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Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD., Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted., Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model., Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Abstract: To address acute vaso-occlusive episodes (VOEs), the leading cause of emergency department (ED) visits among individuals with sickle cell disease (SCD), we conducted the clinical study, ALIGN (An Individualized Pain Plan with Patient and Provider Access for Emergency Department care of SCD), across 8 sites. We hypothesized an improvement of 0.5 standard deviations in perceived quality of ED pain treatment of a VOE after implementing individualized pain plans (IPPs) accessible to both patients and providers. Patients with SCD were aged 18 to 45 years, owned a cell phone, and had an ED VOE visit within 90 days prior. Patients completed the perceived quality of care surveys at baseline and within 96 hours after an ED VOE visit. Providers completed surveys regarding comfort managing VOEs at baseline and after managing an enrolled patient. Most of the 153 patients were African American (95.4%), female (64.7%), and had Hb SS/Sβ0 genotype (71.9%). The perceived quality of ED pain treatment was high at both baseline and after implementation of IPPs; our primary outcome hypothesis was not met, because no statistically significant change in the patient-perceived quality of ED treatment occurred. A total of 135 providers completed baseline and follow-up surveys. On a scale of 1 to 7, with 7 being extremely comfortable managing VOEs, 60.5% reported a score ≥6 after IPP implementation vs 57.8% at baseline. Almost all (97.6%) ordered the recommended medication, and 94.7% intended to use IPPs. In this implementation protocol, all sites successfully implemented IPPs. Patients and ED providers both endorsed the use of IPPs. This trial was registered at www.ClinicalTrials.gov as # NCT04584528., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A growing body of research reveals that autistic individuals exhibit motor coordination challenges. Multiple theoretical frameworks propose that the seemingly disparate features of autism may arise from a common underlying process: a diminished ability to make predictions. Sensorimotor skills, such as catching a ball, critically rely on predicting the ball's trajectory as well as anticipatory coordination of the entire body. Here, we assessed four different naturalistic and virtual interception tasks with 31 neurotypical and 23 autistic children (ages 7-12). In a naturalistic setting, participants caught the ball either with their hands or a hand-held funnel with an enlarged catch area that also prevented the ball from bouncing off. A virtual setup reduced whole-body demands, as children only moved a paddle to catch or bounce a ball on a screen. Control tasks, involving rapid reaching to grasp a static object and quiet standing, which largely eliminated the requirements for prediction, were also tested. Results from all task variations demonstrated that autistic children completed fewer successful interceptions, suggesting that predictive requirements, inherent to all interception tasks, played a critical role. Effect sizes in the virtual tasks were smaller. Correlations of the task metrics with behavioral assessments rendered the strongest correlations with Praxis scores. The control tasks showed no differences between autistic and neurotypical children. These findings lend support to the emerging hypothesis that predictive challenges are present in autism. Further research with larger sample sizes will help identify to what extent these visuomotor differences may inform core domains of autism., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Importance: Female patients have higher mortality rates after high-risk surgery than male patients. It is unknown whether this mortality gap is due to different rates of postoperative complications or if complications are addressed differently by sex, causing complications to lead to death-so-called failure to rescue., Objective: To evaluate sex differences in failure to rescue across high-risk surgical procedures., Design, Setting, and Participants: This retrospective cohort study was conducted using data from Medicare beneficiaries from October 2015 to February 2020 who underwent high-risk vascular or cardiac surgical procedures, including abdominal aortic aneurysm repair, coronary artery bypass grafting, aortic valve replacement, and mitral valve replacement or repair. Data analysis was performed from August 2023 to March 2024., Exposures: The primary exposure was patient sex., Main Outcomes and Measures: The primary outcomes were risk-adjusted rates of complications, 30-day mortality, and failure to rescue, which was defined as a death occurring after a serious complication. Categorical variables are presented as frequencies and proportions and compared using χ2 analysis. Continuous variables were tested for normality and compared using a t test., Results: A total of 863 305 Medicare beneficiaries were included in this study cohort, of whom 304 176 (35.2%) were female. Mean (SD) age was slightly higher in female patients (74.8 [9.3] years) than male patients (73.4 [8.5] years), and female patients had more comorbidities than male patients (≥2 Elixhauser comorbidities, female: 262 809 [86.4%] vs male: 465 231 [83.2%]). Female patients were more likely to receive care at large hospitals and hospitals with a higher surgical case volume. Overall, female and male patients had similar rates of complications (female: 14.98% vs male: 14.37%; adjusted relative risk [aRR], 1.04; 95% CI, 1.03-1.05; P < .001). However, female patients had higher rates of 30-day mortality (female: 4.22% vs male: 3.34%; aRR, 1.26; 95% CI, 1.23-1.29; P < .001) and higher rates of failure to rescue (female: 10.71% vs male: 8.58%; aRR, 1.25; 95% CI, 1.22-1.28; P < .001). A similar pattern was observed when stratified by each procedure., Conclusions and Relevance: In this cohort study among Medicare beneficiaries undergoing high-risk surgery, male and female patients experienced similar rates of serious complications, but female patients with complications were more likely to die. In other words, clinicians fail to rescue female patients with complications after high-risk surgery more often than male patients. Improving the recognition and management of female patients' complications postoperatively may narrow the sex disparity after high-risk surgery.

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure., (© 2024. The Author(s).)

Disorders of lipid metabolism such as obesity have become some of the most significant diseases of the twenty-first century. Despite these metabolic diseases affecting more than a third of the population in highly industrialized nations, the mechanisms underlying disease development remain poorly understood. Insect models, such as Drosophila melanogaster, offer a means of systematically examining conserved lipid metabolism and its pathology. Over the past several decades, Drosophila melanogaster has been used to greatly expand on our knowledge of metabolic disease, often taking advantage of the extensive genetic tools available to researchers. Additionally, Drosophila melanogaster has served and will continue to serve as a powerful tool for validating the results of genome-wide approaches to the study of diseases. This chapter explores the advancements of insect models in the study of lipid metabolism disorders as well as highlight opportunities for future areas of research., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Diagnostic stewardship (DxS) has gained traction in recent years as a cross-disciplinary method to improve the quality of patient care while appropriately managing resources within the healthcare system. Clinical microbiology laboratorians have been highly engaged in DxS efforts to guide best practices with conventional microbiology tests and more recently with molecular infectious disease diagnostics. Laboratories can experience resistance to their role in DxS, especially when the clinical benefits, motivations for interventions, and underlying regulatory requirements are not clearly conveyed to stakeholders. Clinical laboratories must not only ensure ethical practices but also meet obligatory requirements to steward tests responsibly. In this review, we aim to support clinical microbiology laboratorians by providing the background and resources that demonstrate the laboratory's essential role in DxS. The heart of this review is to collate regulatory and accreditation requirements that, in essence, mandate DxS practices as a long-standing, core element of high-quality laboratory testing to deliver the best possible patient care. While examples of the clinical impact of DxS are plentiful in the literature, here, we focus on the operational and regulatory justification for the laboratory's role in stewardship activities., Competing Interests: E.M.M. is an employee of Quest Diagnostics, a commercial clinical reference laboratory, and owns stock in the company.

