National Institutes of Health

Background Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed. A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10⁻⁴) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005). Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Purpose of Review Highlight the mechanisms through which vasopressin and hypertonic stress regulate protein metabolism Recent Findings Mammals have an ‘aestivation-like’ response in which hypertonic stress increases muscle catabolism and urea production Vasopressin can directly regulate ureagenesis in the liver and the kidney In humans chronic hypertonic stress is associated with premature aging, diabetes, cardiovascular disease, and premature mortality Summary There is an evolutionarily conserved ‘aestivation-like’ response in humans in which hypertonic stress results in activation of the vasopressin system, muscle catabolism, and ureagenesis in order to promote water conservation.

N‐glycosylation is the most common protein modification in the eukaryotic secretory pathway. It involves the attachment a high mannose glycan to Asn residues in the context of Asn‐X‐Ser/Thr/Cys, a motif known as N‐glycosylation sequon. This process is mediated by STT3A and STT3B, the catalytic subunits of the oligosaccharyltransferase complexes. STT3A forms part of complexes associated with the SEC61 translocon and functions co‐translationally. Vacant sequons have another opportunity for glycosylation by complexes carrying STT3B. Local sequence information plays an important role in determining N‐glycosylation efficiency, but non‐local factors can also have a significant impact. For instance, certain proteins associated with human genetic diseases exhibit abnormal N‐glycosylation levels despite having wild‐type acceptor sites. Here, we investigated the effect of protein stability on this process. To this end, we generated a family of 40 N‐glycan acceptors based on superfolder GFP, and we measured their efficiency in HEK293 cells and in two derived cell lines lacking STT3B or STT3A. Sequon occupancy was highly dependent on protein stability, improving as the thermodynamic stability of the acceptor proteins decreases. This effect is mainly due to the activity of the STT3B‐based OST complex. These findings can be integrated into a simple kinetic model that distinguishes local information within sequons from global information of the acceptor proteins.

Identifying cell types and states remains a time-consuming, error-prone challenge for spatial biology. While deep learning is increasingly used, it is difficult to generalize due to variability at the level of cells, neighborhoods, and niches in health and disease. To address this, we developed TACIT, an unsupervised algorithm for cell annotation using predefined signatures that operates without training data. TACIT uses unbiased thresholding to distinguish positive cells from background, focusing on relevant markers to identify ambiguous cells in multiomic assays. Using five datasets (5,000,000-cells; 51-cell types) from three niches (brain, intestine, gland), TACIT outperformed existing unsupervised methods in accuracy and scalability. Integrating TACIT-identified cell types with a novel Shiny app revealed new phenotypes in two inflammatory gland diseases. Finally, using combined spatial transcriptomics and proteomics, we discovered under- and overrepresented immune cell types and states in regions of interest, suggesting multimodality is essential for translating spatial biology to clinical applications.

Purpose of review Diabetes mellitus (DM) is relatively common following acute pancreatitis (AP), even after mild acute pancreatitis (MAP), the most frequent AP presentation, in which there is no overt beta cell injury. Post-AP related diabetes is widely misdiagnosed, resulting in potentially inappropriate treatment and worse outcomes than type 2 diabetes (T2D). Thus, it is important to understand risk across the spectrum of AP severity. Recent findings Biological mechanisms are unclear and may include local and systemic inflammation leading to beta cell dysfunction and insulin resistance, altered gut barrier and/or gut peptides and possibly islet autoimmunity, though no studies have specifically focused on MAP. While studies examining clinical risk factors on MAP exclusively are lacking, there are studies which include MAP. These studies vary in scientific rigor, approaches to rule out preexisting diabetes, variable AP severity, diagnostic testing methods, and duration of follow-up. Overall, disease related factors, including AP severity, as well as established T2D risk factors are reported to contribute to the risk for DM following AP. Summary Though numerous studies have explored risk factors for DM after AP, few studies specifically focused on MAP, highlighting a key knowledge gap that is relevant to the majority of patients with AP.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92–0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79–0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor’s deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients’ survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.

