A spectrum of altered non-rapid eye movement sleep in schizophrenia.

Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations, are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, ageing, cognitive profiles and medication regimens. Using newly collected high-density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported group-level differences between patients and controls (original N=130) during N2 stage. Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability. We replicated all group-level mean differences and confirmed the high accuracy of our predictive model (AUC=0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics. Although multiple clinical and cognitive factors were associated with NREM metrics, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater contributor to variability. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on the sleep EEG; further, among patients, certain medications exacerbated these effects, in particular olanzapine. Collectively, our results point to a spectrum of N2 sleep deficits among SCZ patients that can be measured objectively and at scale, with relevance to both the etiological heterogeneity of SCZ as well as potential iatrogenic effects of antipsychotic medication.

The Role of Dimensions of Social Support in the Relationship Between Stigma and Mental Health: A Moderation Analysis.

HIV stigma remains a barrier to good health and understanding how social support may reduce the negative impact of stigma on health may help with designing stigma interventions. This study aims to understand how different types of social support may moderate or change the nature of the relationship between stigma and mental health. We recruited 327 participants to complete the People Living with HIV Stigma Index at baseline (t1) between August 2018 and September 2019 and at follow-up (t2) between February 2021 and October 2021. Separate moderation models were created with different types of social support (emotional/informational, tangible, affectionate, positive social interaction) as moderators, baseline stigma (internalized, enacted, anticipated) as the antecedent, and mental health (t2) as the outcome. Emotional/informational support was a significant moderator for the relationship between enacted (b = -2.12, 95% CI: -3.73, -0.51), internalized (b = -1.72, 95% CI: -3.24, -0.20), and anticipated (b = -2.59, 95% CI: -4.59, -0.60) stigma at t1 and mental health at t2. Tangible support was a significant moderator for internalized stigma (b = -1.54, 95% CI: -2.74, -0.35). Lastly, positive social interaction was a significant moderator for internalized (b = -1.38, 95% CI: -2.71, -0.04) and anticipated stigma (b = -2.14, 95% CI: -3.93, -0.36). In general, the relationship between social support and better mental health was stronger for participants with low stigma. Intervention strategies aimed at both stigma reduction and boosting social supports with different functions may be important for improving the mental health of people living with HIV.

Electroencephalographic Microstates During Sleep and Wake in Schizophrenia.

Background: Aberrant functional connectivity is a hallmark of schizophrenia. The precise nature and mechanism of dysconnectivity in schizophrenia remains unclear, but evidence suggests that dysconnectivity is different in wake versus sleep. Microstate analysis uses electroencephalography (EEG) to investigate large-scale patterns of coordinated brain activity by clustering EEG data into a small set of recurring spatial patterns, or microstates. We hypothesized that this technique would allow us to probe connectivity between brain networks at a fine temporal resolution and uncover previously unknown sleep-specific dysconnectivity. Methods: We studied microstates during sleep in patients with schizophrenia by analyzing high-density EEG sleep data from 114 patients with schizophrenia and 79 control participants. We used a polarity-insensitive k-means analysis to extract a set of 6 microstate topographies. Results: These 6 states included 4 widely reported canonical microstates. In patients and control participants, falling asleep was characterized by a shift from microstates A, B, and C to microstates D, E, and F. Microstate F was decreased in patients during wake, and microstate E was decreased in patients during sleep. The complexity of microstate transitions was greater in patients than control participants during wake, but this reversed during sleep. Conclusions: Our findings reveal behavioral state-dependent patterns of cortical dysconnectivity in schizophrenia. Furthermore, these findings are largely unrelated to previous sleep-related EEG markers of schizophrenia such as decreased sleep spindles. Therefore, these findings are driven by previously undescribed sleep-related pathology in schizophrenia.

EEG microstates are stereotyped patterns of scalp voltage topography that provide information about brain activity at millisecond-level temporal resolution. We used this method to study brain activity in schizophrenia during sleep and wake. We found state-dependent case-control differences in EEG microstates that were unrelated to the results of classic EEG analyses. These differences reflect aberrant neural functioning during sleep in patients with schizophrenia.

