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Abstract Lichen sclerosus is a debilitating and chronic disease that typically affects the anogenital area, although it can also be found on extragenital locations such as the shoulders, neck, trunk, breasts, and arms. Facial involvement is rare, but there have been a few reported cases of extragenital lichen sclerosus affecting the infraorbital area. To our knowledge, there are 7 documented cases of extragenital lichen sclerosus affecting the eyelid in medical literature. This is a novel case and documented report of a patient with extragenital lichen sclerosus located on the eyelid with eyelash margin involvement.

Background: Menstrual health is an important indicator of overall health and has large impacts on quality of life. Despite number and impact, discussion of menstruation remains largely taboo within health care. Patients and physicians are not engaging in regular, meaningful discussions on menstruation. Family physicians, as primary care providers, can facilitate these important conversations. Objectives: We sought to understand the profile of menstrual care providing family physicians and assessed physician comfort, knowledge, training, and perceived importance regarding menstrual care. Design/Methods: This is a cross-sectional analysis of the 2022 Council of Academic Family Medicine Educational Research Alliance survey. The survey included actively practicing US physicians who are members of the Council of Academic Family Medicine organizations. Descriptive demographic statistics were calculated; chi-square tests were generated for menstrual care-specific items; logistic regression models were fit to determine the association between receiving formal menstrual care training, importance of physician training in menstrual care, and demographic factors. Results: Eighty-five percent of respondents report frequently providing menstrual care. Participants of younger age, or who had earned their degree more recently, were significantly more likely to provide frequent menstrual care. Respondents who earned their medical degree at an earlier year were significantly more likely to believe that physician training in menstrual care was of limited importance (OR = 1.02, 95% CI = 1.00, 1.03). Conclusions: Our findings show that family physicians are providing menstrual care, despite non-uniform training, and recognize its importance to patients. By understanding physician profile and the care they provide, we can work toward comprehensive physician education in menstrual care and providing appropriate menstrual care to patients.

BackgroundWhen a genie is freed from its bottle, things cannot be restored to the way they were before. At the beginning of the global COVID-19 pandemic, health care systems adjusted how they delivered care overnight. Primary care practices switched from seeing patients in person to virtual care applications, including video and phone visits, e-visits, e-consults, and messaging with clinicians. Prior to the pandemic, these applications were not as widely used, but discussions around their advantages and disadvantages in some settings were being explored. Emergency regulatory changes spurred by the pandemic freed this virtual care “genie” from its bottle. Wide-scale adoption of virtual care in family medicine has much potential, as primary care services are often a patient’s first point of contact with the health care system. ObjectiveThis study aims to analyze family medicine providers’ experiences using virtual visits during the pandemic, perceived outcomes of the shift to virtual visits, and discusses its implications for the future of family medicine. MethodsThis qualitative study took place at 3 academic primary care clinics between June and December 2020. Data were collected through one-on-one Zoom (version 5.2.1) interviews with family medicine clinical faculty who experienced the rapid transition of in-person visits to mostly “virtual” visits. The interviews were recorded, deidentified, and transcribed. We adopted a constructivist approach to qualitative content analysis to evaluate the results. ResultsIn total, 25 participants were eligible, and 20 individuals participated in this study (80% participation rate). The mean age was 43.4 years, and 85% (17/20) of the participants were female. We identified 3 main themes: the care process, patient engagement, and team-based care. ConclusionsThis study highlights the transition from in-person to virtual visits during the pandemic from the perspective of family medicine providers. Generally, family medicine providers’ perceptions of the shift to virtual visits were positive, especially regarding team-based care. Challenges involved virtual inhibition, particularly for providers. Providers described ways they integrated virtual care with aspects of in-person care, creating a hybrid environment. The genie is out of the bottle—things will not be the same—but family medicine now has the opportunity to evolve.