The Centers for Disease Control and Prevention (CDC) guidelines for hepatitis C virus (HCV) testing, although effective, may miss crucial diagnostic opportunities. The goal of this study was to assess the utility of an antibody (Ab) and antigen (Ag) combination immunoassay as an alternative to traditional HCV screening. Remnant specimens from 1,341 patients with concurrent third-generation serologic (Roche anti-HCV-II) and nucleic acid amplification testing (NAAT) were assessed using the HCV Duo Ab/Ag immunoassay (Roche). Patient demographics, risk factors, and standard of care (SOC) laboratory results from the medical records were recorded. Overall, 99.0% (197/199) of the HCV Duo Ab+/Ag+specimens accurately identified active infections as confirmed by NAAT, and 99.9% (670/671) Ab-/Ag- samples corresponded to those without HCV infections. Individually, the HCV Duo Ab component demonstrated a 95.6% positive percent agreement (PPA) (95% CI = 93.8-96.9) and 99.1% negative percent agreement (NPA) (98.8-99.6) compared with SOC anti-HCV II Ab assay. The HCV Duo Ag had a 73.5% PPA (67.9-78.4) and 99.8% NPA (99.3-100) with NAAT. Among RNA+ specimens, 73.4% (197/267) were HCV Duo Ag+, and 265/267 (99.3%) were successfully detected on the HCV Duo Ab component. Notably, 5/7 (71.4%) Ab-/RNA +specimens were detected by HCV Duo, which would have been missed by traditional algorithmic testing. Fourth generation HCV Duo Ab/Ag assay demonstrated comparable performance to SOC testing and shortens the diagnostic window but does not eliminate the need for NAAT in all patients. Ab/Ag testing identified several Ab-/RNA+ cases, a subgroup often undiagnosed by current algorithmic testing, demonstrating promise for improved diagnostic efficiency and accuracy in HCV detection.IMPORTANCEThis study highlights the potential of a combined hepatitis C virus (HCV) Duo antibody (Ab) and antigen (Ag) immunoassay to improve early detection of HCV infections. Traditional Ab-only screening methods recommended by the Centers for Disease Control and Prevention may miss early-stage infections. The HCV Duo assay showed high accuracy, detecting nearly all active infections confirmed by nucleic acid amplification testing. Dual detection of HCV Ab and Ag shortens the diagnostic window, enabling intervention and treatment in a single visit, which is crucial for improving patient outcomes and reducing HCV transmission, especially in areas with limited access to confirmatory molecular testing., Competing Interests: T.I.B. has no conflict of interest. N.W.A. has served on scientific advisory boards for Roche Diagnostics and Diasorin Molecular. C.W.F. has served on scientific advisory boards for Werfen, Abbott Laboratories, Roche Diagnostics, and Cytovale and received research funding from Beckman Coulter, Abbott Laboratories, Roche Diagnostics, Cepheid, Siemens Healthineers, and Biomerieux.

Medical microbiologists, defined as doctoral-level laboratory directors with subspecialty training in medical microbiology, lead the clinical laboratory operations through activities such as clinical consultations, oversight of diagnostic testing menu, institutional leadership, education, and scholastic activities. However, unlike their clinical colleagues, medical microbiologists are largely unable to bill for clinical consultations performed within the hospital and, therefore, unable to generate relative value units or a similar quantifiable metric. As hospital budgets tighten and justification of staffing becomes a necessity, this may present a challenge to the medical microbiologist attempting to prove their value to the organization. To aid in providing tangible data, the Personnel Standards and Workforce subcommittee of the American Society for Microbiology conducted a multi-center study across seven medical centers to document clinical consultations and their impact. Consults were generated equally from internal (laboratory-based) and external (hospital-based) parties, with the majority directly impacting patient management. Near universal acceptance of the medical microbiologist's recommendation highlights the worth derived from their expertise. External consults required more time commitment from the medical microbiologist than internal consults, although both presented ample opportunity for secondary value, including impact through stewardship, education, clinical guidance, and cost reduction. This study is a description of the content and impact of consultations that underscore the importance of the medical microbiologist as a key member of the healthcare team., Importance: Medical microbiologists are invaluable to the clinical microbiology laboratory and the healthcare system as a whole. However, as medical microbiologists do not regularly generate relative value units, capturing and quantifying the value provided is challenging. As hospital budgets tighten, justification of staffing becomes a necessity. To aid in providing tangible data, the Personnel Standards and Workforce subcommittee of the American Society for Microbiology conducted a multi-center study across seven medical centers to document clinical consultations and their impact. To our knowledge, this is the first study to provide detailed evaluation of the consultative value provided by medical microbiologists., Competing Interests: The authors declare no conflict of interest.

Background: The discovery of viruses in small mammalian populations, particularly rodents, has expanded the family Paramyxoviridae. The overlap in habitats between rodents and humans increases the risk of zoonotic events, underscoring the importance of active surveillance. Rodent species, such as Apodemus agrarius, are natural hosts for Paramyxoviridae in the Republic of Korea (ROK). However, it is unknown whether Paramyxoviridae is present in Micromys minutus, another common rodent., Method: Here, we screened M. minutus collected from the Gangwon Province in the ROK for paramyxoviruses using nested polymerase chain reaction and confirm positive samples by next-generation metagenomic sequencing. Complete paramyxovirus genomes were further characterized by phylogenetic analysis, amino acid similarity, secondary structure, and cophylogeny., Result: Overall, 57 of 145 (39.3%) M. minutus kidney samples tested positive for paramyxoviruses. Among them, four whole genome sequences were identified and clustered within the genus Jeilongvirus. One sequence was determined as Samak Micromys paramyxovirus 1 (SMPV-1; 19,911 nucleotides long) and three sequences as Samak Micromys paramyxovirus 2 (SMPV-2; 18,199 nucleotides long). SMPV-1 has a smaller hydrophobic gene and a longer glycoprotein gene than SMPV-2. Cophylogenetic analysis suggests that SMPV-1 evolved through co-divergence, whereas SMPV-2 was inferred to have undergone transfer events., Conclusion: These findings highlight the prevalence of paramyxoviruses in the wild and the potential of M. minutus as a natural viral reservoir. The discovery of SMPV-1 and SMPV - 2 also reveals the genetic diversity and evolutionary history of the genus Jeilongvirus in the Paramyxoviridae., (© 2024. The Author(s).)

