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The Division of AIDS (DAIDS) Good Clinical Laboratory Practice (GCLP) Guidelines establish a framework to guide the oversight of laboratories supporting DAIDS-sponsored clinical research or trials. Compliance with these guidelines promotes data reliability, consistency, and validity, and the safety of the clinical research or trial participants and laboratory staff, as well as ensures adherence to regulatory requirements. This article describes the application of the DAIDS GCLP Guidelines, the DAIDS Integrated Laboratory Oversight Framework, and the coordinated efforts of the collaborative oversight team of laboratory experts to support and monitor the performance of over 175 participating laboratories worldwide. Data from two self-administered online surveys conducted in 2017 and 2023 assessed the laboratory staff's experience implementing the GCLP Guidelines. The results of the 2017 survey were instrumental in informing changes to GCLP audit activities and promoting harmonization in the approach to laboratory oversight. A key finding from the 2023 survey results is the preference for hybrid GCLP training, encompassing face-to-face and online modules. Overall, both surveys acknowledged satisfaction with applying and implementing GCLP Guidelines. The need to effectively disseminate information about DAIDS laboratory oversight requirements to support the improved implementation of GCLP Guidelines was notable from both survey results. The collaborative team of laboratory experts and the integrated oversight approach promote knowledge-sharing and accountability to support the application of the GCLP Guidelines and compliance monitoring. The systematic implementation of the integrated laboratory oversight activities helped identify valuable lessons for improving laboratory performance and opportunities to strengthen quality oversight for laboratories participating in clinical research or trials. [ABSTRACT FROM AUTHOR]

Metformin (1, 1-dimethyl biguanide) represents the "gold standard" for the treatment of diabetes mellitus type 2. Despite its important role in reducing mortality and morbidity in the diabetic population, metformin is associated with an increased risk of stroke. A simple, novel, specific, and sensitive gas chromatography-mass spectrometry method (GC-MS) for the determination of metformin was developed. Several parameters such as reaction time and temperature were optimized. There was no interfering peak from the blank at the retention time of metformin. Linearity was demonstrated over the concentration range of 4.024-24.144ppm with a coefficient of determination (R2) above 0.9999. Accuracy and precision were within acceptable limits. The method was fully validated using parameters such as specificity, linearity, limits of detection and quantification, precision, accuracy, recovery, range, robustness, and ruggedness. The developed method was successfully applied for the identification and quantification of metformin in the market tablet formulation. [ABSTRACT FROM AUTHOR]

This talk will describe the fabrication of periodically poled lithium niobate non-linear waveguides for the emerging quantum technology industry. It will address the challenges of optical engineering high-efficiency frequency conversion devices for the field and their application.

Obesity is a recognized factor influencing immune function and infectious disease outcomes. Characterization of the influence of obesity on SARS-CoV-2 humoral vaccine immunogenicity is required to properly tailor vaccine type (mRNA, viral-vector, protein subunit vaccines) and dosing schedule. Data from a prospective cohort study collected over 34 months was used to evaluate the slope of antibody production and decay and neutralizing capacity following SARS-CoV-2 vaccination in individuals with and without obesity at baseline. Most participants were female (65.4%), white (92.4%), and received mRNA vaccines. 210 were obese and 697 non-obese. Sex and infection-acquired immunity were identified as effect modifiers for the relationship between obesity and COVID-19 vaccine humoral immunogenicity. No consistent influence of obesity on peak titres, titre retention, antibody isotype (IgG, IgM, IgA), or neutralization was identified when controlling for other key variables. It may not be necessary to consider this variable when developing SARS-CoV-2 vaccine dosing strategies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events., Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores., Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high., Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Reproductive counseling is crucial for women's health, especially for those with inflammatory bowel disease (IBD), which often affects younger patients during their childbearing years. Patients with IBD need special considerations when planning for pregnancy. Preconception counseling is important as it helps patients make informed decisions about pregnancy and allows for optimal management of IBD before, during, and after pregnancy. In this review, we aim to provide guidance for managing and treating patients with IBD throughout the preconception, pregnancy, and postpartum period., Competing Interests: None declared., (Thieme. All rights reserved.)