Identifying strategies to enhance the milking and operator efficiency of herringbone and rotary parlor systems in Ireland.

International trends of increasing dairy herd sizes coupled with scarcity of labor has necessitated the enhancement of labor efficiency for dairy production systems. This study quantified the effects of infrastructure, automation, and management practices on the milking and operator efficiency of herringbone and rotary parlors used on pasture-based farms in Ireland. Data from 592 milkings across 26 farms (16 herringbones and 10 rotaries) was used. The metrics of cows milked per hour (cows/h), cows milked per operator per hour (cows/h per operator) and liters of milk harvested per hour (L/h) described milking efficiency. The metrics of total process time per cow (TPT, s/cow), milk process time per cow (MPT, s/cow), work routine time (WRT, s/cow), cluster time (CT, s/cluster), and attachment time per cow (ATC, s/cow) described operator efficiency. Automations investigated were backing gates, cluster flush, plant wash, cluster removers (ACRs), feeders, entry gates, rapid-exit, and teat spray. Additional operator presence at milking was also investigated. Herringbone and rotary parlors were assigned to quartiles from their cows/h per operator values to examine infrastructure, automations, and management practices variations. Fourth quartile herringbones based on cows/h per operator values (Q4) averaged 93 cows/h per operator using average system sizes of 24 clusters with 5 parlor automations. Q4 rotaries averaged 164 cows/h per operator using average system sizes of 47 clusters and an average CT of 13 s/cluster. Cows/h per operator values for Q4 herringbone and rotary parlors were 82% and 54% higher, respectively, than values observed on Q1 parlors, indicating the considerable potential to improve efficiency. To determine if infrastructure, automations, or additional operators at milking significantly affected operator efficiencies, general linear mixed models were developed. For parlor infrastructure, additional clusters had greater significance on operator efficiencies (MPT) for herringbones (-1.3 s/cow) as opposed to rotaries (-0.2 s/cow). Hence, increases in system size was likely to result in improved efficiencies for herringbones but less so for rotaries. For automations, ACRs significantly reduced herringbone TPT, CT, and WRT values by 13.3 s/cow, 18.9 s/cluster, and 32.6 s/cow, respectively, whereas rapid-exit significantly lowered CT by 18.6 s/cluster. We found no significant effect on rotary TPT, MPT, CT, or WRT values from the use of automatic teat sprayers. An additional operator at milking was found to significantly reduce herringbone TPT but not MPT or CT. For rotaries, a second operator had no significant effect on TPT, MPT, CT, or WRT values. We documented strong negative correlations between operator efficiencies (TPT, MPT) and milking efficiency (cows/h) for both herringbone (-0.91, -0.84) and rotaries (-0.98, -0.89). Strong negative correlations between the herringbone automation count and TPT (-0.80), MPT (-0.72), and CT (-0.75) suggested highly automated parlors were likely to achieve greater operator efficiencies than less automated parlors. The strong negative correlation (-0.81) between rotary milking efficiency (cows/h) and CT suggested lower CT values (i.e., rotation speed) resulted in increased milking efficiency. In conclusion, our study quantified the effects of parlor infrastructure, automation, and management practices on the milking and operator efficiency of herringbone and rotary parlors.

The impact of determinants of health on the relationship between stigma and health in people living with HIV.

Determinants of health are important drivers of health states, yet there is little work examining their role in the relationship between HIV stigma and health. This study uses moderation analysis to examine how determinants of health affect the relationship between enacted, internalized, and anticipated stigma and mental health. Quantitative data was collected on 337 participants in Ontario, Canada at baseline (t1) between August 2018 and September 2019 and at follow-up (t2) between February 2021 and October 2021. Separate moderation models were created with each determinant of health (age, gender, sexual orientation, ethnicity, geographic region, education, employment, and basic needs) acting as the moderator between types of stigma at t1 and mental health at t2. Age was a significant moderator for the relationship between internalized and enacted stigma at t1 and mental health at t2. Region was a moderator for enacted and anticipated stigma and mental health. Sexual orientation was a moderator for anticipated stigma and mental health. Lastly, having basic needs was a moderator for enacted and anticipated stigma and mental health. Our findings suggest that intervention strategies may be more effective by incorporating supports for these determinants of health in addition to stigma reduction to improve mental health.