CD2AP was identified as a genetic risk factor for late-onset Alzheimer's disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases β-amyloid (Aβ) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP, but not blocking Aβ-production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics. Significance statement CD2AP is a candidate genetic risk factor of late-onset Alzheimer's disease (LOAD) expressed in neurons with an unknown impact on synapse dysfunction, one of the causal LOAD mechanisms. Our research has revealed CD2AP as a new synaptic protein and established a connection between a LOAD genetic variant in CD2AP and synaptic dysfunction independent of beta-amyloid accumulation. This study suggests an explanation for the CD2AP-mediated predisposition to AD. Furthermore, we have found that controlling CD2AP's impact on spinal F-actin could be a potential target for therapeutic intervention against LOAD., (Copyright © 2024 the authors.)

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.

Widespread vaccination and natural infection have resulted in greatly decreased rates of severe disease, hospitalization and death after subsequent infection or reinfection with SARS-CoV-2. New vaccine formulations are based on circulating strains of virus, which have tended to evolve to more readily transmit human to human and to evade the neutralizing antibody response. An assumption of this approach is that ancestral strains of virus will not recur. Recurrence of these strains could be a problem for individuals not previously exposed to ancestral spike protein by vaccination or infection. Here, we addressed this question by infecting mice with recent SARS-CoV-2 variants and then challenging them with a highly pathogenic mouse-adapted virus closely related to the ancestral Wuhan-1 strain (SARS2-N501YMA30). We found that challenged mice were protected from death and substantial weight loss, even though they generally had low or no neutralizing antibody response to SARS2-N501YMA30 at the time of reinfection. T cell depletion from the previously infected mice did not diminish infection against clinical disease, although it did result in delayed kinetics of virus clearance in the nasal turbinate and in some cases, in the lungs. Levels of tissue resident memory T cells were significantly elevated in the nasal turbinate of previously infected mice compared to mice that had no previous exposure to SARS-CoV-2. However, this phenotype was not seen in lung tissues. Together, these results indicate that the immune response to newly circulating variants afforded protection against re-infection with the ancestral virus that was at least in part T cell based.

Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to disclose.

Atopic Dermatitis (AD) is associated with a number of published disparities, including those related to self-identified racial/ethnic populations. Black/African American populations in the United States experience greater AD prevalence, severity, and persistence compared to other demographic groups, such as those who self-identify as White. There is consistent evidence that healthcare, environmental, and socioeconomic factors affect the prevalence, severity, and/or persistence of AD. Additionally, because of institutional and systemic racism, these same risk factors are more prevalent in racial and ethnic minority populations. Herein, we review the underlying causes of racial/ethnic disparities in AD and potential strategies to improve AD diagnosis and disease control., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To describe the incidence, mechanisms, and clinical characteristics of patients diagnosed with traumatic iritis in a U.S. Midwestern county population., Methods: Retrospective population-based cohort of all residents of Olmsted County, Minnesota diagnosed with traumatic iritis from January 1, 2006, to December 31, 2015. The medical records of patients with traumatic iritis were identified using the Rochester Epidemiology Project database, which contains virtually all medical care in the county. Medical records were reviewed for demographics, presentation, and follow-up data. Incidence rates were calculated per 100,000 per year., Results: There were 156 incident diagnoses of traumatic iritis during the 10-year study period, yielding an age- and sex-adjusted incidence rate of 10.7 per 100,000 per year. Traumatic iritis disproportionately occurred in male ( p  < 0.001) and Black ( p  < 0.001) patients. The mean age of diagnosis was 33 years (range: 4-96 years), mean number of traumatic iritis-specific follow-up visits was 2.1 (range: 0-26), and median duration of traumatic iritis-specific follow-up was 11 days (range: 1 day-1.6 years). There were 155 (99.4%) patients with unilateral disease. The most frequent mechanisms of traumatic iritis were sports-related ( N  = 29, 18.6%), assault-related ( N  = 23, 14.7%), scratch ( N  = 22, 14.1%), and work-related ( N  = 21, 13.5%) injuries. The mean initial and final best-corrected visual acuity (BCVA) of the affected eye was 20/40 and 20/30, respectively. Loss of follow-up was more frequently observed in Black patients ( p  < 0.001) and patients with smoking history ( p = 0.004)., Conclusion: Traumatic iritis was most frequently observed in younger males and Black patients. Common mechanisms included sports, assault, scratch, and work-related injuries.

The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline., (© 2024 Shepherdson et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Whether antibiotic de-escalation reduces the risk of subsequent antibiotic resistance is uncertain. We sought to determine if beta-lactam (BL) antibiotic de-escalation is associated with decreased incidence of new Gram-negative resistance in hospitalized patients with sepsis., Methods: In a retrospective cohort study, patients with sepsis who were treated with at least 3 consecutive days of BL antibiotics, the first 2 days of which were with a broad-spectrum BL agent defined as a spectrum score (SS) of ≥7 were enrolled. Patients were grouped into three categories: (1) de-escalation of beta-lactam spectrum score (BLSS), (2) no change in BLSS, or (3) escalation of BLSS. The primary outcome was the isolation of a new drug-resistant Gram-negative bacteria from a clinical culture within 60 days of cohort entry. Fine-Gray proportional hazards regression modeling while accounting for in-hospital death as a competing risk was performed., Findings: Six hundred forty-four patients of 7742 (8.3%) patients developed new gram-negative resistance. The mean time to resistance was 23.7 days yielding an incidence rate of 1.85 (95% confidence interval [CI]: 1.71-2.00) per 1000 patient-days. The lowest incidence rate was observed in the de-escalated group 1.42 (95% CI: 1.16-1.68) per 1000 patient-days. Statistically significant reductions in the development of new gram-negative resistance were associated with BL de-escalation compared to no-change (hazards ratio (HR) 0.59 [95% CI: .48-.73])., Conclusions: De-escalation was associated with a decreased risk of new resistance development compared to no change. This represents the largest study to date showing the utility of de-escalation in the prevention of antimicrobial resistance., Competing Interests: Potential conflicts of interest. M. H. K.’s efforts were supported by the Barnes-Jewish Hospital Foundation. B. F. T.’s contribution occurred while he was working at the University of Health Sciences and Pharmacy in St. Louis; he is now an employee of Melinta Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention., Objective: To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates., Methods: Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment., Results: A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height., Conclusion: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The definitive demonstration of protein localization on primary cilia has been a challenge for cilia biologists. Primary cilia are solitary thread-like projections that have a specialized protein composition, but as the ciliary structure overlays the cell membrane and other cell parts, the identity of ciliary proteins are difficult to ascertain by conventional imaging approaches like immunofluorescence microscopy. Surface scanning electron microscopy combined with immunolabeling (immuno-SEM) bypasses some of these indeterminacies by unambiguously showing protein expression in the context of the three-dimensional ultrastructure of the cilium. Here, we apply immuno-SEM to specifically identify proteins on the primary cilia of mouse and human pancreatic islets, including post-translationally modified tubulin, intraflagellar transport (IFT)88, the small GTPase Arl13b, as well as subunits of axonemal dynein. Key parameters in sample preparation, immunolabeling and imaging acquisition are discussed to facilitate similar studies by others in the cilia research community., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Importance: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD., Objective: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values., Design, Setting, and Participants: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection., Exposure: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2])., Main Outcomes and Measures: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated., Results: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%])., Conclusions and Relevance: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.