Study Background: The experience of discrimination through stereotyping, profiling, and bias-informed care not only leads to poor access to healthcare services, but low retention rates of Indigenous health professionals (IHP). As health systems transformation evolves, a significant gap remains in supporting IHP to safely address racism, to be supported culturally to bring their authentic selves and voices to work, and to attend to one's own intellectual, physical, relational, cultural and spiritual wellness within a westernized model of care., Purpose: The aim of the study was to investigate the experiences of IHP working in mainstream healthcare in order to understand how their work environment impacts the delivery of cultural safe practices. What is reported in this manuscript, as an exercise in truth-telling, is findings about lived experiences of IHP working in one mainstream provincial healthcare region, and not the whole context and outcomes of the study., Methods: Using Indigenous research methodologies, we embodied our Indigeneity into every facet of the research process. We facilitated three talking circles with participants grounded in a distinct cultural and ceremonial context following Secwepemc protocols., Results: The collective voices of IHP revealed the following common experiences: confronting genocide; addressing Indigenous-specific racism; uprooting toxicity and inequities; and upholding Indigenous human rights while enhancing accountability of systems transformation., Conclusions: The experience of IHP working in health systems goes beyond mere individual employment obligations, its often about a families and communities advocacy for Indigenous rights, culturally safe working environments and access to dignified and respectful healthcare service. This study highlights the need for IHP to be actively involved in health system transformation to ensure the redesigning and restructuring of healthcare service delivery by and for Indigenous Peoples remains centered on Indigenous health and human rights., 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.

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening immune-mediated emergency classically associated with heparin therapy. This review focuses on type II HIT, characterized by the development of antibodies against platelet-factor 4 (PF4) bound to heparin after exposure, causing life-threatening thrombocytopenia, arterial thrombosis, and/or venous thrombosis. The high morbidity and mortality rates emphasize the need for early recognition and urgent intervention with discontinuation of heparin and initiation of non-heparin anticoagulation. We discuss the management of HIT with an emphasis on recent developments: (i) incorporating the phases of HIT (i.e., suspected, acute, subacute A and B, and remote) into its management, categorized according to platelet count, immunoassay, and functional assay results and (ii) direct-acting oral anticoagulants (DOACs), which are increasingly used in appropriate cases of acute HIT (off-label). In comparison to parenteral options (e.g., bivalirudin and danaparoid), they are easier to administer, are more cost-effective, and obviate the need for transition to an oral anticoagulant after platelet recovery. We also identify the knowledge gaps and suggest areas for future research.

Over the years, research regarding the Zika virus has been steadily increasing. Early immunization for ZIKV is a priority for preventing complications such as microencephaly and Guillain-Barré syndrome (GBS). Unlike traditional vaccination approaches, oral dissolving films (ODFs) or mucoadhesive film technology is an emerging, exciting concept that can be used in the field of pharmaceuticals for vaccine design and formulation development. This attractive and novel method can help patients who suffer from dysphagia as a complication of a disease or syndrome. In this study, we investigated a microparticulate Zika vaccine administered via the buccal route with the help of thin films or oral dissolving films (ODFs) with a prime dose and two booster doses two weeks apart. In vitro, the ODFs displayed excellent physiochemical properties, indicating that the films were good carriers for vaccine microparticles and biocompatible with the buccal mucosa. In vivo results revealed robust humoral (IgG, subtypes IgG1 and IgG2a) and T-cell responses (CD4+/CD8+) for ZIKV-specific immunity. Both the Zika MP vaccine and the adjuvanted Zika MP vaccine affected memory (CD45R/CD27) and intracellular cytokine (TNF-α and IL-6) expression. In this study, ZIKV vaccination via the buccal route with the aid of ODFs demonstrated great promise for the development of pain-free vaccines for infectious diseases.

In the 21 st century, impact of social media, particularly Social Networking Sites (SNSs) has been linked to a wide range of human beliefs and expectations. Growing body of research has indicated that body image concerns along with exercise motivation and social comparison are on the rise among young adults. The present study aimed to examine the sex difference in body image, exercise motivation and social comparison among people who use Instagram in the age group 20-30. A total of 212 participants (men=106, women=106) aged 20-30 years, who are users of Instagram completed Body Self Image Questionnaire Short Form as a measure of Body image, Exercise Motivation Inventory - 2 as a measure of Exercise Motivation and Instagram as a Tool for Social Comparison as a measure of Social Comparison. Results showed that a significant difference in body image exist across gender with body image issues higher among females and significant difference in exercise motivation across gender with exercise motivation higher among males. No sex differences were seen in social comparison. It was concluded that body image concerns are higher among females and the drive for exercise is higher among males who used Instagram. It was found that body image concerns were higher among people who exercised regularly as well as among those who followed fitness related pages on Instagram as compared to those who did not. These results provide an insight into the sex differences between the variables and future directions can be aimed at conducting an in-depth analysis using body image, exercise motivation and social comparison., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Nimiya A et al.)

