Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure. METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal. RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased. DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.

Associations of physical activity levels with fatigue in people with inflammatory rheumatic diseases in the LIFT trial.

Objectives: The overall aim of the current study was to quantify physical activity levels in inflammatory rheumatic diseases (IRDs) and to explore their role in fatigue. Methods: We conducted a secondary analysis of data from the Lessening the Impact of Fatigue in IRDs (LIFT) trial of the personalized exercise program (PEP) intervention for fatigue. Participants with IRDs were recruited from 2017 to 2019 and the current analysis used fatigue, measured by the Chalder Fatigue Scale (CFS) and the Fatigue Severity Scale (FSS), and accelerometer measured physical activity data collected at baseline and at the 6-month follow-up. Physical activity levels were quantified and associations with fatigue and effects of PEP investigated. Results: Of the 337 included participants, 195 (68.4%) did not meet the current recommendations for moderate-vigorous physical activity (MVPA). In baseline cross-sectional analysis, many dimensions of physical activity were associated with fatigue. After mutual adjustment, overall physical activity (vector magnitude) was associated with CFS [-0.88 (95% CI -0.12, -1.64)] and distribution of time spent at different activity intensities was associated with FSS [-1.16 (95% CI -2.01, -0.31)]. Relative to usual care, PEP resulted in an increase in upright time, with trends for increases in step count and overall physical activity. People who increased overall physical activity (vector magnitude) more had greater improvements in CFS and FSS, while those who increased step count and MVPA more had greater improvements in FSS. Conclusion: Increasing physical activity is important for fatigue management in people with IRDs and further work is needed to optimize PEPs to target the symptoms and impact of fatigue. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT03248518.

Drug-Induced Alopecia Areata From Upadacitinib.

This case report describes an unexpected occurrence of alopecia areata (AA) in a 55-year-old woman undergoing treatment with upadacitinib for atopic dermatitis. This patient developed AA approximately one year into her upadacitinib treatment for atopic dermatitis. This case highlights possible upadacitinib-induced AA, which has not been reported in the literature. Not only does this case demonstrate the typical timeline for drug-induced alopecia, but it also raises questions about whether upadacitinib can cause drug-induced alopecia.

Quality of participants' relationships to peer recovery support specialists as a function of perceived similarities: An exploratory analysis.

Background: A growing evidence base supports the value of peer recovery support specialists (PRSS), particularly due to shared lived experience with participants (recipients of PRSS services). However, little research has examined whether congruence on certain aspects of "peerness" (e.g., demographics, experiences) matters for PRSS-participant relationships. Methods: Through a pilot study under the NIDA-funded Initiative for Justice and Emerging Adult Populations (JEAP), adults who had recently received PRSS services (N=100) were interviewed. Participants completed a modified version of the Scales for Participant Alliance with Recovery Coach (SPARC), a measure of PRSS-participant relationship quality, and rated themselves as different/similar to their PRSS in several domains using a six-point scale. Results: Participants had met with their PRSS for a median of 10 sessions over two months. SPARC scores were unrelated to participant demographics or lived experiences. However, better-quality relationships were reported by participants who believed their PRSS was similar to them in relationships with family (p=.004), spirituality/religion (p=.001), age (p<.001), and overall recovery pathway (p<.001). Total SPARC scores were not significantly correlated with perceived PRSS-participant similarities on gender, race/ethnicity, substances of choice, and history of incarceration or substance use treatment. Discussion: Results from this pilot study suggest that PRSS-participant alignment on past experiences (e.g., prior incarceration, choice of drugs) may not be needed to establish good-quality working relationships. However, similarities on factors related to current life stage (e.g., age, family relationships) and/or recovery process (e.g., overall pathway, spirituality) may be more important. Future research should employ mixed-methods approaches to elucidate these unique findings.

Dynamics of splenic transient elastography in patients with alcohol use disorder.

INTRODUCTION: Splenic stiffness measurement (SSM) is an evolving non-invasive assessment to evaluate portal hypertension. Studies with respect to SSM in patients with alcohol use disorder (AUD) are limited. METHODS: We studied patients seeking treatment for AUD in an inpatient treatment protocol at the NIH and parsed SSM into 3 groups based on degree of change. RESULTS: The "improved" SS group had statistically higher initial SSM and a non-statistically increased liver stiffness measurement (LSM) compared to others. DISCUSSION: SS is dynamic in a subset of patients immediately after alcohol cessation and improved SS is associated with a normalization of platelet count.

