showed an antigen-specific humoral response with typical IgM and IgG kinetics in patient 1, but an absence of an endogenous adaptive immune response in patient 2. INTERPRETATION: We report the first two cases of fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease who had received vaccination and mAb-based treatment in the Democratic Republic of the Congo. Our findings highlight the importance of long-term monitoring of survivors, including continued clinical, virological, and immunological profiling, as well as the urgent need for novel therapeutic strategies to prevent and mitigate the individual and public health consequences of Ebola virus persistence. FUNDING: Ministry of Health of the Democratic Republic of the Congo, Institut National de Recherche Biomédicale, Infectious Disease Rapid Response Reserve Fund, US Centers for Disease Control and Prevention, French National Research Institute for Development, and WHO.

Updates in non-neoplastic orthopaedic pathology: what you don't know can hurt you!

Even though the average surgical pathologist reviews far more non-neoplastic orthopaedic pathology on a daily basis, most current research focuses on rare tumours and their even less frequent molecular events. Our experiences among consults and focused conferences strongly suggest that there remains a practice gap regarding knowledge and diagnosing specific non-neoplastic orthopaedic conditions. One of the most frequent intraoperative consultations performed in the USA, among both academic and private institutions, relates to revision arthroplasty and the determination of infection in periprosthetic joints. Pathologists play a critical role in this algorithm, helping determine intraoperatively whether patients require antibiotic spacers prior to reimplantation. Many pathology departments have abandoned the examination of arthroplasty specimens because they (and their surgeons) mistakenly believe there is little clinically relevant information to be gained by thorough pathological examination. However, recent literature has challenged this concept, emphasising the importance of distinguishing avascular necrosis (from osteoarthritis/degenerative joint disease with secondary osteonecrosis), subchondral insufficiency fracture, septic arthritis (from so-called 'sterile' osteomyelitis/pseudoabscesses), underlying crystalline diseases and incidental/occult neoplasia. Histological evaluation of historically insignificant orthopaedic specimens, such as tenosynovium from carpal tunnel syndrome/trigger finger, is now seen as valuable in early diagnosis of cardiac amyloidosis. Not infrequently, orthopaedic conditions like haemosiderotic synovitis, osteocartilaginous loose bodies or rheumatoid nodules, may histologically mimic bona fide neoplasms, notably diffuse tenosynovial giant cell tumour, synovial chondromatosis and epithelioid sarcoma, respectively. Here is a review of the more common non-neoplastic orthopaedic conditions, those likely to be examined by the practising surgical pathologist, with updates and guidelines for establishing clinically relevant diagnoses.

Higher Rate of SBP Recurrence with Secondary SBP Prophylaxis Compared to No Prophylaxis in Two National Cirrhosis Cohorts.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) bacteriology has changed over time. Reappraisal of primary SBP prophylaxis showed an increased rate of resistance in patients on primary prophylaxis with resultant discontinuation of this prophylaxis throughout the VA. We aimed to re-evaluate the risk-benefit ratio of secondary SBP prophylaxis (SecSBPPr). METHODS: Using validated ICD 9/10 codes, we utilized the VA Corporate Data Warehouse and the Non-VA National TriNetX database to identify patients in two different large US systems who survived their first SBP diagnosis (with chart review from two VA centers) between 2009-2019. We evaluated the prevalence of SecSBPPr and compared outcomes between those started on SecSBPPr versus not. RESULTS: We identified 4673 Veterans who survived their index SBP episode; 54.3% of whom were prescribed SecSBPPr. Multivariable analysis showed higher SBP recurrence risk in those on vs. off SecSBPPr(HR-1.63[1.40-1.91], p<0.001). This was accompanied by higher fluroquinolone-resistance odds in SecSBPPr patients (OR=4.32[1.36-15.83], p=0.03). In TriNetX we identified 6708 patients who survived their index SBP episode; 48.6% were on SecSBPPr. Multivariable analysis similarly showed SecSBPPr increased SBP recurrence risk (HR-1.68[1.33-1.80], p<0.001). Both datasets showed higher SBP recurrence trends over time in SecSBPPr patients. Results remained consistent at 6-month and 2-year timepoints. CONCLUSION: In two national data sets of >11,000 patients with SBP we found that SecSBPPr was prescribed in roughly half of patients. When initiated, SecSBPPr, compared to no prophylaxis after SBP, increased the risk of SBP recurrence in multivariable analysis by 63-68%, and this trend worsened over time. SecSBPPr should be reconsidered in cirrhosis.