Background: Over the last two decades, significant research interest has led to the development of a wide variety of supraglottic airways (SGAs) for anaesthesia providers to choose from., Methods: In this network meta-analysis, we analysed 111 studies, enrolling 12 045 patients undergoing airway management with 29 SGAs. We targeted outcomes that contribute to clinicians' choice of one SGA over another. The primary outcome was the incidence of postoperative sore throat (POST). Secondary outcomes were first-attempt insertion success, bleeding complications, and oropharyngeal leak pressure (OLP). Based on credible intervals, we created a 'rank order' to guide decision-making for clinicians., Results: The highest-ranking devices based on credible intervals for POST, bleeding complications, first-attempt insertion success, and OLP were LMA Ambu, Jcerity Endoscoper, LMA Blockbuster, and LMA Baska Mask, respectively. Air-Q and i-gel ranked favourably across multiple outcomes, with i-gel being the only device to rank within the top six SGAs for POST, bleeding, and first-attempt success despite ranking poorly for OLP., Conclusions: Our data support the use of LMA-Ambu, Jcerity-Endoscoper, Air-Q, and i-gel when considering patient-centred outcomes. Clinician familiarity with these devices and their continued expansion into anaesthetic practice will have important implications on the perioperative patient experience., Systematic Review Protocol: PROSPERO (CRD42022383136)., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: HIV clinical guidelines recommend hypertension detection and management to lower cardiovascular disease risk, but these have not been effectively implemented for people living with HIV (PWH). Addressing this implementation gap requires community-engaged implementation studies focused on addressing implementation barriers specific to the HIV care context., Methods: This protocol describes a type 2 effectiveness-implementation hybrid study conducted in nine primary care clinics in Johannesburg. The study will evaluate the effect of implementation strategies on guideline-recommended blood pressure assessment and management in HIV clinics and the effects of assessment/management on patient blood pressure. A stepped-wedge, cluster randomized study design was used to randomize clinics to the time at which they receive the implementation strategies and patient intervention. The implementation strategies tested include identifying and preparing care champions, changing record systems, conducting ongoing training, providing audit and feedback, and changing the physical structure/equipment. The patient intervention tested includes detection of elevated blood pressure, educational materials, lifestyle modification advice, and medication where needed. Implementation outcomes include adoption, fidelity (co-primary outcome), cost, and maintenance of the blood pressure assessment protocol in participating clinics, while patient outcomes include reach, effectiveness (co-primary outcome), and long-term effects of the intervention on patient blood pressure. These will be assessed via direct observation, study records, staff logs, medical chart reviews, and patient and healthcare worker surveys. To examine effects on the implementation (intervention fidelity) and effectiveness (patient blood pressure changes) co-primary outcomes, we will use the standard Hussey and Hughes model for analysis of stepped-wedge designs which includes fixed effects for both interventions and time periods, and a random effect for sites. Finally, we will examine the costs for the implementation strategies, healthcare worker time, and patient-facing intervention materials, as well as the cost-effectiveness and cost-utility of the intervention using study records, patient surveys, and a time and motion assessment., Discussion: This study will address knowledge gaps around implementation of cardiovascular disease preventive practices in HIV care in South Africa. In doing so, it will provide a dual opportunity to promote evidence-based care in the South African HIV care context and help refine implementation research methods to better serve HIV populations globally., Trial Registration: ClinicalTrials.gov: NCT05846503. Registered on May 6, 2023. https://classic., Clinicaltrials: gov/ct2/show/NCT05846503 ., (© 2024. The Author(s).)