Correction: Different cadences and resistances in sub-maximal synchronous handcycling in able-bodied men: Effects on efficiency and force application.

[This corrects the article DOI: 10.1371/journal.pone.0183502.].

Alterations in the molecular regulation of mitochondrial metabolism in human alveolar epithelial cells in response to cigarette- and heated tobacco product emissions.

Mitochondrial abnormalities in lung epithelial cells have been associated with chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke (CS) can induce alterations in the molecular pathways regulating mitochondrial function in lung epithelial cells. Recently, heated tobacco products (HTPs) have been marketed as harm reduction products compared with regular cigarettes. However, the effects of HTP emissions on human alveolar epithelial cell metabolism and on the molecular mechanisms regulating mitochondrial content and function are unclear. In this study, human alveolar epithelial cells (A549) were exposed to cigarette or HTP emissions in the form of liquid extracts. The oxygen consumption rate of differently exposed cells was measured, and mRNA and protein abundancy of key molecules involved in the molecular regulation of mitochondrial metabolism were assessed. Furthermore, we used a mitophagy detection probe to visualize mitochondrial breakdown over time in response to the extracts. Both types of extracts induced increases in basal-, maximal- and spare respiratory capacity, as well as in cellular ATP production. Moreover, we observed alterations in the abundancy of regulatory molecules controlling mitochondrial biogenesis and mitophagy. Mitophagy was not significantly altered in response to the extracts, as no significant differences compared to vehicle-treated cells were observed.

ß2 integrins impose a mechanical checkpoint on macrophage phagocytosis.

Phagocytosis is an intensely physical process that depends on the mechanical properties of both the phagocytic cell and its chosen target. Here, we employed differentially deformable hydrogel microparticles to examine the role of cargo rigidity in the regulation of phagocytosis by macrophages. Whereas stiff cargos elicited canonical phagocytic cup formation and rapid engulfment, soft cargos induced an architecturally distinct response, characterized by filamentous actin protrusions at the center of the contact site, slower cup advancement, and frequent phagocytic stalling. Using phosphoproteomics, we identified ß2 integrins as critical mediators of this mechanically regulated phagocytic switch. Macrophages lacking ß2 integrins or their downstream effectors, Talin1 and Vinculin, exhibited specific defects in phagocytic cup architecture and selective suppression of stiff cargo uptake. We conclude that integrin signaling serves as a mechanical checkpoint during phagocytosis to pair cargo rigidity to the appropriate mode of engulfment.

IL-17A Levels and Progression of Kidney Disease Following Hospitalization with and without Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is associated with increased mortality and new or progressive chronic kidney disease (CKD). Inflammatory cells play an important role in acute organ injury. We previously demonstrated that serum IL-17A levels were significantly elevated in critically ill patients with AKI and independently associated with hospital mortality. We hypothesize that IL-17A levels are elevated in hospitalized patients with AKI at diagnosis, and sustained elevation after discharge is associated with subsequent CKD incidence or progression. METHODS: Observational convenience sampling study of hospital survivors of Stage 2 or 3 AKI and controls without AKI from the ASSESS-AKI study. Patients were classified as progression or non-progression based on a composite of CKD incidence, progression, or end-stage kidney disease. IL-17A levels were evaluated with S-Plex assay (MSD) at 0- (during hospitalization), 3- and 12-month post-discharge, and analyzed along with clinical and biomarker data up to 84 months following discharge. RESULTS: Among 171 AKI and 175 non-AKI participants, IL-17A levels were elevated in AKI vs. non-AKI patients at 0M, 3M and 12M timepoints (p<0.05 for all comparisons). Further, IL-17A levels were elevated in the progression vs. non-progression group at the 3- and 12-month timepoints for outcomes occurring at 3-6 months and 12-84 months, respectively (p<0.05 for both). In adjusted multivariable models, IL-17A levels were not independently associated with progression of kidney disease. IL-17A levels were positively correlated with kidney disease and immune activation biomarkers at all timepoints (p<0.001). CONCLUSIONS: IL-17A was higher in patients with AKI vs. without AKI during hospitalization and up to 1-year post-discharge. IL-17A was higher in patients with progression of kidney disease after hospitalization but not independently associated with subsequent progression of kidney disease in fully adjusted models.

Evaluation of the long-term protection conferred by an organosilicon-based disinfectant formulation against bacterial contamination of surfaces.

