Distinct metabolic requirements regulate B cell activation and germinal center responses.

Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.

Transcatheter Valve Replacement in Severe Tricuspid Regurgitation.

BACKGROUND: Severe tricuspid regurgitation is associated with disabling symptoms and an increased risk of death. Data regarding outcomes after percutaneous transcatheter tricuspid-valve replacement are needed. METHODS: In this international, multicenter trial, we randomly assigned 400 patients with severe symptomatic tricuspid regurgitation in a 2:1 ratio to undergo either transcatheter tricuspid-valve replacement and medical therapy (valve-replacement group) or medical therapy alone (control group). The hierarchical composite primary outcome was death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, an improvement of at least 10 points in the score on the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS), an improvement of at least one New York Heart Association (NYHA) functional class, and an improvement of at least 30 m on the 6-minute walk distance. A win ratio was calculated for the primary outcome by comparing all possible patient pairs, starting with the first event in the hierarchy. RESULTS: A total of 267 patients were assigned to the valve-replacement group and 133 to the control group. At 1 year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001). In comparisons of patient pairs, those in the valve-replacement group had more wins than the control group with respect to death from any cause (14.8% vs. 12.5%), postindex tricuspid-valve intervention (3.2% vs. 0.6%), and improvement in the KCCQ-OS score (23.1% vs. 6.0%), NYHA class (10.2% vs. 0.8%), and 6-minute walk distance (1.1% vs. 0.9%). The valve-replacement group had fewer wins than the control group with respect to the annualized rate of hospitalization for heart failure (9.7% vs. 10.0%). Severe bleeding occurred in 15.4% of the valve-replacement group and in 5.3% of the control group (P = 0.003); new permanent pacemakers were implanted in 17.4% and 2.3%, respectively (P<0.001). CONCLUSIONS: For patients with severe tricuspid regurgitation, transcatheter tricuspid-valve replacement was superior to medical therapy alone for the primary composite outcome, driven primarily by improvements in symptoms and quality of life. (Funded by Edwards Lifesciences; TRISCEND II ClinicalTrials.gov number, NCT04482062.).

Triple-helix potential of the mouse genome.

Certain DNA sequences, including mirror-symmetric polypyrimidine•polypurine runs, are capable of folding into a triple-helix­containing non­B-form DNA structure called H-DNA. Such H-DNA­forming sequences occur frequently in many eukaryotic genomes, including in mammals, and multiple lines of evidence indicate that these motifs are mutagenic and can impinge on DNA replication, transcription, and other aspects of genome function. In this study, we show that the triplex-forming potential of H-DNA motifs in the mouse genome can be evaluated using S1-sequencing (S1-seq), which uses the single-stranded DNA (ssDNA)­specific nuclease S1 to generate deep-sequencing libraries that report on the position of ssDNA throughout the genome. When S1-seq was applied to genomic DNA isolated from mouse testis cells and splenic B cells, we observed prominent clusters of S1-seq reads that appeared to be independent of endogenous double-strand breaks, that coincided with H-DNA motifs, and that correlated strongly with the triplex-forming potential of the motifs. Fine-scale patterns of S1-seq reads, including a pronounced strand asymmetry in favor of centrally positioned reads on the pyrimidine-containing strand, suggested that this S1-seq signal is specific for one of the four possible isomers of H-DNA (H-y5). By leveraging the abundance and complexity of naturally occurring H-DNA motifs across the mouse genome, we further defined how polypyrimidine repeat length and the presence of repeat-interrupting substitutions modify the structure of H-DNA. This study provides an approach for studying DNA secondary structure genome-wide at high spatial resolution.

Impact of Right Ventricular Dysfunction on Outcomes in Acute Myocardial Infarction and Cardiogenic Shock: Insights from the National Cardiogenic Shock Initiative.