BackgroundAtherosclerosis and consequent risk of cardiovascular events or mortality can be accurately assessed by quantifying coronary artery calcium score (CACS) derived from computed tomography. HMG-CoA-reductase inhibitors (statins) are the primary pharmacotherapy used to reduce cardiovascular events, yet there is growing data that support statin use may increase coronary calcification. We set out to determine the likelihood of severe CACS in the context of chronic statin therapy.MethodsWe established a retrospective, case-control study of 1,181 U.S. veterans without coronary artery disease (CAD) from a single site, the Providence VA Medical Center. Duration of statin therapy for primary prevention was divided into 5-year categorical increments. The primary outcome was CACS derived from low-dose lung cancer screening computed tomography (LCSCT), stratified by CACs severity (none = 0; mild = 1-99; moderate = 100-399; and severe ≥400 AU). Statin duration of zero served as the referent control. Ordinal logistic regression analysis determined the association between duration of statin use and CACS categories. Proportional odds assumption was tested using likelihood ratio test. Atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index, and CKD (glomerular filtration rate of ResultsThe mean age of the study population was 64.7±7.2 years, and 706 (60%) patients were prescribed a statin at baseline. Duration of statin therapy was associated with greater odds of having increased CACS (>0-5 years, OR: 1.71 [CI: 1.34-2.18], p5-10 years, OR: 2.80 [CI: 2.01-3.90], p10 years, OR: 5.30 [CI: 3.23-8.70], p0-5 years, OR: 1.49 [CI: 1.16-1.92], p = 0.002; >5-10 years, OR: 2.38 [CI: 1.7-3.35], p10 years, OR: 4.48 [CI: 2.7-7.43], pConclusionsLong-term use of statins is associated with increased likelihood of severe CACS in patients with significant smoking history. The use of CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.

Interferon regulatory factor 2 binding protein 2 (Irf2bp2), a co-repressor of Irf2, is required for fetal hepatic erythropoiesis through the expansion of erythromyeloid progenitors. Mice with germline ablation of the entire Irf2bp2 transcript produced no viable Irf2bp2-null pups in first litters. In subsequent litters, fewer than 1/3 of the expected Irf2bp2-null pups were born and half survived to adulthood. As in humans with somatic mutations in IRF2BP2, adult Irf2bp2-null mice developed lymphoma. Transcriptome profiling of liver, heart, and skeletal muscle from Irf2bp2-null adult mice revealed a predominant upregulation of interferon-responsive genes. Of interest, hematopoietic stem cell-enriched transcription factors (Etv6, Fli1, Ikzf1, and Runx1) were also elevated in Irf2bp2-null livers. Intriguingly, Irf2bp2-positive myeloid (but not lymphoid) cells were detected in the livers of adult Irf2bp2-null mice. In female Irf2bp2-null mice, these cells carried a Y chromosome while in male Irf2bp2-null livers, no cells with Barr bodies (inactivated X chromosomes) were detected, indicating that Irf2bp2-positive erythromyeloid cells might be acquired only from male siblings of prior litters by transmaternal microchimerism. These cells likely rescue the deficit in fetal erythropoiesis, but not adult-onset lymphomagenesis, caused by Irfb2p2 ablation.

Objective: Zolpidem is associated with sleep-related eating disorder (SRED). We compiled case reports and performed a descriptive study to identify etiology and aggravating factors. Methods: A literature search on PubMed's MeSH search feature, CINAHL, and SciFinder was performed using search terms “Zolpidem,” “Feeding and Eating Disorders/chemically induced,” “Dyssomnias,” “sleep eating disorder,” and “sleep-related eating disorder.” Three reviewers examined all English and Spanish citations and extracted pertinent information. A narrative synthesis of the evidence was prepared. Results: We identified 40 case reports of which 65% were female, and the mean age was 53 years. SRED onset was most commonly seen with daily zolpidem doses of 10 mg or higher (95% of patients). Prior medical history included obstructive sleep apnea (OSA) (35%), depression (32.5%), and restless leg syndrome (RLS) (25%). Even with controlled RLS and OSA, SRED developed in some patients. All patients had either partial or full amnesia with compulsive eating. Onset of SRED occurred as early as the first dose to after 9 years of use. SRED symptoms occurred nightly in 57.5% of patients. Discontinuation of zolpidem resolved SRED in all patients (n = 36). Conclusion: SRED associated with zolpidem can occur with any dose, but was most common with higher doses of zolpidem. Therefore, prescribers should initiate lower doses of zolpidem. Interestingly, many patients had underlying disorders known to affect sleep (RLS, OSA, depression). Although it is recommended to control these underlying disorders prior to initiating zolpidem, SRED may still occur. Zolpidem discontinuation resolved all cases of SRED.

Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC) has been demonstrated to accumulate in atherosclerotic lesions and regulates expression of more than 1,000 genes in human aortic endothelial cell (HAEC). Among the most highly induced is heme oxygenase-1 (HO-1), a cell-protective antioxidant enzyme, which is sensitively induced by oxidative stress. To identify the pathway by which Ox-PAPC induces HO-1, we focused on the plasma membrane electron transport (PMET) complex, which contains ecto-NADH oxidase 1 (eNOX1) and NADPH:quinone oxidoreductase 1 (NQO1) and affects cellular redox status by regulating levels of NAD(P)H. We demonstrated that Ox-PAPC and its active components stimulated electron transfer through the PMET complex in HAECs from inside to outside [as determined by extracellular 2-(4-iodophenyl)-3-(44-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) reduction] and from outside to inside of the cell (as determined by intracellular NBT reduction). Chemical inhibitors of PMET system and siRNAs to PMET components (NQO1 and eNOX1) significantly decreased HO-1 induction by Ox-PAPC. We present evidence that Ox-PAPC activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in HAEC plays an important role in the induction of HO-1 and PMET inhibitors blocked Nrf2 activation by Ox-PAPC. We hypothesized that PMET activation by Ox-PAPC causes intracellular NAD(P)H depletion, which leads to the increased oxidative stress and HO-1 induction. Supporting this hypothesis, cotreatment of cells with exogenous NAD(P)H and Ox-PAPC significantly decreased oxidative stress and HO-1 induction by Ox-PAPC. Taken together, we demonstrated that the PMET system in HAEC plays an important role in the regulation of cellular redox status and HO-1 expression by Ox-PAPC.

ABSTRACT New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 µg/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens. IMPORTANCE Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.

Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2) is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation.EC monolayer permeability in human pulmonary artery endothelial cells (HPAEC) and human aortic endothelial cells (HAEC) was monitored by changes in transendothelial electrical resistance (TER) across EC monolayers. Actin cytoskeleton was examined by immunostaining with Texas Red labeled phalloidin. Phosphorylation of myosin light chains (MLC) and VE-Cadherin was examined by Western blot and immunofluorescence techniques. The role of VEGFR2 in OxPAPC-induced permeability and cytoskeletal arrangement were determined using siRNA-induced VEGFR2 knockdown.Low OxPAPC concentrations (5-20 µg/ml) induced a barrier protective response in both HPAEC and HAEC, while high OxPAPC concentrations (50-100 µg/ml) caused a rapid increase in permeability; actin stress fiber formation and increased MLC phosphorylation were observed as early as 30 min after treatment. VEGFR2 knockdown dramatically decreased the amount of MLC phosphorylation and stress fiber formation caused by high OxPAPC concentrations with modest effects on the amount of VE-cadherin phosphorylation at Y(731). We present evidence that activation of Rho is involved in the OxPAPC/VEGFR2 mechanism of EC permeability induced by high OxPAPC concentrations. Knockdown of VEGFR2 did not rescue the early drop in TER but prevented further development of OxPAPC-induced barrier dysfunction.This study shows that VEGFR2 is involved in the delayed phase of EC barrier dysfunction caused by high OxPAPC concentrations and contributes to stress fiber formation and increased MLC phosphorylation.