Memory B cells are long-lived cells that are induced following infection or vaccination. Upon antigen re-encounter, memory B cells rapidly differentiate into antibody-secreting or germinal center B cells. While memory B cells are an important component of long-term protective immunity following vaccination, they also contribute to the progression of diseases such as autoimmunity and allergy. Numerous subsets of memory B cells have been identified in mice and humans that possess important phenotypic and functional differences. Here, we review the transcriptional circuitry governing memory B cell differentiation and function. We then summarize emerging evidence that the inflammatory environment in which memory B cells develop has an important role in shaping their phenotype and examine the pathways regulating the development of memory B cells during a type 1-skewed and type-2 skewed immune response., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background Early discharge (ED) after colectomy has become a target outcome for multiple reasons, but the factors associated with ED are not well characterized. This study investigated the factors associated with ED and evaluated the impact of ED on overall outcome. Methods Data from ACS-NSQIP were used to identify patients who underwent non-emergent colectomy from 2012 to 2021. ED was defined as length of stay ≤ 2 days. Unpaired t-tests, chi-square tests and adjusted multivariate logistic regression modeling were used to estimate associated factors for ED. Bounceback readmission was defined as readmission within 7 days of discharge. Results In this cohort of 282,490 patients, 43,137 (15.3%) met the criteria for ED. Robotic colectomy (OR 14.35; 95% CI [13.63-15.12]) was more strongly associated with ED than any other patient characteristic, including laparoscopic colectomy (6.82 [6.51-7.14], ref open colectomy). ED vs. non-ED patients had lower rates of 30-day (5.84 vs. 10.37%, p < 0.01) and bounceback (3.56 vs. 5.75%, p < 0.01) readmissions, overall complications (5.65 vs. 18.63%, p < 0.01) and post-discharge complications (4.21 vs. 7.49%, p < 0.01). Conclusions Robotic surgery was the variable most strongly associated with ED, with greater odds of ED compared to both laparoscopic and open colectomy. Patients who had ED after robotic surgery had lower rates of complications and readmission compared to non-ED patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objectives: Successful implementation of machine learning-augmented clinical decision support systems (ML-CDSS) in perioperative care requires the prioritization of patient-centric approaches to ensure alignment with societal expectations. We assessed general public and surgical patient attitudes and perspectives on ML-CDSS use in perioperative care., Materials and Methods: A sequential explanatory study was conducted. Stage 1 collected public opinions through a survey. Stage 2 ascertained surgical patients' experiences and attitudes via focus groups and interviews., Results: For Stage 1, a total of 281 respondents' (140 males [49.8%]) data were considered. Among participants without ML awareness, males were almost three times more likely than females to report more acceptance (OR = 2.97; 95% CI, 1.36-6.49) and embrace (OR = 2.74; 95% CI, 1.23-6.09) of ML-CDSS use by perioperative teams. Males were almost twice as likely as females to report more acceptance across all perioperative phases with ORs ranging from 1.71 to 2.07. In Stage 2, insights from 10 surgical patients revealed unanimous agreement that ML-CDSS should primarily serve a supportive function. The pre- and post-operative phases were identified explicitly as forums where ML-CDSS can enhance care delivery. Patients requested for education on ML-CDSS's role in their care to be disseminated by surgeons across multiple platforms., Discussion and Conclusion: The general public and surgical patients are receptive to ML-CDSS use throughout their perioperative care provided its role is auxiliary to perioperative teams. However, the integration of ML-CDSS into perioperative workflows presents unique challenges for healthcare settings. Insights from this study can inform strategies to support large-scale implementation and adoption of ML-CDSS by patients in all perioperative phases. Key strategies to promote the feasibility and acceptability of ML-CDSS include clinician-led discussions about ML-CDSS's role in perioperative care, established metrics to evaluate the clinical utility of ML-CDSS, and patient education., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: 68Ga-DOTATATE PET/CT targeting somatostatin receptors is commonly utilized in the imaging of neuroendocrine tumors. However, other malignancies such as lymphomas (both Hodgkin and non-Hodgkin) also have expression of somatostatin receptors, albeit to a lesser degree compared with the neuroendocrine tumors, and thus can be positive on a 68Ga-DOTATATE PET/CT. We describe an atypical presentation of an aggressive large B-cell lymphoma mimicking a metastatic neuroendocrine tumor at initial presentation with high somatostatin receptor expression demonstrated on the 68Ga-DOTATATE PET/CT and a rapidly progressing course on the subsequent 18F-FDG PET/CT., Competing Interests: Conflicts of interest and sources of funding: None., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Secondary data analysis of the NIH sponsored study on Adult Symptomatic Lumbar Scoliosis (ASLS)., Objectives: The purpose of this study is to perform a cost-effectiveness analysis comparing operative versus non-operative care for ASLS eight years after enrollment., Summary of Background Data: A prior cost-effectiveness analysis of the current cohort comparing operative to non-operative care at five years after enrollment showed and ICER of $44,033 in the As-Treated analysis and a ICER of $27,480 in the Intent-to-treat analysis., Methods: Data was collected every three months for the first two years, then every six months for the remainder of the study. Data included use of non-operative modalities, medications and employment status. Costs for index and revision surgeries and non-operative modalities were determined using Medicare Allowable rates. Medication costs were determined using the RedBook and indirect costs were calculated based on reported employment status and income. Quality Adjusted Life Years (QALY) was determined using the SF6D., Results: There were 101 cases in the Operative (Op) and 103 in the Non-operative (Non-Op) group with complete eight year data. Thirty-eight patients (37%) in the Non-Op group had surgery from 3 to 72 months after enrollment. An As-Treated analysis including only cases who never had surgery (N=65) or cases with complete eight-year post-operative data (N=101) showed that operative treatment was favored with an ICER of $20,569 per QALY gained which is within Willingness-to-Pay (WTP) thresholds. An Intent-to-Treat analysis demonstrated greater QALY gains and lower cost in the Op group (ICER = $-13,911). However, Intent-to-Treat analysis is influenced by Non-Op patients who crossed over to operative treatment at variable times during follow-up., Conclusion: Operative treatment was more cost-effective than non-operative treatment for ASLS at eight-year follow-up. The ICER continued to improve as compared to the five-year values ($20,569 vs. $44,033)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

For over 2 decades, the mainstay of lymphedema treatment has been complete decongestive therapy, however, surgical options are available when conservative treatment is not successful in reducing lymphedema. Standardized pre-surgical and post-surgical guidelines for candidates are not readily available. As part of the 2023 Lymphedema Summit that was sponsored by the American Cancer Society, and the Lymphology Association of North America, an expert consensus workgroup was formed and developed an expert consensus which affirms the importance of pre-surgical guidelines for candidates with lymphedema. The workgroup recommended that guidelines should be tailored to four major end-user groups: (1) patients, (2) referring physicians, (3) allied health professionals, and (4) surgeons., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite the well-known prognostic role of lymph node metastasis (LNM) in pNETs, less is known about the importance of lymphovascular invasion (LVI) among patients with these tumors., Methods: Patients undergoing pancreatectomy for pNET between 2002 and 2020 were identified in the US Neuroendocrine Tumor Study Group database. Cox regression analysis was utilized to identify the impact of LVI on recurrence-free survival (RFS) among patients with node-negative pNET., Results: Among 853 patients who underwent resection for pNET, 214 patients (25.1%) had LNM, while 116 (13.6%) and 523 individuals (61.3%) were LVI + N0 and LVI - N0, respectively. The overall incidence of LVI among patients with N0 pNET was 18.1%; the incidence of LVI increased with increasing tumor size and Ki-67 levels (size < 2 cm and Ki-67 < 3%: 5.5%; size < 2 cm and Ki-67 ≥ 3%: 17.2%; size ≥ 2 cm and Ki-67 < 3%: 22.2%; size ≥ 2 cm and Ki-67 ≥ 3%: 43.1%, p < 0.001). Five-year RFS was highest among patients with LVI - N0 disease followed by individuals with LVI + N0 and N+ pNETs (92.8% vs. 61.6% vs. 58.3%, p < 0.001). On multivariable analysis, the presence of LVI on pathology remained independently associated with almost 2.5 times higher hazards of recurrence (HR 2.47, 05% CI 1.44-4.24) among individuals with N0 pNETs., Conclusion: The incidence of LVI varied according to tumor size and Ki-67. LVI was associated with a higher likelihood of recurrence among individuals who underwent formal pancreatic resection for N0 pNETs. LVI is an important prognostic indicator among patients with node-negative pNETs., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background and Objectives: The RAPIDO trial showed promising rates of pathologic complete response (pCR) after neoadjuvant short-course radiation with consolidation chemotherapy (total neoadjuvant therapy [SC TNT]) for rectal cancer. Only single-center reviews comparing tumor downstaging between SC TNT and long-course chemoradiation (LCRT) have been published in the United States. We reviewed our multi-institutional experience with both., Methods: The US Rectal Cancer Consortium database (2007-2018) including data from six high-volume rectal cancer care centers was reviewed. Patients with nonmetastatic, rectal adenocarcinoma who had neoadjuvant LCRT alone or SC TNT before excision or definitive nonoperative management were included. The primary outcome was the rate of complete response (CR), including pCR or durable (12 month) clinical complete response., Results: Of 857 included patients, 175 (20%) received SC TNT and 682 (80%) received LCRT. The LCRT group had more low tumors (51.8% vs. 37.1%, p < 0.0001) and more clinically node-negative disease (31.8% vs. 22.3%, p < 0.0001). The CR rate was higher after SC TNT (34.1% vs. 20.3%, p = 0.0001). SC TNT was a predictor of CR (OR: 2.52, CI: 1.68-3.78). SC TNT patients completing 5-6 months of consolidation chemotherapy had a CR rate of 42.9%. There was no difference in 3-year PFS., Conclusions: SC TNT increases CR rate when compared to LCRT. For patients seeking nonoperative options or fewer radiation treatments, SC TRT should be preferred over LCRT alone., (© 2024 Wiley Periodicals LLC.)