Approximate maximum likelihood estimation in cure models using aggregated data, with application to HPV vaccine completion.

Research into vaccine hesitancy is a critical component of the public health enterprise, as rates of communicable diseases preventable by routine childhood immunization have been increasing in recent years. It is therefore important to estimate proportions of "never-vaccinators" in various subgroups of the population in order to successfully target interventions to improve childhood vaccination rates. However, due to privacy issues, it may be difficult to obtain individual patient data (IPD) needed to perform the appropriate time-to-event analyses: state-level immunization information services may only be willing to share aggregated data with researchers. We propose statistical methodology for the analysis of aggregated survival data that can accommodate a cured fraction based on a polynomial approximation of the mixture cure model log-likelihood function relying only on summary statistics. We study the performance of the method through simulation studies and apply it to a real-world data set from a study examining reminder/recall approaches to improve human papillomavirus (HPV) vaccination uptake. The proposed methods may be generalized for use when there is interest in fitting complex likelihood-based models but IPD is unavailable due to data privacy or other concerns.

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.

Association between growth differentiation factor-15 and adverse outcomes among patients with heart failure: A systematic literature review.

Growth differentiation factor-15 (GDF-15) is an emerging biomarker in several conditions. This SLR, conducted following PRISMA guidelines, examined the association between GDF-15 concentration and range of adverse outcomes in patients with heart failure (HF). Publications were identified from Embase® and Medline® bibliographic databases between January 1, 2014, and August 23, 2022 (congress abstracts: January 1, 2020, to August 23, 2022). Sixty-three publications met the eligibility criteria (55 manuscripts and 8 abstracts; 45 observational studies and 18 post hoc analyses of randomized controlled trials [RCTs]). Of the 19 outcomes identified, the most frequently reported longitudinal outcomes were mortality (n = 32 studies; all-cause [n = 27] or cardiovascular-related [n = 6]), composite outcomes (n = 28; most commonly mortality ± hospitalization/rehospitalization [n = 19]), and hospitalization/re-hospitalization (n = 11). The most common cross-sectional outcome was renal function (n = 22). Among longitudinal studies assessing independent relationships with outcomes using multivariate analyses (MVA), a significant increase in risk associated with higher baseline GDF-15 concentration was found in 22/24 (92 %) studies assessing all-cause mortality, 4/5 (80 %) assessing cardiovascular-related mortality, 13/19 (68 %) assessing composite outcomes, and 4/8 (50 %) assessing hospitalization/rehospitalization. All (7/7; 100 %) of the cross-sectional studies assessing the relationship with renal function by MVA, and 3/4 (75 %) assessing exercise capacity, found poorer outcomes associated with higher baseline GDF-15 concentrations. This SLR suggests GDF-15 is an independent predictor of mortality and other adverse but nonfatal outcomes in patients with HF. A better understanding of the prognostic role of GDF-15 in HF could improve clinical risk prediction models and potentially help optimize treatment regimens.

Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation.

Human cytomegalovirus (HCMV) glycoprotein B (gB) is a class III membrane fusion protein required for viral entry. HCMV vaccine candidates containing gB have demonstrated moderate clinical efficacy, but no HCMV vaccine has been approved. Here, we used structure-based design to identify and characterize amino acid substitutions that stabilize gB in its metastable prefusion conformation. One variant containing two engineered interprotomer disulfide bonds and two cavity-filling substitutions (gB-C7), displayed increased expression and thermostability. A 2.8 Å resolution cryoelectron microscopy structure shows that gB-C7 adopts a prefusion-like conformation, revealing additional structural elements at the membrane-distal apex. Unlike previous observations for several class I viral fusion proteins, mice immunized with postfusion or prefusion-stabilized forms of soluble gB protein displayed similar neutralizing antibody titers, here specifically against an HCMV laboratory strain on fibroblasts. Collectively, these results identify initial strategies to stabilize class III viral fusion proteins and provide tools to probe gB-directed antibody responses.

Physiological and communicative emotional disconcordance in children on the autism spectrum.