AIMS: The aim of this work was to evaluate the efficacy of an organosilicon-based, commercially available antimicrobial formulation in the My-shield® product line against bacterial surface contamination. METHODS AND RESULTS: The antimicrobial product was tested in vitro for its long-term persistence on surfaces and effectiveness against Staphylococcus aureus biofilms in comparison to 70% ethanol and 0.1% or 0.6% sodium hypochlorite. Field testing was also conducted over 6 weeks at a university athletic facility. In vitro studies demonstrated the log reductions achieved by the test product, 70% ethanol, and 0.1% sodium hypochlorite were 3.6, 3.1, and 3.2, respectively. The test product persisted on surfaces after washing and scrubbing, and pre-treatment with this product prevented S. aureus surface colonization for up to 30 days. In comparison, pre-treatment with 70% ethanol or 0.6% sodium hypochlorite was not protective against S. aureus biofilm formation after seven days. The field test demonstrated that weekly applications of the test product were more effective at reducing surface bacterial load than daily applications of a control product. CONCLUSIONS: The test product conferred greater long-term protection against bacterial growth and biofilm formation by S. aureus than ethanol and sodium hypochlorite. Even with less frequent applications, the test product maintained a high level of antimicrobial activity.

Long-Term survival across breslow thickness categories: Findings from a Population-Based study of 210,042 Australian melanoma patients.

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the four AJCC 8th Edition T-categories by analyzing Australian registry data for 210,042 melanoma patients diagnosed from 1982-2014. The 30-year incidence rates of death due to melanoma and non-melanoma causes (with 95% confidence intervals) were 7.1% (CI 6.9-7.3%) and 32.8% (CI 32.3-33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (CI 21.0-22.3%) and 35.6% (CI 34.7-36.6%), for T3 melanomas 34.2% (CI 33.4-35.1%) and 39.6% (CI 38.5-40.8%), and for T4 melanomas 44.3% (CI 43.2-45.3%) and 39.6% (CI 38.3-41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years but there were ongoing melanoma-related deaths for the other T-categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T-categories.

AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys.

OBJECTIVES: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. METHODS: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. RESULTS: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects. CONCLUSIONS: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.

Trends in adoption of extravascular cardiac implantable electronic devices: the Dutch cohort.

INTRODUCTION: Conventional implantable cardioverter-defibrillators (ICDs) and pacemakers carry a risk of pocket- and lead-related complications in particular. To avoid these complications, extravascular devices (EVDs) have been developed, such as the subcutaneous ICD (S-ICD) and leadless pacemaker (LP). However, data on patient or centre characteristics related to the actual adoption of EVDs are lacking. OBJECTIVE: To assess real-world nationwide trends in EVD adoption in the Netherlands. METHODS: Using the Netherlands Heart Registration, all consecutive patients with a de novo S­ICD or conventional single-chamber ICD implantation between 2012-2020, or de novo LP or conventional single-chamber pacemaker implantation between 2014-2020 were included. Trends in adoption are described for various patient and centre characteristics. RESULT: From 2012-2020, 2190 S­ICDs and 10,683 conventional ICDs were implanted; from 2014-2020, 712 LPs and 11,103 conventional pacemakers were implanted. The general use has increased (S-ICDs 8 to 21%; LPs 1 to 8%), but this increase seems to have reached a plateau. S­ICD recipients were younger than conventional ICD recipients (p < 0.001) and more often female (p < 0.001); LP recipients were younger than conventional pacemaker recipients (p < 0.001) and more often male (p = 0.03). Both S­ICDs and LPs were mainly implanted in high-volume centres with cardiothoracic surgery on-site, although over time S­ICDs were increasingly implanted in centres without cardiothoracic surgery (p < 0.001). CONCLUSION: This nationwide study demonstrated a relatively quick adoption of innovative EVDs with a plateau after approximately 4 years. S­ICD use is especially high in younger patients. EVDs are mainly implanted in high-volume centres with cardiothoracic surgery back-up, but S­ICD use is expanding beyond those centres.

Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro.