Finite element studies of the tibiofemoral joint have increased use in research, with attention often placed on the material models. Few studies assess the effect of meniscus modelling assumptions in image-based models on contact mechanics outcomes. This work aimed to assess the effect of modelling assumptions of the meniscus on knee contact mechanics and meniscus kinematics. A sensitivity analysis was performed using three specimen-specific tibiofemoral models and one generic knee model. The assumptions in representing the meniscus attachment on the tibia (shape of the roots and position of the attachment), the material properties of the meniscus, the shape of the meniscus and the alignment of the joint were evaluated, creating 40 model instances. The values of material parameters for the meniscus and the position of the root attachment had a small influence on the total contact area but not on the meniscus displacement or the force balance between condyles. Using 3D shapes to represent the roots instead of springs had a large influence in meniscus displacement but not in knee contact area. Changes in meniscus shape and in knee alignment had a significantly larger influence on all outcomes of interest, with differences two to six times larger than those due to material properties. The sensitivity study demonstrated the importance of meniscus shape and knee alignment on meniscus kinematics and knee contact mechanics, both being more important than the material properties or the position of the roots. It also showed that differences between knees were large, suggesting that clinical interpretations of modelling studies using single geometries should be avoided., (© 2024. The Author(s).)

Objective: To explore associations of the main component (P100) of visual evoked potentials (VEP) to pre- and postchiasmatic damage in multiple sclerosis (MS)., Methods: 31 patients (median EDSS: 2.5), 13 with previous optic neuritis (ON), and 31 healthy controls had VEP, optical coherence tomography and magnetic resonance imaging. We tested associations of P100-latency to the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell/inner plexiform layers (GCIPL), lateral geniculate nucleus volume (LGN), white matter lesions of the optic radiations (OR-WML), fractional anisotropy of non-lesional optic radiations (NAOR-FA), and to the mean thickness of primary visual cortex (V1). Effect sizes are given as marginal R 2 (mR 2 )., Results: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100-latency was significantly associated with GCIPL (mR 2  = 0.26), and less strongly with OR-WML (mR 2  = 0.17), NAOR-FA (mR 2  = 0.13) and pRNFL (mR 2  = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR 2  = 0.41). In ON-patients, P100-latency was significantly associated with LGN volume (mR 2  = -0.56)., Conclusions: P100-latency is affected by anterior and posterior visual pathway damage. In ON-patients, damage at the synapse-level (LGN) may additionally contribute to latency delay., Significance: Our findings corroborate post-chiasmatic contributions to the VEP-signal, which may relate to distinct pathophysiological mechanisms in MS., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression., Methods: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient., Results: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001)., Discussion: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Background and Objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA., Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses., Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002)., Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Introduction: Hyperthyroidism, characterized by excessive thyroid hormone production, is a common endocrine disorder that affects various physiological processes, including brain function. Recent advancements in neuroimaging techniques have enabled researchers to investigate structural alterations in the brain associated with hyperthyroidism. This study aimed to examine regional cortical thickness and cortical volume differences across the brain between hyperthyroid patients and control subjects., Methods: We examined localized cortical thicknesses and volumes in 34 hyperthyroid patients and 35 control subjects with high-resolution T1-weighted images using FreeSurfer software and assessed group differences with analysis of covariance (covariates: age, sex, education, and total intracranial volume). Spearman and partial correlations were performed between clinical variables and cortical thicknesses/volumes and between neuropsychological scores and cortical thicknesses/volumes, respectively., Results: Hyperthyroid patients exhibited significantly increased cortical thickness in bilateral superior temporal and superior frontal gyri, along with higher cortical volumes in various regions, including the right superior temporal gyrus, right superior parietal gyrus, right rostral and caudal middle frontal gyrus, and left superior frontal gyrus. Notably, thyroid hormones (fT3, fT4) correlated positively with cortical thicknesses and volumes in the superior temporal gyrus and superior frontal gyrus. Additionally, recognition memory scores negatively correlated with the right superior temporal gyrus and right superior frontal gyrus cortical thickness., Conclusion: The observed cortical thickening and increased cortical volume in specific brain areas provide new insights into the pathophysiological mechanism associated with brain impairment in hyperthyroidism., (© 2024 S. Karger AG, Basel.)

Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence-based, and targeted disease-modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first-in-class myosin modulator, changing the paradigm for the pharmacological treatment of HCM., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Individual differences exist in performance in tasks that require visual search, such as camouflage detection (CD). Field dependence/independence (FD/I), as assessed using the Group Embedded Figures Test (GEFT), is an extensively studied dimension of cognitive style that classifies participants based on their visual perceptual styles. Materials and Methods: In the present study, we utilized fMRI on 46 healthy participants to investigate the underlying neural mechanisms specific to the cognitive styles of FD/FI while performing a CD task using both activation magnitude and an exploratory functional connectivity (FC) analysis. Group differences between high and low performers on the two extremes of the accuracy continuum of GEFT were studied. Results: No statistically significant group differences were observed using whole-brain voxel-wise comparison. However, the exploratory FC analysis revealed an enhanced communication between various regions subserving the cognitive traits required for visual search by FI participants over and above their FD counterparts. Conclusion: These enhanced connectivities suggest additional recruitment of cognitive functions to provide computational support that might facilitate superior performance in CD task by the participants who display a field-independent cognitive style.

Purpose: Emerging data indicate that metformin may prevent the development of age-related macular degeneration (AMD). Whereas the underlying mechanisms of metformin's anti-aging properties remain undetermined, one proposed avenue is the gut microbiome. Using the laser-induced choroidal neovascularization (CNV) model, we investigate the effects of oral metformin on CNV, retinal pigment epithelium (RPE)/choroid transcriptome, and gut microbiota., Methods: Specific pathogen free (SPF) male mice were treated via daily oral gavage of metformin 300 mg/kg or vehicle. Male mice were selected to minimize sex-specific differences to laser induction and response to metformin. Laser-induced CNV size and macrophage/microglial infiltration were assessed by isolectin and Iba1 immunostaining. High-throughput RNA-seq of the RPE/choroid was performed using Illumina. Fecal pellets were analyzed for gut microbiota composition/pathways with 16S rRNA sequencing/shotgun metagenomics, as well as microbial-derived metabolites, including small-chain fatty acids and bile acids. Investigation was repeated in metformin-treated germ-free (GF) mice and antibiotic-treated/GF mice receiving fecal microbiota transplantation (FMT) from metformin-treated SPF mice., Results: Metformin treatment reduced CNV size (P < 0.01) and decreased Iba1+ macrophage/microglial infiltration (P < 0.005). One hundred forty-five differentially expressed genes were identified in the metformin-treated group (P < 0.05) with a downregulation in pro-angiogenic genes Tie1, Pgf, and Gata2. Furthermore, metformin altered the gut microbiome in favor of Bifidobacterium and Akkermansia, with a significant increase in fecal levels of butyrate, succinate, and cholic acid. Metformin did not suppress CNV in GF mice but colonization of microbiome-depleted mice with metformin-derived FMT suppressed CNV., Conclusions: These data suggest that oral metformin suppresses CNV, the hallmark lesion of advanced neovascular AMD, via gut microbiome modulation.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting., Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW)., Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate., Exposure: Association between NfL z scores and CDW., Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively., Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years)., Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Background: Anthracycline-based chemotherapy has improved the prognosis of various malignancies, but increases the long-term risk of heart failure (HF). Identification of patients at risk prior to treatment initiation is warranted. Therefore, the aim of this study was to evaluate if a familial predisposition to HF increases the risk of anthracycline related HF., Methods: Using nationwide Danish registries, all patients treated with anthracycline from 2004 to 16 were identified. The primary outcome was long-term HF risk. First-degree relatives were identified in the Danish Family Registry and exposure was defined as a first-degree biological relative with prior HF. Risk of HF was evaluated in a cumulative incidence function and the association in a multivariable Cox regression model., Results: A total of 11,651 patients (median age 49.1 years (IQR: 43.6-53.7), 12.2% male) were included after exclusion of 46 with preanthracycline HF. Median follow-up was 3.8 years (IQR 1.9-6.4). In the group with a first-degree relative with HF (n = 1,608) 35 patients (2.2%) were diagnosed with HF vs 133 (1.3%) in the group without a first-degree relative with HF (n = 10,043), corresponding to incidence rates per 1,000 patient-years of 5.2 (CI:3.8-7.3) vs 3.0 (CI:2.5-3.5). The cumulative incidence of HF after 10 years was higher in the first-degree relative group (3.2% vs 2.0%, P = .004); adjusted hazard ratio 1.53 (CI:1.05-2.23, P = .03)., Conclusion: In this nationwide register-based study having a first-degree relative with HF was associated with increased risk of anthracycline related HF, suggesting that attention towards family predisposition may be warranted when estimating the risk of anthracycline related cardiotoxicity., Competing Interests: Disclosures None declared., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI)., Materials and Methods: From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE)., Results: A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92-1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42-1.52]), cardiovascular death (OR 1.71 [95% CI 1.64-1.78]) and heart failure (OR 1.13 [95% CI 1.07-1.20]) compared with patients presumed periodontally healthy., Conclusions: Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Introduction: Proteins are the most common biological macromolecules in living system and are building blocks of life. They are extremely dynamic in structure and functions. Due to several modifications, proteins undergo misfolding, leading to aggregation and thereby developing neurodegenerative and systemic diseases. Understanding the pathology of these diseases and the techniques used to diagnose them is therefore crucial for their effective management . There are several techniques, currently being in use to diagnose them and those will be discussed in this review., Aim/objectives: Current review aims to discuss an overview of protein aggregation and the underlying mechanisms linked to neurodegeneration and systemic diseases. Also, the review highlights protein misfolding disorders, their clinical diagnosis, and treatment strategies., Methodology: Literature related to neurodegenerative and systemic diseases was explored through PubMed, Google Scholar, Scopus, and Medline databases. The keywords used for literature survey and analysis are protein aggregation, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, systemic diseases, protein aggregation mechanisms, etc. DISCUSSION /CONCLUSION: This review summarises the pathogenesis of neurodegenerative and systemic disorders caused by protein misfolding and aggregation. The clinical diagnosis and therapeutic strategies adopted for the management of these diseases are also discussed to aid in a better understanding of protein misfolding disorders. Many significant concerns about the role, characteristics, and consequences of protein aggregates in neurodegenerative and systemic diseases are not clearly understood to date. Regardless of technological advancements, there are still great difficulties in the management and cure of these diseases. Therefore, for better understanding, diagnosis, and treatment of neurodegenerative and systemic diseases, more studies to identify novel drugs that may aid in their treatment and management are required., 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.)