BACKGROUND: Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion. METHODS: Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2-4 and 8-12 years) participated in a low-level stress task whilst wearing a wireless electrocardiogram. Children's negative emotional expressions (facial, vocal, bodily) were coded following standardized protocols. Alexithymia traits were assessed using the Children's Alexithymia Measure with school-aged children only. Data analyses involved ANOVAs, correlations, and sensitivity analyses. RESULTS: There were no group differences in physiological arousal (heart rate) or in communicative expressions of stress to the stress task. For TD preschoolers, physiological arousal during the stress task was associated with vocal expressions and for TD school-aged children, they were associated with facial and bodily expressions. By contrast, for children on the autism spectrum, physiological arousal during the stress tasks was not associated with communicative expressions across age groups. CONCLUSIONS: Our findings suggest that children on the autism spectrum might experience emotional disconcordance, in that their physiological arousal does not align with their communicative expressions. Therefore, the internally experienced stress of children on the autism spectrum may be inadvertently missed by teachers and caregivers and, consequently, learning opportunities for teaching emotional communication and regulation may be also missed. Our results support the use of wearable biosensors to facilitate such interventions in children on the autism spectrum.

Exposure to organophosphate ester flame retardants and plasticizers and associations with preeclampsia and blood pressure in pregnancy.

BACKGROUND: Organophosphate esters (OPEs), flame retardants and plasticizers found widely in consumer products, may impact vascularization processes in pregnancy. Yet, the association between maternal exposure to OPEs and both preeclampsia and blood pressure during pregnancy remains understudied. METHODS: Within the LIFECODES Fetal Growth Study (N=900), we quantified 8 OPE metabolites from maternal urine collected at up to 3 time points during pregnancy and created within-subject geometric means. Outcomes included diagnosis of preeclampsia and longitudinal systolic (SBP) and diastolic (DBP) blood pressure measurements (mean=14 per participant). Cox proportional models were used to estimate associations between OPE metabolites and preeclampsia. Associations between average OPE metabolite concentrations and repeated blood pressure measurements were estimated using generalized estimating equations. RESULTS: Five OPE metabolites were detected in at least 60% of samples; 3 metabolites detected less frequently (5-39%) were examined in an exploratory analysis as ever vs. never detectable in pregnancy. There were 46 cases of preeclampsia in our study population. Associations between OPE metabolites and preeclampsia were null. We noted several divergent associations between OPE metabolites and longitudinal blood pressure measurements. An interquartile range (IQR) difference in average bis(2-chloroethyl) phosphate concentrations was associated with a decrease in SBP (-0.81 mmHg, 95% confidence interval [CI]: -1.62, 0.00), and, conversely, bis(1-chloro-2-propyl) phosphate was associated with a slight increase in SBP (0.94 mmHg, 95% CI: 0.28, 1.61). We also noted a decrease in SBP in association with several metabolites with low detection frequency. CONCLUSIONS: We observed null associations between OPE metabolites and preeclampsia, but some positive and some inverse associations with blood pressure in pregnancy. While our study was well-designed to assess associations with blood pressure, future studies with a larger number of preeclampsia cases may be better poised to investigate the association between OPE metabolites and phenotypes of this heterogenous hypertensive disorder of pregnancy.

High-Intensity Accelerations and Decelerations During Intercounty Camogie Match Play.