Geriatric femur fractures: Index fracture pattern is associated with the risk of subsequent peri-implant fracture.

Introduction: Following an index femoral fragility fracture, patients are at risk of a subsequent peri-implant fracture. Management of these injuries are further complicated by patient factors and multi-institutional care. This study quantifies such events and compare rate of identification between in-system and out-of-system patients. Methods: A retrospective chart review of index operative femoral fragility fractures at a level I trauma center from January 1, 2005 to January 1, 2018 identified 840 patients with twenty-two subsequent peri-implant fractures. Kaplan Meier survival analyses assessed associations between patient and injury characteristics with the subsequent fracture while accounting for differential follow-up. Cumulative incidence curves were reported, and Cox regression analyses estimated hazard ratios for statistically significant associations. In-system and out-of-system patients were compared with absolute rate of identifying subsequent fracture and follow-up time. Results: Cumulative incidence of subsequent fracture was 2.1 % at 2 years, 3.4 % at 4 years, and 4.6 % at 6 years. The index fracture pattern (intertrochanteric vs other) was associated with a cumulative incidence of subsequent peri-implant fracture (0.8 % at 2 years, 1.4 % at 4 years, and 2.7 % at 6 years for intertrochanteric fractures vs 3.4 % at 2 years, 5.3 % at 4 years, and 6.4 % at 6 years for non-intertrochanteric fractures), p = 0.029. Follow-up was shorter for out-of-system patients (median 6 versus 28 months, p < 0.001), and only 1 of 348 out-of-system patients (0.3 %) vs. 21 of 492 in-system patients (4.3 %) were diagnosed with a subsequent peri-implant fracture (p < 0.001). There was no association of subsequent peri-implant fracture with patient demographics or comorbidity burden. Conclusion: Cumulative incidence of subsequent peri-implant fracture was higher for non-intertrochanteric (femoral neck, shaft and distal femur) fractures than intertrochanteric fractures. Out-of-system patients had shorter follow-up and were less likely to be diagnosed with a subsequent peri-implant fracture, indicating ascertainment bias and underscoring the importance of accounting for loss to follow-up. Level of evidence: Therapeutic Level III.

Characterization of therapeutic antibody efficacy against multiple SARS-CoV-2 variants in the hamster model.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and onset of the coronavirus disease-19 (COVID-19) pandemic led to an immediate need for therapeutic treatment options. Therapeutic antibodies were developed to fill a gap when traditional antivirals were not available. In late 2020, the United States Government undertook an effort to compare candidate therapeutic antibodies in virus neutralization assays and in the hamster model of SARS-CoV-2 infection. With the emergence of SARS-CoV-2 variants, the effort expanded to evaluate the efficacy of nearly 50 products against major variants. A subset of products was further evaluated for therapeutic efficacy in hamsters. Here we report results of the hamster studies, including pathogenicity with multiple variants, neutralization capacity of products, and efficacy testing of products against Delta and Omicron variants. These studies demonstrate the loss of efficacy of early products with variant emergence and support the use of the hamster model for evaluating therapeutics.

Transfusion Camp: The UK experience and its value in improving knowledge of transfusion medicine among postgraduate trainees.

OBJECTIVES: To report the UK experience of rolling out Transfusion Camp. BACKGROUND: Transfusion Camp is a structured education programme developed in Toronto, with the aim of reducing knowledge gaps in transfusion medicine in postgraduate trainees. It consists of didactic lectures viewed online by the participants, then interactive, locally delivered seminars. Since 2015, it has been rolled out in the United Kingdom, and is now available in four centres. Here, we report the UK experience of Transfusion Camp and outcomes. METHODS: Trainees are recruited via the training programme directors in each region. Pre- and post-course assessments are administered using the validated BEST (Biomedical Excellence for Safer Transfusion) test, with possible scores 0-20, and confidence measured on an A-E Likert scale. RESULTS: Since 2015, 130 trainees have participated in Transfusion Camp in the United Kingdom. Trainees from all specialties significantly improved their BEST-test scores after attending the course (mean score 11.6/20 before the course, compared with 14.3/20 after the course), and confidence in managing transfusion-related issues was also significantly improved. CONCLUSION: We recommend that all centres consider offering Transfusion Camp to trainees in haematology and other specialties that frequently use blood transfusions, such as anaesthesia/ICU, Internal Medicine and others.