Background: Upper extremity function (UEF) is often compromised in multiple sclerosis (MS), although its importance is regularly underrecognized relative to ambulation. We explored the concurrent presence of impairment in UEF and ambulation by examining various aspects of UEF across different levels of ambulation., Methods: The cohort consisted of 247 patients with clinically definite MS or clinically isolated syndrome according to the revised 2010 McDonald criteria. The Nine-Hole Peg Test and the Expanded Disability Status Scale were used to stratify patients into clinically different subgroups. For UEF, cerebellar function (finger-to-nose test), pyramidal function (pronator drift test), and the ability to perform a task of activities of daily living (drinking-from-cup test) were examined. Patient-reported limitations of UEF in daily life were assessed using the Arm Function in Multiple Sclerosis Questionnaire., Results: Patients in more severely impaired ambulation groups displayed poorer performance on all UEF measures. Although most patients had normal to mild (n = 147) or moderate (n = 46) ambulatory impairment, 87.7% exhibited some level of UEF impairment as defined using the Nine-Hole Peg Test. Most patients had mild UEF impairment (n = 174), accounting for the largest proportion in all ambulation groups (51.9%-77.8%)., Conclusions: A distinct pattern of impairment was found for ambulation and multiple aspects of UEF. Independent assessment of multiple aspects of disability may be helpful in treatment decision-making and could support the development of rehabilitation strategies that specifically target UEF impairment., Competing Interests: FINANCIAL DISCLOSURES: Dr van Munster has received travel support from Novartis Pharma AG, Sanofi Genzyme, Teva Pharmaceuticals, and Merck Serono; honoraria for lecturing and consulting from Novartis Pharma AG, Biogen Idec, and Merck Serono; and compensation for serving on a scientific advisory board from Biogen Idec, Roche, Merck Serono, and Sanofi Genzyme. Dr Burggraaff has received travel support from Novartis Pharma AG. Dr Kamm has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Bayer Schweiz AG, Teva Pharmaceuticals, Merck, Sanofi Genzyme, Roche, Celgene, and the Swiss MS Society. Dr D’Souza has received travel support from Bayer AG, Hoffmann-La Roche, Teva Pharmaceuticals, and Sanofi Genzyme and research support from the University Hospital Basel. Drs Dorn, Walsh, and Dahlke are employees of Novartis Pharma AG. Dr Uitdehaag has received consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals. Dr Steinheimer and M. Diederich declare no conflicts of interest. In the past 3 years, Dr Kappos’ institution (University Hospital Basel) received and used exclusively for research support for the Department of Neurology steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, df-mp, Excemed, GeNeuro SA, Genzyme, Merck, Minoryx, Mitsubishi Pharma, Novartis, Receptos, Roche, Sanofi Aventis, Santhera, Teva Pharmaceuticals, and Vianex and royalties from Neurostatus products. For department educational activities, the institution received honoraria from Allergan, Almirall, Bayer, Biogen, Excemed, Genzyme, Merck, Novartis, Pfizer, Sanofi Aventis, Teva Pharmaceuticals, and UCB., (© 2023 Consortium of Multiple Sclerosis Centers.)