There exists a complex relationship between steatotic liver disease (SLD) and atherosclerotic cardiovascular disease (CVD). CVD is a leading cause of morbidity and mortality among individuals with SLD, particularly those with metabolic dysfunction-associated SLD (MASLD), a significant proportion of whom also exhibit features of insulin resistance. Recent evidence supports an expanded role of very low-density lipoprotein (VLDL) in the pathogenesis of CVD in patients, both with and without associated metabolic dysfunction. VLDL represents the major vehicle for exporting neutral lipid from hepatocytes, with each particle containing one molecule of apolipoproteinB100 (APOB100). VLDL production becomes dysregulated under conditions characteristic of MASLD including steatosis and insulin resistance. Insulin resistance not only affects VLDL production but also mediates the pathogenesis of atherosclerotic CVD. VLDL assembly and secretion therefore represents an important pathway in the setting of cardiometabolic disease and offers several candidates for therapeutic targeting, particularly in metabolically complex patients with MASLD at increased risk of atherosclerotic CVD. Here we review the clinical significance as well as the translational and therapeutic potential of key regulatory steps impacting VLDL initiation, maturation, secretion, catabolism, and clearance., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

With aging, bone mass declines and the anabolic effects of skeletal loading diminish. While much research has focused on gene transcription, how bone ages and loses its mechanoresponsiveness at the protein level remains unclear. We developed a novel proteomics approach and performed a paired mass spectrometry and RNA-seq analysis on tibias from young-adult (5-month) and old (22-month) mice. We report the first correlation estimate between the bone proteome and transcriptome (Spearman ρ = 0.40), which is in line with other tissues but indicates that a relatively low amount of variation in protein levels is explained by the variation in transcript levels. Of 71 shared targets that differed with age, eight were associated with bone mineral density in previous GWAS, including understudied targets Asrgl1 and Timp2. We used complementary RNA in situ hybridization to confirm that Asrgl1 and Timp2 had reduced expression in osteoblasts/osteocytes in old bones. We also found evidence for reduced TGF-beta signaling with aging, in particular Tgfb2. Next, we defined proteomic changes following mechanical loading. At the protein level, bone differed more with age than with loading, and aged bone had fewer loading-induced changes. Overall, our findings underscore the need for complementary protein-level assays in skeletal biology research.

Excessive alcohol consumption is a leading cause of preventable death worldwide. To improve understanding of neurobiological mechanisms associated with alcohol use disorder (AUD) in humans, we compared gene expression data from deceased individuals with and without AUD across two addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Bulk RNA-seq data from NAc and DLPFC (N ≥50 with AUD, ≥46 non-AUD) were analyzed for differential gene expression using modified negative binomial regression adjusting for technical and biological covariates. The region-level results were meta-analyzed with those from an independent dataset (N NAc  = 28 AUD, 29 non-AUD; N PFC  = 66 AUD, 77 non-AUD). We further tested for heritability enrichment of AUD-related phenotypes, gene co-expression networks, gene ontology enrichment, and drug repurposing. We identified 176 differentially expressed genes (DEGs; 12 in both regions, 78 in NAc only, 86 in DLPFC only) for AUD in our new dataset. After meta-analyzing with published data, we identified 476 AUD DEGs (25 in both regions, 29 in NAc only, 422 in PFC only). Of these DEGs, 17 were significant when looked up in GWAS of problematic alcohol use or drinks per week. Gene co-expression analysis showed both concordant and unique gene networks across brain regions. We also identified 29 and 436 drug compounds that target DEGs from our meta-analysis in NAc and PFC, respectively. This study identified robust AUD-associated DEGs, contributing novel neurobiological insights into AUD and highlighting genes targeted by known drug compounds, generating opportunity for drug repurposing to treat AUD., (© 2024. The Author(s).)

Advances in antiretroviral therapy (ART) have made it possible for persons with human immunodeficiency virus (HIV) to live a lifespan approaching that of people without HIV, without progressing to AIDS or transmitting HIV to sexual partners or infants. There is, therefore, increasing emphasis on maintaining health throughout the lifespan. To receive optimal medical care and achieve desired outcomes, persons with HIV must be consistently engaged in care and able to access uninterrupted treatment, including ART. Comprehensive evidence-based HIV primary care guidance is, therefore, more important than ever. Creating a patient-centered, stigma-free care environment is essential for care engagement. Barriers to care must be decreased at the societal, health system, clinic, and individual levels. As the population ages and noncommunicable diseases arise, providing comprehensive health care for persons with HIV becomes increasingly complex, including management of multiple comorbidities and the associated challenges of polypharmacy, while also attending to HIV-specific health concerns. Clinicians must address issues specific to preventive health, including cancer screening, providing recommended vaccinations, as well as promoting sexual health, including sexually transmitted infection diagnosis, treatment, and prevention. Clinicians also must address issues for specific populations, including persons of childbearing potential, including during preconception and pregnancy; children; adolescents; and transgender and gender-diverse individuals. This guidance from an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America updates the previous 2020 HIV Primary Care Guidance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This real-world study explored factors affecting persistence with macitentan and selexipag treatment from the perspective of 23 healthcare professionals (HCPs) and 134 patients with pulmonary arterial hypertension between 2019 and 2022. Continuous patient/HCP communication and education were key drivers of persistence, as were early discussion and management of side effects., (© 2024 Actelion Pharmaceuticals US, Inc. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Introduction: COVID-19 changed scholarly publishing. Yet, its impact on medical education publishing is unstudied. Because journal articles and their corresponding publication timelines can influence academic success, the field needs updated publication timelines to set evidence-based expectations for academic productivity. This study attempts to answer the following research questions: did publication timelines significantly change around the time of COVID-19 and, if so, how?, Methods: We conducted a bibliometric study; our sample included articles published between January 2018, and December 2022, that appeared in the Medical Education Journals List-24 (MEJ-24). We clustered articles into three time-based groups (pre-COVID, COVID-overlap, and COVID-endemic), and two subject-based groups (about COVID-19 and not about COVID-19). We downloaded each article's metadata from the National Library of Medicine and analyzed data using descriptive statistics, analysis of variance, and post-hoc tests to compare mean time differences across groups., Results: Overall, time to publish averaged 300.8 days ( SD = 200.8). One-way between-groups ANOVA showed significant differences between the three time-based groups F (2, 7473) = 2150.7, p < .001. The post-hoc comparisons indicated that COVID-overlap articles took significantly longer ( n = 1470, M = 539; SD = 210.6) as compared to pre-COVID ( n = 1281; M = 302; SD = 172.5) and COVID-endemic articles ( n = 4725; M = 226; SD = 136.5). Notably, COVID-endemic articles were published in significantly less time than pre-pandemic articles, p < .001., Discussion: Longer publication time was most pronounced for COVID-overlap articles. Publication timelines for COVID-endemic articles have shortened. Future research should explore how the shift in publication timelines has shaped medical education scholarship., Competing Interests: Lauren A. Maggio is Deputy Editor in Chief for Perspectives on Medical Education. She was removed from all editorial processes relating to the handling of this submission. The authors have no additional competing interests to declare., (Copyright: © 2024 The Author(s).)