Influence of phospholipid head and tail molecular structures on cell membrane mechanical response under tension.

Biological cell membranes are primarily comprised of a diverse lipid bilayer with multiple phospholipid (lipid) types, each of which is comprised of a hydrophilic headgroup and two hydrophobic hydrocarbon tails. The lipid type determines the molecular structure of head and tail groups, which can affect membrane mechanics at nanoscale and subsequently cell viability under mechanical loading. Hence, using molecular dynamics simulations, the current study investigated seven membrane phospholipids and the effect of their structural differences on physical deformation, mechanoporation damage, and mechanical failure of the membranes under tension. The inspected phospholipids showed similar yield stresses and strains, as well as pore evolution and damage, but significantly different failure strains. In general, failure occurred at a lower strain for lipids with a larger equilibrium area per lipid. The obtained results suggest that larger headgroup structure, greater degree of unsaturation, and tail-length asymmetry influenced the phospholipids' ability to pack against each other, increased the fluidity and equilibrium area per lipid of the membrane, and resulted in lower failure strain. Overall, this study provides insights on how different phospholipid structures affect membrane physical responses at the molecular level and serves as a reference for future studies of more complex membrane systems with intricate biophysical properties.

Artificial Intelligence Machine Learning Algorithms Versus Standard Linear Demographic Analysis in Predicting Implant Size of Anatomic and Reverse Total Shoulder Arthroplasty.

BACKGROUND: Accurate and precise templating is paramount for anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RSA) to enhance preoperative planning, streamline surgery, and improve implant positioning. We aimed to evaluate the predictive potential of readily available patient demographic data in TSA and RSA implant sizing, independent of implant design. METHODS: A total of 578 consecutive, primary, noncemented shoulder arthroplasty cases were retrospectively reviewed. Demographic variables and implant characteristics were recorded. Multivariate linear regressions were conducted to predict implant sizes using patient demographic variables. RESULTS: Linear models accurately predict TSA implant sizes within 2 millimeters of humerus stem sizes 75.3% of the time, head diameter 82.1%, head height 82.1%, and RSA glenosphere diameter 77.6% of the time. Linear models predict glenoid implant sizes accurately 68.2% and polyethylene thickness 76.6% of the time and within one size 100% and 95.7% of the time, respectively. CONCLUSION: Linear models accurately predict shoulder arthroplasty implant sizes from demographic data. No significant statistical differences were observed between linear models and machine learning algorithms, although the analysis was underpowered. Future sufficiently powered studies are required for more robust assessment of machine learning models in predicting primary shoulder arthroplasty implant sizes based on patient demographics.

Identification of cellular and noncellular components of mature intact human peripheral nerve.

BACKGROUND AND AIMS: The goal of this study was to define basic constituents of the adult peripheral nervous system (PNS) using intact human nerve tissues. METHODS: We combined fluorescent and chromogenic immunostaining methods, myelin-selective fluorophores, and routine histological stains to identify common cellular and noncellular elements in aldehyde-fixed nerve tissue sections. We employed Schwann cell (SC)-specific markers, such as S100ß, NGFR, Sox10, and myelin protein zero (MPZ), together with axonal, extracellular matrix (collagen IV, laminin, fibronectin), and fibroblast markers to assess the SC's relationship to myelin sheaths, axons, other cell types, and the acellular environment. RESULTS: Whereas S100ß and Sox10 revealed mature SCs in the absence of other stains, discrimination between myelinating and non-myelinating (Remak) SCs required immunodetection of NGFR along with axonal and/or myelin markers. Surprisingly, our analysis of NGFR+ profiles uncovered the existence of at least 3 different novel populations of NGFR+/S100ß- cells, herein referred to as nonglial cells, residing in the stroma and perivascular areas of all nerve compartments. An important proportion of the nerve's cellular content, including circa 30% of endoneurial cells, consisted of heterogenous S100ß negative cells that were not associated with axons. Useful markers to identify the localization and diversity of nonglial cell types across different compartments were Thy1, CD34, SMA, and Glut1, a perineurial cell marker. INTERPRETATION: Our optimized methods revealed additional detailed information to update our understanding of the complexity and spatial orientation of PNS-resident cell types in humans.

Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex.

Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus's glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

RBD design increases the functional antibody titers elicited by SARS-CoV-2 spike vaccination.

Most COVID-19 vaccines contain the SARS-CoV-2 spike protein as an antigen, but they lose efficacy as neutralizing antibody titers wane and escape variants emerge. Modifying the spike antigen to increase neutralizing antibody titers would help counteract this decrease in titer. We previously used a structure-based computational design method to identify nine amino acid changes in the receptor-binding domain (RBD) of spike that stabilize the RBD and increase the neutralizing antibody titers elicited by vaccination. Here, we introduce those enhancing amino acid changes into a full-length spike (FL-S-2P) ectodomain representative of most approved vaccine antigens. These amino acid changes can be incorporated into the FL-S-2P protein without negatively effecting expression or stability. Furthermore, the amino acid changes improved functional antibody titers in both mice and monkeys following vaccination. These amino acid changes could increase the duration of protection conferred by most COVID-19 vaccines.

Correlates of Problematic Gambling in Emerging Adult University Students in Ireland.

INTRODUCTION: Understanding the correlates of problematic gambling among emerging adult university students is crucial for developing effective approaches to minimise harm. METHODS: This cross-sectional survey study reports on 397 18-25 year old emerging adults studying at Irish universities who completed an online survey about problematic gambling and a range of biopsychosocial variables. Chi-square and binary logistic regression analyses explored the relationships between problematic gambling and the biopsychosocial variables measured. RESULTS: Chi-square analyses showed that being male, having an online gambling account, having a mobile gambling app, novelty seeking (impulsivity), harm avoidance (fear of uncertainty), and high alcohol volume consumption were significantly associated with problematic gambling. Regression analyses showed that individuals were more likely to report problematic gambling if they were male (OR = 9.57 times), had an online gambling account (OR = 17.05 times), had a mobile gambling app (OR = 20.37 times), scored high in impulsivity (OR = 7.79 times), and reported high alcohol volume consumption (OR = 4.66 times). Individuals were less likely to report problematic gambling if they scored high in fear of uncertainty (OR = 0.26 times). CONCLUSIONS: A high rate of problematic gambling was observed among the current study sample. Participants were more likely to reported problematic gambling if they were male, had online gambling accounts, mobile gambling apps, scored high in impulsivity, scored low in fear of uncertainty, or consumed high volumes of alcohol in typical drinking sessions. These findings have implications for Irish legislation and policy-makers, Irish higher education institutions, and young adult Irish university students.

The prevalence of anxiety in respiratory and sleep diseases: A systematic review and meta-analysis.

BACKGROUND: Anxiety is common in those with chronic physical health conditions and can have significant impacts on both quality of life and physical health outcomes. Despite this, there are limited studies comprehensively investigating the prevalence of anxiety in respiratory and sleep medicine settings. This systematic review and meta-analysis aims to provide insight into the global prevalence of anxiety symptoms/disorders in respiratory and sleep medicine outpatients. METHODS: PubMed, Embase, Cochrane, PsycINFO and Google Scholar databases were searched from database inception to January 23, 2023 for studies assessing the prevalence of anxiety in adult (≥16 years) respiratory and sleep medicine outpatients. Data was screened and extracted independently by two investigators. Anxiety was measured using various self-report questionnaires, structured interviews, and/or patient records. Using CMA software for the meta-analysis, a random-effects model was used for pooled estimates, and subgroup analysis was conducted on relevant models using a mixed-effects model. RESULTS: 116 studies were included, featuring 36,340 participants across 40 countries. The pooled prevalence of anxiety was 30.3 % (95%CI 27.9-32.9 %, 10,679/36,340). Subgroup analysis found a significant difference across type of condition, with pulmonary tuberculosis the highest at 43.1 % and COVID-19 outpatients the lowest at 23.4 %. No significant difference was found across anxiety types, country or age. Female sex and the use of self-report measures was associated with significantly higher anxiety estimates. CONCLUSIONS: Anxiety is a common experience amongst patients in respiratory and sleep medicine outpatient settings. Thus, it is crucial that anxiety identification and management is considered by physicians in the field. REGISTRATION: The protocol is registered in PROSPERO (CRD42021282416).

Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Advances in Host Depletion and Pathogen Enrichment Methods for Rapid Sequencing-Based Diagnosis of Bloodstream Infection.

Bloodstream infection is a major cause of morbidity and death worldwide. Timely and appropriate treatment can reduce mortality among critically ill patients. Current diagnostic methods are too slow to inform precise antibiotic choice, leading to the prescription of empirical antibiotics, which may fail to cover the resistance profile of the pathogen, risking poor patient outcomes. Additionally, overuse of broad-spectrum antibiotics may lead to more resistant organisms, putting further pressure on the dwindling pipeline of antibiotics, and risk transmission of these resistant organisms in the health care environment. Therefore, rapid diagnostics are urgently required to better inform antibiotic choice early in the course of treatment. Sequencing offers great promise in reducing time to microbiological diagnosis; however, the amount of host DNA compared with the pathogen in patient samples presents a significant obstacle. Various host-depletion and bacterial-enrichment strategies have been used in samples, such as saliva, urine, or tissue. However, these methods have yet to be collectively integrated and/or extensively explored for rapid bloodstream infection diagnosis. Although most of these workflows possess individual strengths, their lack of analytical/clinical sensitivity and/or comprehensiveness demands additional improvements or synergistic application. This review provides a distinctive classification system for various methods based on their working principles to guide future research, and discusses their strengths and limitations and explores potential avenues for improvement to assist the reader in workflow selection.

Outcomes of Percutaneous Endoscopic Gastrostomy in Huntington's Disease at a Tertiary Center.

BACKGROUND: Clinically assisted nutrition and hydration via percutaneous endoscopic gastrostomy (PEG) is a therapeutic option to ameliorate the difficulties associated with enhanced catabolism, weight loss, and dysphagia in Huntington's disease (HD). OBJECTIVES: The objective is to provide insights into demographics, staging (Shoulson-Fahn), complications, weight trajectories, and survival rates in people with HD (pwHD) who underwent PEG. METHODS: This retrospective study included 705 consecutive pwHD who attended our HD clinic between July 2006 and March 2024, of whom 52 underwent PEG. A control group (n = 52), comprising pwHD without PEG, were closely matched for sex, stage, age, CAG length, and disease burden score at PEG. The study was registered as a service evaluation at the National Hospital for Neurology and Neurosurgery. RESULTS: PEG prevalence was 15.0% (n = 52/347) among manifest pwHD: 4.8% (n = 3/62) for Stage 3; 33.3% (n = 16/48) for stage 4; and 44.1% (n = 30/68) for stage 5. Commonest indications were dysphagia, weight loss, and inadequate oral intake. Complications included chest infection, tube dislodgement, and peristomal and skin infections. Modeling of weight trajectories after PEG found no difference between PEG and non-PEG groups. Mortality rate was 34.6% (n = 18/52) in the PEG and 36.5% (n = 19/52) in the non-PEG groups (P = 0.84). Treatment duration (until study endpoint or death) was 3.48 years (interquartile range = 1.71-6.02; range = 0.23-18.8), with 65.4% (n = 34/52) alive at the study endpoint. CONCLUSION: PEG in pwHD at-risk for weight loss may help slow weight loss. Prospective studies are required to strengthen PEG decision-making in pwHD. PEG survival was much longer than other dementias, highlighting the need to consider PEG independently in pwHD.