Aims: This research explores how health care providers determine the mental health needs of immigrant women in the perinatal phase of childbirth. The contextual factors that affect the mental health of these women and influence their engagement with the British Columbian communities in which they reside are investigated., Method: Using a critical ethnographic approach, eight health care providers were interviewed to gain insight into health care provider's health literacy and immigrant perinatal women's mental health. Each participant was interviewed for 45-60 min in the period from January to February 2021 to obtain relevant data., Results: Three themes emerged from the data analysis: the health care provider's role and his/her health literacy, the health literacy of the participant, and the impact of the ongoing COVID-19 pandemic on the participant's situation., Conclusions: The findings indicate that a healthy working relationship between the health care provider and an immigrant woman in the perinatal phase of childbirth is essential to facilitate an effective interchange of health information.

Purpose: Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach., Methods: We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list., Results: The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies., Conclusion: This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP., 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., (© 2023 Xie, Hilkert Rodriguez, Xie, D'Souza, Reem, Sulakhe and Skondra.)

Aims: Recent studies suggest that atrial fibrillation (AF) burden (time AF is present) is an independent risk factor for stroke. The aim of this trial was to study the feasibility and accuracy to identify AF episodes and quantify AF burden in patients with a known history of paroxysmal AF with a photoplethysmography (PPG)-based wearable., Methods and Results: In this prospective, single-centre trial, the PPG-based estimation of AF burden was compared with measurements of a conventional 48 h Holter electrocardiogram (ECG), which served as the gold standard. An automated algorithm performed PPG analysis, while a cardiologist, blinded for the PPG data, analysed the ECG data. Detected episodes of AF measured by both methods were aligned timewise.Out of 100 patients recruited, 8 had to be excluded due to technical issues. Data from 92 patients were analysed [55.4% male; age 73.3 years (standard deviation, SD: 10.4)]. Twenty-five patients presented AF during the study period. The intraclass correlation coefficient of total AF burden minutes detected by the two measurement methods was 0.88. The percentage of correctly identified AF burden over all patients was 85.1% and the respective parameter for non-AF time was 99.9%., Conclusion: Our results demonstrate that a PPG-based wearable in combination with an analytical algorithm appears to be suitable for a semiquantitative estimation of AF burden in patients with a known history of paroxysmal AF., Trial Registration Number: NCT04563572., Competing Interests: Conflict of interest: D.P. is an employee of Preventicus. J.E. owns 0.5% virtual shares of Preventicus. All remaining authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Proliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR., Methods: We queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists., Results: Our query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR., Conclusions: This bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations., Translational Relevance: Novel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