BACKGROUND: This study aimed to compare acceleration and deceleration demands of intercounty Camogie players, and differences across playing positions and halves of play. HYPOTHESIS: The middle 3 positions will have greatest accelerations and decelerations variables across match play and halves of play. STUDY DESIGN: Nonrandomized, repeated measures design. LEVEL OF EVIDENCE: Level 4. METHODS: Global positioning systems (GPS) (10 Hz) collected data from 28 participants during 18 competitive matches across 2 seasons; 206 individual player datasets were analyzed. RESULTS: Half-backs (P < 0.05; effect size [ES], -1.75) and midfielders (P < 0.05; ES, -1.68) covered significantly greater total number of accelerations than full-forwards. In acceleration zone 4, midfielders (P < 0.05; ES, = -1.67) and half forwards covered a significantly greater number than full-forwards (P < 0.01; ES, = -1.41). Midfielders accumulated a significantly greater distance in acceleration zone 4 than full-backs (P < 0.05; ES, = -0.57). Significant decrements were observed between halves in total number of accelerations (P < 0.01; ES, = 0.49), accelerations in zones 1 to 4 (P < 0.01; ES, 0.16-0.43), total distance of accelerations, and acceleration distance in zones 2 to 4 (P < 0.05; ES, 0.25; P < 0.01; ES, 0.45; P < 0.01; ES, 0.38). There were significant decrements in the total number of decelerations (P < 0.01; ES, 0.43), number of decelerations in zones 2 (P < 0.05; ES, 0.25), 3 (P < 0.01; ES, 0.45), and 4 (P < 0.01; ES, 0.38), and total deceleration distance (P < 0.01; ES, 0.16). CONCLUSION: Half-backs and midfielders covered significantly greater total number of accelerations than full-forwards. Significant decrements in several acceleration and deceleration variables were observed between halves. CLINICAL RELEVANCE: Players competing in intercounty Camogie should receive progressive exposure to acceleration and deceleration-based movement demands to prepare players for intercounty Camogie match play.

TR-107, An Agonist of Caseinolytic Peptidase Proteolytic Subunit, Disrupts Mitochondrial Metabolism and Inhibits the Growth of Human Colorectal Cancer Cells.

Oxidative phosphorylation (OXPHOS) is an essential metabolic process for cancer proliferation and therapy resistance. The ClpXP complex maintains mitochondrial proteostasis by degrading misfolded proteins. Madera Therapeutics has developed a class of highly potent and selective small-molecule activators (TR compounds) of the ClpXP component caseinolytic peptidase proteolytic subunit (ClpP). This approach to cancer therapy eliminates substrate recognition and activates non-specific protease function within mitochondria, which has shown encouraging preclinical efficacy in multiple malignancies. The class-leading compound, TR-107, has demonstrated significantly improved potency in ClpP affinity and activation and enhanced pharmacokinetic properties over the multi-targeting clinical agent ONC201. In this study, we investigate the in vitro efficacy of TR-107 against human colorectal cancer (CRC) cells. TR-107 inhibited CRC cell proliferation in a dose- and time-dependent manner and induced cell cycle arrest at low nanomolar concentrations. Mechanistically, TR-107 downregulated the expression of proteins involved in the mitochondrial unfolded protein response (UPRmt) and mtDNA transcription and translation. TR-107 attenuated oxygen consumption rate and glycolytic compensation, confirming inactivation of OXPHOS and a reduction in total cellular respiration. Multi-omics analysis of treated cells indicated a downregulation of respiratory chain complex subunits and an upregulation of mitophagy and ferroptosis pathways. Further evaluation of ferroptosis revealed a depletion of antioxidant and iron toxicity defenses that could potentiate sensitivity to combinatory chemotherapeutics. Together, this study provides evidence and insight into the subcellular mechanisms employed by CRC cells in response to potent ClpP agonism. Our findings demonstrate a productive approach to disrupting mitochondrial metabolism, supporting the translational potential of TR-107.

Phase 1 trial of an investigational Tdap booster vaccine with CpG 1018 adjuvant compared with Boostrix in healthy adults and adolescents.

This phase 1 trial assessed the safety and immunogenicity of an investigational tetanus/diphtheria/acellular pertussis vaccine combined with CpG 1018 adjuvant 1500 µg (Tdap-1018 1500 µg) or 3000 µg (Tdap-1018 3000 µg) in adults and adolescents. In this randomized, active-controlled, multicenter, dose-escalation trial, healthy participants aged 10 to 22 years received 1 dose of Tdap-1018 1500 µg, Tdap-1018 3000 µg, or Boostrix. Geometric mean concentrations (GMCs) and booster response rates (BRRs) for antibodies against pertussis (pertussis toxin, filamentous hemagglutinin, pertactin), tetanus, and diphtheria antigens, and neutralizing antibodies against pertussis toxin were assessed 4 weeks after vaccination. Safety and tolerability were assessed for solicited post-injection reactions within 7 days after vaccination and unsolicited adverse events up to 12 weeks after vaccination. Of 117 enrolled participants, 80 adults (92%) and 30 adolescents (100%) completed the study. Both Tdap-1018 formulations were generally well tolerated, with no vaccine-related serious adverse events. Frequency and severity in post-injection reactions after Tdap-1018 administration were similar to Boostrix except for higher proportions of moderate pain for Tdap-1018. In adults at week 4, ratio of GMCs and BRRs for all antigens in the 3000-µg group were similar to or higher than Boostrix, with significantly higher GMC ratios for anti-pertussis toxin (2.1 [1.5-3.0]) and anti-tetanus (1.8 [1.1-2.9]) and significantly higher BRRs for anti-pertussis toxin (difference [95% CI]: 34.5% [13.4-54.6]), anti-pertactin (19.2% [4.4-38.1]), and anti-tetanus (30.0% [3.6-52.7]) antibodies. For adolescents, in the 3000-µg group, ratio of GMCs and BRRs were similar to or higher than Boostrix for all antigens. Both Tdap-1018 formulations showed acceptable safety and tolerability profiles. Tdap-1018 3000 µg induced similar or higher immune responses than Boostrix. ACTRN12620001177943 (Australian New Zealand Clinical Trials Registry; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12620001177943p).