Within the past decade, there have been multiple innovations in the field of nerve surgery. In this review, we highlight critical changes and innovations that have helped advance the field and present opportunities for further study. This includes the modification and clarification of the classification schema for nerve injuries which informs prognosis and treatment, and a refined understanding and application of electrodiagnostic studies to guide patient selection. We provide indications for operative intervention based on this nerve injury classification and propose strategies best contoured for varying injury presentations at differing time points. Lastly, we discuss new developments in surgical techniques and approaches based on these advancements., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: Pediatric patients with life-limiting diagnoses frequently seek care in the pediatric emergency department (PED) during times of acute illness, or at end-of-life (EOL) . Although the population of patients with life-limiting diagnoses is heterogenous, clinician expertise in EOL communication is essential to providing family-centered care. In this study, we explored PED physician and nurse experiences with communication when eliciting EOL values, including factors specified to the PED environment, clinician perceptions of family supports and preferences, and clinicians' self-reflection of their skills and challenges in this sphere., Methods: We performed a prospective qualitative study using semistructured interviews of PED physicians and nurses recruited from a quaternary care center. Thematic content analysis was performed on the transcribed interviews to identify codes and, ultimately, themes., Results: We interviewed 17 emergency department clinicians, including 10 physicians and 7 nurses. Thematic content analysis revealed 6 salient themes. The first theme related to contextual factors of the emergency department environment. Two additional themes related to patient and family characteristics, including unique patient and family factors and clinician interpretation of parental/family needs. Lastly, we found 3 clinician-focused themes including knowledge gaps in EOL communication, communication styles and priorities in EOL conversations with families, and coping with ethical challenges., Conclusions: PED clinicians report communication-related challenges to providing optimal care for families and patients with life-limiting diagnoses. Participants self-identified gaps in communication skills in this area. Future studies should focus on clinician educational interventions on the basis of this needs assessment and include family perspectives to develop best practice., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to this article to disclose., (Copyright © 2024 by the American Academy of Pediatrics.)

Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials. It further proposes a simple framework to put biomarker guidance in the context of amyloid-pathway-targeted disease modification, delineates factors that impact biomarker data in clinical trials, and highlights knowledge gaps and future directions. Increased knowledge and data on biomarkers in the context of disease progression and disease modification will help to better design future AD trials and guide the clinical management of patients on AD-modifying therapies, bringing us closer to the implementation of precision medicine in AD., Competing Interests: Declaration of interests J.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter for p-tau assays and Aβ-targeting therapeutics. J.D. has served as a consultant or on advisory boards for Prevail Therapeutics, Eisai, Abbvie, Genotix Biotechnologies Inc., Gates Ventures, Karuna Therapeutics, AlzPath Inc., and Cognito Therapeutics, Inc. and received research support from Lilly, ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. J.D. has received speaker fees from LabCorp and Eli Lilly and Company. J.D. is a founder and advisor for Monument Biosciences. J.D. has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc., and Monument Biosciences. H.H. is an employee of Eisai and serves as reviewing editor for the Journal Alzheimer’s & Dementia. H.H. is inventor of 11 patents and has received no royalties for “In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” patent no. 8916388; “In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases,” patent no. 8298784; “Neurodegenerative Markers for Psychiatric Conditions,” publication no. 20120196300; “In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” publication no. 20100062463; “In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” publication no. 20100035286; “In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases,” publication no. 20090263822; “In Vitro Method for The Diagnosis of Neurodegenerative Diseases,” patent no. 7547553; “CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases,” publication no. 20080206797; “In Vitro Method for The Diagnosis of Neurodegenerative Diseases,” publication no. 20080199966; “Neurodegenerative Markers for Psychiatric Conditions,” publication no. 20080131921; “Method for Diagnosis of Dementias and Neuroinflammatory Diseases Based on an Increased Level of Procalcitonin in Cerebrospinal Fluid,” US patent no. 10921330. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. S.H. is an owner and employee of Pentara Corporation, a company that consults with dozens of companies in the Alzheimer’s space, including Biogen. No consulting fees were paid for work on this publication. Y.H., M.C., and P.S. are employees of Eisai., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To investigate the impact of preoperative glycosylated hemoglobin A1C (HbA1c) among patients following curative-intent resection of nonfunctional gastroentropancreatic neuroendocrine tumors (GEP-NETs)., Methods: Patients who underwent curative-intent resection for GEP-NETs from 2000 to 2020 were identified from the US Neuroendocrine Tumor Study Group (US-NETSG). Preoperative blood HbA1c levels were defined as high HbA1c (≥ 6.5%) versus low HbA1c group (< 6.5%). Impact of HbA1c level on postoperative short-term and long-term overall (OS) were investigated., Results: A total of 130 patients with HbA1c < 6.5% and 60 patients with HbA1c ≥ 6.5% were included. Patients with HbA1c ≥ 6.5% had higher proportion of comorbidities, such as hypertension, obesity, anemia, and lower preoperative albumin levels versus patients with HbA1c < 6.5% (all p < 0.05). In addition, high level of preoperative HbA1c was associated with increased incidence of wound and infectious complications, as well as decreased long-term OS (median OS: high Hb1Ac 89.8 months vs. low Hb1Ac not reached, HR 3.487, p = 0.004) among patients with nonfunctional GEP-NETs, as well as among the subset of pancreatic NET patients (median OS: high Hb1Ac 74.3 months vs. low Hb1Ac not reached, p = 0.004), and patients with normal fasting blood glucose (< 140 mg/dL) (median OS: high Hb1Ac 75.4 months vs. low Hb1Ac not reached, p = 0.001)., Conclusions: Hb1Ac might have value as a screening tool to identify high-risk patients following surgical resection of nonfunctional GEP-NETs for consideration of more strict postoperative surveillance and treatment of elevated Hb1Ac level., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Competing Interests: Disclosure The following authors disclosed financial relationships: K. K. Das: Patent with Interpace Biosciences; food and beverage compensation from Medtronic, Inc. D. Chen: Food and beverage compensation from Ambu Inc. V. S. Akshintala: Board member for Origin Endoscopy Inc; consultant for Dragonfly Endoscopy Inc; research support from Abbvie, Boston Scientific Corporation, and Medtronic; travel compensation from Mauna Kea Technologies, Inc; food and beverage compensation from Mauna Kea Technologies, Inc, Boston Scientific Corporation, and AbbVie Inc. Y.-I. Chen: President of Chess Medical; consultant for Boston Scientific Corporation. A. Kahn: Consultant for MiMedx. G. Mishra: Consultant for Pentax of America, Inc and Cook Medical LLC; travel compensation from Pentax of America, Inc; food and beverage compensation from Pentax of America, Inc, Cook Medical LLC, Ambu Inc, Boston Scientific Corporation, and Wilson Cook Medical Incorporated. V. Raman Muthusamy: Consultant for Medtronic and Boston Scientific Corporation; research support from Boston Scientific Corporation; stock options and equity in Capsovision; advisory board for Endogastric Solutions and Motus GI; travel compensation from Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation, Steris Corporation, Medtronic, Inc, Apollo Endosurgery US Inc, Endogastric Solutions, Inc, Cook Medical LLC, Pentax of America, Inc, and Olympus America Inc. J. V. Obando: Shareholder with Surgenly LLC. F. U. Onyibma: Food and beverage compensation from Endogastric Solutions, Inc and Medtronic, Inc. S. Pawa: Consultant for Boston Scientific Corporation. T. Rustagi: Consultant for Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation and Merit Medical Systems Inc. S. Sakaria: Food and beverage compensation from AbbVie Inc. G. Trikudanathan: Consultant for Boston Scientific Corporation; food and beverage compensation from Boston Scientific Corporation. R. Law: Consultant for ConMed Corporation, Boston Scientific Corporation, Medtronic USA Inc, and Olympus America Inc; royalties from UpToDate; food and beverage compensation from Olympus America Inc, Boston Scientific Corporation, and Ethicon Inc. All other authors disclosed no financial relationships.