Plasmonic gold nanostructures are a prevalent tool in modern hypersensitive analytical techniques such as photoablation, bioimaging, and biosensing. Recent studies have shown that gold nanostructures generate transient nanobubbles through localized heating and have been found in various biomedical applications. However, the current method of plasmonic nanoparticle cavitation events has several disadvantages, specifically including small metal nanostructures (≤10 nm) which lack size control, tuneability, and tissue localization by use of ultrashort pulses (ns, ps) and high-energy lasers which can result in tissue and cellular damage. This research investigates a method to immobilize sub-10 nm AuNPs (3.5 and 5 nm) onto a chemically modified thiol-rich surface of Qβ virus-like particles. These findings demonstrate that the multivalent display of sub-10 nm gold nanoparticles (AuNPs) caused a profound and disproportionate increase in photocavitation by upward of 5-7-fold and significantly lowered the laser fluency by 4-fold when compared to individual sub-10 nm AuNPs. Furthermore, computational modeling showed that the cooling time of QβAuNP scaffolds is significantly extended than that of individual AuNPs, proving greater control of laser fluency and nanobubble generation as seen in the experimental data. Ultimately, these findings showed how QβAuNP composites are more effective at nanobubble generation than current methods of plasmonic nanoparticle cavitation.

The burden of disease attributable to obesity is rapidly increasing and becoming a public health challenge globally. Using a nationally representative sample in Australia, this study aims to examine the association of obesity with healthcare service use and work productivity across outcome distributions. We used Household, Income and Labour Dynamics Australia (HILDA) Wave 17 (2017-2018), including 11,211 participants aged between 20 and 65 years. Two-part models using multivariable logistic regressions and quantile regressions were employed to understand variations in the association between obesity levels and the outcomes. The prevalence of overweight and obesity was 35.0% and 27.6%, respectively. After adjusting for socio-demographic factors, low socioeconomic status was associated with a higher probability of overweight and obesity (Obese III: OR = 3.79; 95% CI 2.53-5.68) while high education group was associated with a lower likelihood of being high level of obesity (Obese III OR = 0.42, 95% CI 0.29-0.59). Higher levels of obesity were associated with higher probability of health service use (GP visit Obese, III: OR = 1.42 95% CI 1.04-1.93,) and work productivity loss (number of paid sick leave days, Obese III: OR = 2.40 95% CI 1.94-2.96), compared with normal weight. The impacts of obesity on health service use and work productivity were larger for those with higher percentiles compared to lower percentiles. Overweight and obesity are associated with greater healthcare utilisation, and loss in work productivity in Australia. Australia's healthcare system should prioritise interventions to prevent overweight and obesity to reduce the cost on individuals and improve labour market outcomes., (© 2023. The Author(s).)

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis and pneumonia in children ages five years and below. Recent outbreaks of the virus have proven that RSV remains a severe burden on healthcare services. Thus, a vaccine for RSV is a need of the hour. Research on novel vaccine delivery systems for infectious diseases such as RSV can pave the road to more vaccine candidates. Among many novel vaccine delivery systems, a combined system with polymeric nanoparticles loaded in dissolving microneedles holds a lot of potential. In this study, the virus-like particles of the RSV fusion protein (F-VLP) were encapsulated in poly (D, L-lactide- co -glycolide) (PLGA) nanoparticles (NPs). These NPs were then loaded into dissolving microneedles (MNs) composed of hyaluronic acid and trehalose. To test the in vivo immunogenicity of the nanoparticle-loaded microneedles, Swiss Webster mice were immunized with the F-VLP NPs, both with and without adjuvant monophosphoryl lipid A (MPL) NPs loaded in the MN. The mice immunized with the F-VLP NP + MPL NP MN showed high immunoglobulin (IgG and IgG2a) levels both in the serum and lung homogenates. A subsequent analysis of lung homogenates post-RSV challenge revealed high IgA, indicating the generation of a mucosal immune response upon intradermal immunization. A flowcytometry analysis showed high CD8+ and CD4+ expression in the lymph nodes and spleens of the F-VLP NP + MPL NP MN-immunized mice. Thus, our vaccine elicited a robust humoral and cellular immune response in vivo. Therefore, PLGA nanoparticles loaded in dissolving microneedles could be a suitable novel delivery system for RSV vaccines.

Background: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS)., Objective: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS., Methods: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models., Results: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p < 0.04), total gray matter (p < 0.002), thalamus (p ≤ 0.04), and cerebral cortex (p ≤ 0.003) -both globally and regionally-, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations (p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL., Conclusions: In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis., (© 2023. The Author(s).)

Background: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage., Methods: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage., Results: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity)., Conclusions: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies., (© 2023. The Author(s).)