Background Mechanical thrombectomy (MT) is the standard of care for acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). The SOFAST study collected clinical evidence on the safety and efficacy of the 6 French SOFIA Flow Plus aspiration catheter (SOFIA 6F) when used as first-line treatment. Methods This was a prospective, multicenter investigation to assess the safety and efficacy of SOFIA 6F used for first-line aspiration. Anterior circulation LVO stroke patients were enrolled. The primary endpoint was the final modified Thrombolysis in Cerebral Infarction (mTICI)≥2b rate. Secondary endpoints included first-pass and first-line mTICI≥2b rates, times from arteriotomy to clot contact and mTICI≥2b, and 90-day modified Rankin Scale (mRS)≤2. First-line and final mTICI scores were adjudicated by an independent imaging core lab. Safety events were assessed by an independent clinical events adjudicator. Results A total of 108 patients were enrolled across 12 centers from July 2020 to June 2022. Median age was 67 years, median National Institutes of Health Stroke Scale (NIHSS) was 15.5, and 56.5% of patients received intravenous thrombolytics. At the end of the procedure, 97.2%, 85.2%, and 55.6% of patients achieved mTICI≥2b, ≥2c, and 3, respectively. With SOFIA 6F first-line aspiration, 87.0%, 79.6%, and 52.8% achieved mTICI≥2b, ≥2c, and 3, respectively. After the first pass, 75.0%, 70.4%, and 50.9% achieved mTICI≥2b, ≥2c, and 3, respectively. Median times from arteriotomy to clot contact and successful revascularization were 12 and 17 min, respectively. At 90 days, 66.7% of patients achieved mRS≤2. Conclusions First-line aspiration with SOFIA 6F is safe and effective with high revascularization rates and short procedure times.

Background The United States Preventive Services Task Force (USPSTF) recommend lung-cancer screening for individuals aged 50-80 with ≥20 pack-years and ≤15 quit-years, but uptake is low. The risk and benefit profiles of screening attendees are unknown; consequently, the impact and lost opportunity of ongoing lung-cancer screening in the US remains unclear. Methods We estimated lung-cancer death risk (using the Lung Cancer Death Risk Assessment Tool) and life gained from screening (using the LYFS-CT model) for individuals 50-79 who ever-smoked in the US-representative 2022 Behavioral Risk Factor Surveillance System. We compared lung-cancer death risk and life-gained among USPSTF-eligible individuals by screening status (self-reported screened vs not screened in past year), and estimated the number of lung-cancer deaths averted and life-years gained under current screening levels and if everyone eligible was screened. Results USPSTF-eligibility was 33.7% (95%CI:33.1-34.4%), of whom 17.9% (95%CI : 17.0-18.8%) self-reported screening. Screening uptake increased with increasing lung-cancer death risk quintile (Q1 = 5.2% (95%CI : 3.0%-8.8%); Q5 = 21.8% (95%CI : 20.3%-23.3%)) and life-gain from screening quintile (Q1 = 6.2% (95%CI : 3.8%-9.9%); Q5 = 20.8% (95%CI : 19.5%-22.2%)). Screened individuals had higher lung-cancer death risk (Risk Ratio [RR]=1.35, 95%CI : 1.26-1.46) and life-years gained (RR = 1.19, 95%CI : 1.12-1.25) than unscreened individuals. Currently screening averts 19,306 lung-cancer deaths and gains 237,564 life-years; screening everyone eligible would additionally avert 56,956 lung-cancer deaths and gain 751,850 life-years. Two-thirds of USPSTF-lung-eligible women were up-to-date with breast-cancer screening, but only 17.3% attended lung screening in the past year. Conclusions Eligible screening attendees had higher lung-cancer death risk and benefit from screening. Higher rates of screening could substantially increase the number of lung-cancer deaths prevented.

The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, two members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-MSH, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased POMC immunoreactivity per cell. These results indicate that PTPRNs contribute to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression.

Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal RORγt⁺ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, supplementation of HFD-fed male mice with the fermentable dietary fiber fructooligosaccharides (FOS) was sufficient to maintain RORγt⁺ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. FOS-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited FOS impact on glucose tolerance. Overall, we uncover a pivotal role of cDC2 in the control of the immune and metabolic effects of FOS in the context of HFD feeding.

Racial residential segregation has been deemed a fundamental cause of health inequities. It is a result of historical and contemporary policies such as redlining that have created a geographic separation of races and corresponds with an inequitable distribution of health-promoting resources. Redlining and racial residential segregation may have contributed to racial inequities in COVID-19 vaccine administration in the early stages of public accessibility. We use data from the National Archives (historical redlining), Home Mortgage Disclosure Act (contemporary redlining), American Community Survey from 1940 (historical racial residential segregation) and 2015–2019 (contemporary racial residential segregation), and Washington D.C. government (COVID-19 vaccination administration) to assess the relationships between redlining, racial residential segregation, and COVID-19 vaccine administration during the early stages of vaccine distribution when a tiered system was in place due to limited supply. Pearson correlation was used to assess whether redlining and racial segregation, measured both historically and contemporarily, were correlated with each other in Washington D.C. Subsequently, linear regression was used to assess whether each of these measures associate with COVID-19 vaccine administration. In both historical and contemporary analyses, there was a positive correlation between redlining and racial residential segregation. Further, redlining and racial residential segregation were each positively associated with administration of the novel COVID-19 vaccine. This study highlights the ongoing ways in which redlining and segregation contribute to racial health inequities. Eliminating racial health inequities in American society requires addressing the root causes that affect access to health-promoting resources.

Background A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log 10 (donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: –0.0095 [0.0007] versus –0.0109 [0.0007]; P = 0.15). Conclusions BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

Objective The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24‐h energy expenditure (EE). Methods Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m ² . Measurements included body composition by dual‐energy x‐ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24‐h EE in a whole‐room indirect calorimeter. Results Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high‐density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24‐h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24‐h EE was a partial mediator (40%), but the association remained significant (β = 0.15; p < 0.0001). Conclusions In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24‐h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain.

Background and Objectives. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in western countries. Although the etiology of NAFLD is unknown, insulin resistance is a key mechanism of lipid deposition in hepatocytes leading to steatosis and potentially steatohepatitis in patients with diabetes. These factors accelerate the progression of atherosclerosis and development of cardiovascular diseases (CVD). Methods and Results. In this prospective cohort study, 1197 patients with type 2 diabetes (T2D) were divided into two groups (360 patients with NAFLD and 847 without NAFLD) and were followed for a median of 5 years for the incidence of CVD. Cox regression analysis was used to assess the association between NAFLD, liver enzyme level, aspartate aminotransferase to platelet ratio index (APRI), and the incidence risk of CVD and its subgroups (i.e., myocardial infarction, chronic heart disease, coronary artery bypass grafting, and percutaneous coronary intervention). There was a significant positive association between CVD incidence and NAFLD (HR = 1.488, 95% CI = 1.041–2.124, p value = 0.029). Although patients with NAFLD had higher levels of ALT and AST levels (p value = <0.001), there was no significant association between liver enzymes and the incidence risk of CVD when adjusted for different variables. Furthermore, NAFLD was associated with NAFLD APRI Q (2), APRI Q (3), and APRIQ (4) (1.365 (1.046–1.781), 1.623 (1.234–2.135), and 3.373 (2.509–4.536)), respectively. Conclusion. NAFLD increased the incidence risk of CVD in T2D. However, there was no association between liver enzymes (ALT, AST, ALK-P, and GGT) and a higher incidence risk of CVD in T2D when adjusted for confounding variables.