Evidence of a Bi-Directional Relationship between Arterial Stiffness and Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: There are numerous cross-sectional studies showing an association between arterial stiffness and diabetes, but the temporality of the association is unclear. OBJECTIVE: To investigate the temporal relationship between arterial stiffness and diabetes. METHODS: We searched MEDLINE and Embase from inception to 31 August 2023, to identify cohort studies that assessed whether arterial stiffness, as measured by pulse wave velocity (PWV), was predictive of the development of diabetes and vice versa. We summarised study data, and where possible undertook meta-analysis. RESULTS: We identified 19 studies that included people with type 1, type 2 and gestational diabetes. All 11 studies investigating arterial stiffness as a predictor of diabetes found a significant relationship. Six of those studies were suitable for meta-analysis. The risk of developing diabetes was greater in people with higher PWV at baseline than lower PWV (RR = 2.14, 95%CI 1.65 to 2.79, p < 0.00001) and the mean difference in baseline PWV was higher in people who developed diabetes than those who did not (mean difference: 0.77 m/s, 95%CI 0.47 to 1.06, p < 0.00001). Of 8 studies investigating diabetes as a predictor of arterial stiffness, 7 found a significant relationship. CONCLUSION: There is evidence of a bidirectional relationship between arterial stiffness and diabetes. Arterial stiffness may provide a causal link between diabetes and future cardiovascular disease.

Occupational stressors experienced by healthcare professionals in the course of the COVID-19 crisis.

The novel coronavirus has significantly impacted healthcare systems worldwide, exposing healthcare professionals (HCPs) to work-related stressors to prevent the spread of SARS-CoV-2. This study aimed to assess the occupational stress of HCPs in Lagos State, Nigeria, using a qualitative approach. The study involved nine HCPs from various departments, including doctors, nurses, and medical laboratory technicians. The main causes of stress were workload, policy changes, and extended use of personal protective gear. The study found high levels of occupational stress among HCPs, with workload being the main cause. The impact of the disease outbreak crisis on HCPs' lives and work demands was observed, with occupational demands categorized into safety risk at work and public perceptions. Employers and unions must respond to HCPs' needs for workplace protection and appropriate help to address stressors.

Le nouveau coronavirus a eu un impact significatif sur les systèmes de soins de santé dans le monde entier, exposant les professionnels de la santé (HCP) à des facteurs de stress liés au travail pour empêcher la propagation du SARS-CoV-2. Cette étude visait à évaluer le stress professionnel des HCP dans l'État de Lagos, au Nigeria, en utilisant une approche qualitative. L'étude a impliqué neuf HCP de divers départements, y compris des médecins, des infirmières et des techniciens de laboratoire médical. Les principales causes du stress étaient la charge de travail, les changements de politique et l'utilisation prolongée d'équipements de protection personnelle. L'étude a révélé des niveaux élevés de stress professionnel parmi les HCP, avec la charge de travail étant la principale cause. L'impact de la crise de l'épidémie sur la vie et les exigences professionnelles des HCP a été observé, les demandes de travail étant classées en catégories de risques pour la sécurité au travail et de perceptions du public. Les employeurs et les syndicats doivent répondre aux besoins des HCP en matière de protection des lieux de travail et d'aide appropriée pour faire face aux facteurs de stress.