AIMS: Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation. KEY METHODS: CD3/CD28 and lipopolysaccharide activated peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 6) were treated with phytocannabinoid compounds and terpenes in vitro. Flow cytometry was used to determine regulatory T cell (Treg) and T helper 17 (Th17) cell responses to treatments. Cell pellets were harvested for qRT-PCR gene expression analysis of cytokines, cell activation markers, and inflammation-related receptors. Cell culture supernatants were analysed by ELISA to quantify IL-6, TNF-α and IL-10 secretion. MAIN FINDINGS: In an initial screen of 20 µM cannabinoids and terpenes which were coded to blind investigators, cannabigerol (GL4a), caryophyllene oxide (GL5a) and gamma-terpinene (GL6a) significantly reduced cytotoxicity and gene expression levels of IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC and NFKΒ1. Tetrahydrocannabinol (GL7a) suppression of T cell activation was associated with downregulation of RORC and NFKΒ1 gene expression and reduced IL-6 (p < 0.0001) and IL10 (p < 0.01) secretion. Cannabidiol (GL1b) significantly suppressed activation of Tregs (p < 0.05) and Th17 cells (p < 0.05) in a follow-on in vitro dose-response study. IL-6 (p < 0.01) and IL-10 (p < 0.01) secretion was significantly reduced with 50 µM cannabidiol. SIGNIFICANCE: The study provides the first evidence that cannabidiol and tetrahydrocannabinol suppress extracellular expression of both anti- and pro-inflammatory cytokines in an in vitro PBMC model of inflammation.

The Collaborative Biobank (CoBi): Donor and recipient samples & data to facilitate future research on hematopoietic cell transplantation.

Biobanking provides benefit for future generations by facilitating medical research and subsequent translation and application of research findings. Long-term storage and research involving biological material and associated data necessitate the proper implementation of ethical and legal standards. A key principle includes recognizing informed consent as a crucial element for legitimizing the collection of biological material and data. Furthermore, any collected material and data must be employed exclusively for the research framework that aligns with the explicit consent provided by the participants. Last but not least, data privacy and security are essential in biobanking. This review elucidates chances and limitations of biobanking in the field of allogeneic hematopoietic cell transplantation. We discuss the practical implementation of the requirements, illustrated by the Collaborative Biobank, a collaborative research platform for research in blood cancer.

Introduction of the donor centre virtual crossmatch in Eurotransplant.

On 24 January 2023, Eurotransplant has introduced the virtual crossmatch for kidney and pancreas allocation as a better alternative for the physical Complement Dependent Cytotoxicity (CDC) crossmatches at the donor centre, which were associated with a longer cold ischaemia time and false positive reactions. For the time being, the physical CDC crossmatch at the recipient centre will remain in place as the final histocompatibility check. While Eurotransplant is certainly not the first organ allocation organisation to introduce virtual crossmatching, several novel aspects have been introduced, such as calculation of the virtual panel reactive antibody (vPRA) on 11 loci at the second-field level in addition to the serological broad and split level, electronic HLA typing data transmission using Histoimmunogenetics Markup Language (HML) file format, and the actual virtual crossmatch based on ambiguous, second-field HLA typing of the donor on all 11 loci. This short communication will focus on these novel aspects of the virtual crossmatch in Eurotransplant.

Prevalence of steatotic liver disease, advanced fibrosis and cirrhosis among community-dwelling overweight and obese individuals in the USA.

BACKGROUND: There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA. METHODS: This is a cross-sectional analysis of prospectively enrolled overweight or obese adults aged 40-75 years from primary care and community-based settings in Southern California. Participants were classified as having SLD if MRI proton density fat fraction ≥5%, and subclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-related liver disease (ALD) consistently with the new nomenclature guidance per AASLD-EASL-ALEH. Advanced fibrosis and cirrhosis were defined as magnetic resonance elastography (MRE) ≥3.63 kPa and MRE ≥4.67 kPa, respectively. RESULTS: The cohort included 539 participants with mean (±SD) age of 51.5 (±13.1) years and body mass index of 32.6 (±6.2) kg/m2, respectively. The prevalence of SLD, advanced fibrosis and cirrhosis was 75%, 10.8% and 4.5%, respectively. The prevalence of MASLD, MetALD and ALD was 67.3%, 4.8% and 2.6%, respectively. There was no difference in prevalence of advanced fibrosis and cirrhosis among subcategories. CONCLUSIONS: Using advanced MRI methods among community-dwelling overweight and obese adults, the prevalence of cirrhosis was 4.5%. Most common SLD subcategory was MASLD with 67% of individuals, whereas MetALD and ALD were less common. Systematic screening for advanced fibrosis among overweight/obese adults may be considered.