Aim To evaluate the efficacy of the Akwenda Intervention Program on motor, self‐care, and social function of children and young people with cerebral palsy (CP). Method This was a cluster‐randomized, controlled, single‐blinded, intervention study of 100 participants with CP (2–23 years; 52 males) in rural eastern Uganda. Half were allocated to the intervention program, the remainder served as waitlist controls. Gross Motor Function Measure‐66 (GMFM‐66) and the Ugandan version of Pediatric Evaluation of Disability Inventory (PEDI‐UG) were collected before group allocation and after intervention. General linear models and t‐tests were used to compare changes within and between groups. Cohen's d estimated the effect size of group differences. Change scores were evaluated by age and mobility subgroups. Results Significant group by time interactions were found for GMFM‐66 (p =0.003) and PEDI‐UG outcomes (p <0.001), except mobility, with the intervention group demonstrating greater changes. Both groups increased their scores on the GMFM‐66 and child PEDI‐UG, while only the intervention group had significant increases in caregiver assistance scores and across all age and mobility subgroups. Cohen's d showed large effect sizes (d >0.8) of differences for PEDI‐UG outcomes except mobility. Interpretation The Akwenda Intervention Program had a large positive impact on functioning and activity across age and mobility levels.

The epithelial cell lining of the oviduct plays an important role in oocyte pickup, sperm migration, preimplantation embryo development, and embryo transport. The oviduct epithelial cell layer comprises ciliated and non-ciliated secretory cells. The ciliary function has been shown to support gamete and embryo movement in the oviduct, yet secretory cell function has not been well characterized. Therefore, our goal is to generate a secretory cell-specific Cre recombinase mouse model to study the role of the oviductal secretory cells. A knock-in mouse model, Ovgp1Cre:eGFP, was created by expressing Cre from the endogenous Ovgp1 (oviductal glycoprotein 1) locus, with enhanced green fluorescent protein (eGFP) as a reporter. EGFP signals were strongly detected in the secretory epithelial cells of the oviducts at estrus in adult Ovgp1Cre:eGFP mice. Signals were also detected in the ovarian stroma, uterine stroma, vaginal epithelial cells, epididymal epithelial cells, and elongated spermatids. To validate recombinase activity, progesterone receptor (PGR) expression was ablated using the Ovgp1Cre:eGFP; Pgrf/f mouse model. Surprisingly, the deletion was restricted to the epithelial cells of the uterotubal junction (UTJ) region of Ovgp1Cre:eGFP; Pgrf/f oviducts. Deletion of Pgr in the epithelial cells of the UTJ region had no impact on female fecundity. In summary, we found that eGFP signals were likely specific to secretory epithelial cells in all regions of the oviduct. However, due to a potential target-specific Cre activity, validation of appropriate recombination and expression of the gene(s) of interest is absolutely required to confirm efficient deletion when generating conditional knockout mice using the Ovgp1Cre:eGFP line.

Purpose Cancer-related fatigue (CRF) is challenging to diagnose and manage due to a lack of consensus on its definition and assessment. The objective of this scoping review is to summarize how CRF has been defined and assessed in adult patients with cancer worldwide. Methods Four databases (PubMed, Embase, CINAHL Plus, PsycNet) were searched to identify eligible original research articles published in English over a 10-year span (2010–2020); CRF was required to be a primary outcome and described as a dimensional construct. Each review phase was piloted: title and abstract screening, full-text screening, and data extraction. Then, two independent reviewers participated in each review phase, and discrepancies were resolved by a third party. Results 2923 articles were screened, and 150 were included. Only 68% of articles provided a definition for CRF, of which 90% described CRF as a multidimensional construct, and 41% were identical to the National Comprehensive Cancer Network definition. Studies were primarily conducted in the United States (19%) and the majority employed longitudinal (67%), quantitative (93%), and observational (57%) study designs with sample sizes ≥ 100 people (57%). Participant age and race were often not reported (31% and 82%, respectively). The most common cancer diagnosis and treatment were breast cancer (79%) and chemotherapy (80%; n = 86), respectively. CRF measures were predominantly multidimensional (97%, n = 139), with the Multidimensional Fatigue Inventory (MFI-20) (26%) as the most common CRF measure and “Physical” (76%) as the most common CRF dimension. Conclusion This review confirms the need for a universally agreed-upon definition and standardized assessment battery for CRF.