Objective: Presentation with multiple ground glass opacities (GGOs) is an increasingly common occurrence, and the optimal management of these lesions is unclear. Active surveillance has been increasingly adopted as a management strategy for other low-grade malignancies. We hypothesized that active surveillance could be a feasible and safe option for patients with multiple GGOs., Methods: Patients with ≥2 GGOs (ground glass predominant, <50% solid, ≤3 cm) were enrolled in a multi-institutional registry and prospectively followed up on active surveillance with computed tomography scans every 6 to 12 months. Each GGO was catalogued and measured individually at each follow-up visit., Results: Target accrual was met, with 337 patients from 23 institutions. The mean age was 70 years (interquartile range, 65-77 years), and 74% were women. Most were former (70%) or current (9%) smokers, with a mean exposure of 30 pack-years (interquartile range [IQR], 15-44 pack-years). Half of the patients (51%) had a previous lung cancer, and the majority (86%) were already under surveillance at the time of study entry. The median number of GGOs per patient was 3 (IQR, 2-5), with a total of 1467 GGOs under surveillance. The median GGO size was 0.9 cm (IQR, 0.7-1.3 cm). Most GGOs were 0.5 to 1 cm in size., Conclusions: Active surveillance, rather than immediate intervention, was an acceptable option to patients, and accrual to this registry trial was feasible. Safety endpoints and long-term outcomes will be assessed in the planned 5-year follow-up in accordance with the protocol., (Copyright © 2024. Published by Elsevier Inc.)

Background: Type 1 diabetes (T1D) management is challenging for young adults, who are expected to transfer from the pediatric to adult T1D healthcare system while also managing typical developmental demands (e.g., social, financial, work/school, residential). Many young adults have extended gaps in care before following up in adult care, increasing risk for poor health outcomes. There are few evidence-based programs to support young adults with T1D to promote a timelier transition during this period. This paper reports on the design of DiaBetter Together, a randomized controlled trial to evaluate a 12-month Peer Mentor-delivered intervention compared to usual care among young adults with T1D during the transfer from pediatric to adult care., Methods: One-hundred young adults (age 17-25) with T1D and 29 Peer Mentors enrolled in this randomized clinical trial. Peer Mentors are experienced, older young adults with T1D, trained by the study team to share transition experiences and strategies to successfully navigate the adult healthcare system, help young adults prepare for the first adult care visit, and use strengths-based support strategies to teach and model skills for managing T1D-related challenges., Results: The primary outcome of the trial is HbA1c, and secondary outcomes include time to adult care, engagement in diabetes self-management behaviors, and psychosocial well-being., Conclusion: The goal of this research is to evaluate a developmentally appropriate, supportive intervention that can improve T1D self-management and successful transfer of care during the difficult young adult years and promote optimal T1D health outcomes., (Copyright © 2024. Published by Elsevier Inc.)

High-level disinfection and sterilization are complex processes, requiring initial and ongoing training of frontline staff. 1 A key component of appropriate disinfection and sterilization is point-of-use pre-cleaning performed by front-line staff. Our facility implemented an annual hospital-wide education and competency program for staff that perform pre-cleaning of reusable medical devices., Competing Interests: Declaration of Competing Interest No relevant conflict of interest. Dr. Warren reports personal fees from Mölnlycke Health Care AB, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Background: Open groin vascular surgeries are important in managing peripheral arterial diseases. Given its inherent risks and the diverse patient profiles, there is a need for risk assessment tools. This study aimed to develop a 30-d point-scoring risk calculator for patients undergoing open groin vascular surgeries., Methods: Patients underwent open groin vascular surgery, including aortobifemoral, axillofemoral, femorofemoral, iliofemoral, femoral-popliteal, and femoral-tibial bypass as well as thromboendarterectomy, were identified in American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2021. Patients were randomly sampled into experimental (2/3) and validation (1/3) groups. The George Washington (GW) groin score, a weighted point-scoring system, was developed for 30-d mortality from multivariable regression on preoperative risk variables by Sullivan's method. GW groin score was subjected to internal and external validation. Furthermore, the effectiveness of GW groin score was evaluated in 30-d major surgical complications., Results: A total of 129,424 patients were analyzed, with 86,715 allocated to experimental group and 42,709 to validation group. GW groin score is derived as follows: aortobifemoral bypass (2 points), axillofemoral bypass (1 point), age (>75 y, 2 points; 65-75 y, 1 point), disseminated cancer (2 points), emergent presentation (1 point), American Society of Anesthesiology score 4 or 5 (1 point), dialysis (1 point), and preoperative sepsis (1 point).GW groin score exhibited robust discrimination (c-statistic = 0.794, 95% CI = 0.786-0.803) and calibration (Brier score = 0.029). The transition from individual preoperative variables (c-statistic = 0.809, 95% CI = 0.801-0.818) to the point-scoring system was successful and external validation of the score was confirmed (c-statistic = 0.789, 95% CI = 0.777-0.801, Brier score = 0.030). Furthermore, GW groin score can effectively discriminate major surgical complications., Conclusions: This study developed GW groin score, a concise and comprehensive 10-point risk calculator. This well-validated score demonstrates robust discriminative and predictive abilities for 30-d mortality and major surgical complications following open groin vascular surgeries. GW groin score can anticipate potential perioperative complications and guide treatment decisions., (Copyright © 2024 Elsevier Inc. All rights reserved.)