BackgroundEvidence suggests inflammation plays a role in the pathophysiology of psychosis even in early illness, indicating a potential avenue for anti-inflammatory interventions that simultaneously address high rates of metabolic disease in this population. The aim of this study is to design a novel anti-inflammatory diet intervention (DI) that is feasible to implement in a first-episode psychosis (FEP) population.MethodsEligible FEP Participants are aged 15–30. The DI is currently being refined through a multi-phase process that includes the recruitment of focus groups that provide insight into feasibility of measures and nutritional education, as well as the implementation of the DI. The phases in the study are the Development Phase, Formative Phase, and the Feasibility Phase.ResultsThe Development phase has resulted in the creation of a flexible DI for FEP based on existing research on nutritional health and informed by providers. This study has just completed the Formative phase, recruiting eligible participants to join focus groups that gleaned information about dietary habits, preferences, and food environments to further refine the DI.ConclusionFindings from earlier phases have advised the current Feasibility Phase in which this novel DI is being administered to a small cohort of FEP participants (N = 12) to determine acceptability of the DI from a lived experience perspective. Naturalistic changes in inflammatory biomarkers, metabolic health, and symptoms will also be measured.

Ex vivo genetically-modified cellular immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapies, have generated significant clinical and commercial outcomes due to their unparalleled response rates against relapsed and refractory blood cancers. However, the development and scalable manufacture of these novel therapies remains challenging and further process understanding and optimisation is required to improve product quality and yield. In this study, we employ a quality-by-design (QbD) approach to systematically investigate the impact of critical process parameters (CPPs) during the expansion step on the critical quality attributes (CQAs) of CAR-T cells. Utilising the design of experiments (DOE) methodology, we investigated the impact of multiple CPPs, such as number of activations, culture seeding density, seed train time, and IL-2 concentration, on CAR-T CQAs including, cell yield, viability, metabolism, immunophenotype, T cell differentiation, exhaustion and CAR expression. Initial studies undertaken in G-Rex® 24 multi-well plates demonstrated that the combination of a single activation step and a shorter, 3-day, seed train resulted in significant CAR-T yield and quality improvements, specifically a 3-fold increase in cell yield, a 30% reduction in exhaustion marker expression and more efficient metabolism when compared to a process involving 2 activation steps and a 7-day seed train. Similar findings were observed when the CPPs identified in the G-Rex® multi-well plates studies were translated to a larger-scale automated, controlled stirred-tank bioreactor (Ambr® 250 High Throughput) process. The single activation step and reduced seed train time resulted in a similar, significant improvement in CAR-T CQAs including cell yield, quality and metabolism in the Ambr® 250 High Throughput bioreactor, thereby validating the findings of the small-scale studies and resulting in significant process understanding and improvements. This study provides a methodology for the systematic investigation of CAR-T CPPs and the findings demonstrate the scope and impact of enhanced process understanding for improved CAR-T production.

Summary: Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.

Abstract Objective Malnourished COVID‐19 patients were prone to higher mortality and longer length of stay (LOS). This study aims to investigate the malnutrition risk prevalence in the COVID‐19 patients and how other nutritional indicators are related to the clinical outcomes in a rehabilitation hospital. Methods A retrospective cross‐sectional study involved 174 COVID‐19 patients during the rehabilitation phase. Malnutrition risk, nutritional indicators, mortality, and LOS were compared among different risk groups. Albumin, nutrition intake, and body mass index (BMI) were investigated for their effects on the clinical outcomes. Results The prevalence of malnutrition risk was 94.9%; those older were higher in malnutrition risk. BMI, energy and protein intakes decreased as the malnutrition risk increased. Albumin, energy and protein intakes were lower in the death group. The high malnutrition risk group and severely underweight patients had 2.7 times and 2.2 times higher in‐hospital death, respectively. For subjects ≥75 years old, the odds ratio to death was 6.2 compared to those