BACKGROUND: Right ventricular dysfunction (RVD) complicates 30%-40% of cases in acute myocardial infarction (AMI) and cardiogenic shock (CS). There are sparse data on the effects of RVD on outcomes and the impact of providing early left ventricular (LV) mechanical circulatory support (MCS) on RV function and hemodynamics. METHODS AND RESULTS: Between July 2016 and December 2020, 80 sites participated in the study. All centers agreed to treat patients with AMI-CS using a standard protocol emphasizing invasive hemodynamic monitoring and rapid initiation of LV-MCS. RVD was defined as a right atrial (RA) pressure of >12 mm Hg and a pulmonary artery pulsatility index (PAPI) of <1 within 24 hours of the index procedure. The primary outcome was survival to discharge. In a subgroup analysis, data available from the Automated Impella Controller console was used to analyze diastolic suction alarms from LV placement signal and its relation to RVD. A total of 361 patients were included in the analysis, of whom 28% had RVD. The median age was 64 years (interquartile range 55-72 years), 22.7% were female and 75.7% were White. There was no difference in age, sex, or comorbidities between those with or without RVD. Patients with RVD had a higher probability of active CPR during LV-MCS implant (14.7% vs 6.3%), Society for Cardiovascular Angiography and Interventions stage E shock (39.2% vs 23.2%), and higher admission lactate levels (5.1 mg/dL vs 3.0 mg/dL). Survival to discharge was significantly lower among those with RVD (61.8% vs 73.4%, odds ratio 0.89, 95% confidence interval 0.36-0.95, P = .031). This association remained significant in the multivariate analysis. There was no significant difference in hemodynamic variables within 24 hours of LV-MCS support among those with or without RVD. At 24 hours, patients with a CPO of >0.6 W and a PAPi of >1 had a trend toward better survival to discharge compared with those with a CPO of ≤0.6 W and a PAPi of ≤1 (77.1% vs 54.6%, P = .092). Patients with RVD were significantly more likely to have diastolic suction alarms within 24 hours of LV-MCS initiation. CONCLUSIONS: RVD in AMI-CS is common and associated with worse survival to discharge. Early LV-MCS decreases filling pressures rapidly within the first 24 hours and decreases the rate of RVD. Achieving a CPO of >0.6 W and a PAPi of >1 within 24 hours is associated with high survival. Diastolic suction alarms may have usefulness as an early marker of RVD.

Clinical journey for patients with aortic regurgitation: A retrospective observational study from a multicenter database.

BACKGROUND: Data using real-world assessments of aortic regurgitation (AR) severity to identify rates of Heart Valve Team evaluation and aortic valve replacement (AVR), as well as mortality among untreated patients, are lacking. The present study assessed these trends in care and outcomes for real-world patients with documented AR. METHODS: Using a deidentified data set (January 2018-March 2023) representing 1,002,853 patients >18 years of age from 25 US institutions participating in the egnite Database (egnite, Inc.) with appropriate permissions, patients were classified by AR severity in echocardiographic reports. Rates of evaluation by the Heart Valve Team, AVR, and all-cause mortality without AVR were examined using Kaplan-Meier estimates and compared using the log-rank test. RESULTS: Within the data set, 845,113 patients had AR severity documented. For moderate-to-severe or severe AR, respectively, 2-year rates (95% confidence interval) of evaluation by the Heart Valve Team (43.5% [41.7%-45.3%] and 65.4% [63.3%-67.4%]) and AVR (19.4% [17.6%-21.1%] and 46.5% [44.2%-48.8%]) were low. Mortality at 2 years without AVR increased with greater AR severity, up to 20.7% for severe AR (p < 0.001). In exploratory analyses, 2-year mortality for untreated patients with left ventricular end-systolic dimension index > 25 mm/m2 was similar for moderate (34.3% [29.2%-39.1%]) and severe (37.2% [24.9%-47.5%]) AR. CONCLUSIONS: Moderate or greater AR is associated with poor clinical outcomes among untreated patients at 2 years. Rates of Heart Valve Team evaluation and AVR were low for those with moderate or greater AR, suggesting that earlier referral to the Heart Valve Team could be beneficial.

Sirolimus-induced Hypertriglyceridemia Leads to Acute Pancreatitis and Diabetic Ketoacidosis Post Stem Cell Transplant for Sickle Cell Disease.

Sirolimus (mammalian target of rapamycin inhibitor) is a potent immunosuppressive agent, used in patients receiving hematopoietic stem cell transplant (HSCT) for Graft vs Host disease prophylaxis. Compared to calcineurin inhibitors, sirolimus has no neurotoxicity or nephrotoxicity, but sirolimus causes dose-dependent thrombocytopenia, leukopenia, delayed wound healing, hyperlipidemia, and hypertriglyceridemia. Here we report a case of acute pancreatitis and diabetic ketoacidosis in a patient with sickle cell disease post haploidentical family donor HSCT which was managed conservatively without plasmapheresis. Based on our review of the literature, this is the first reported case of developing acute pancreatitis as an adverse effect of sirolimus-induced hypertriglyceridemia leading to diabetic ketoacidosis in a recipient of HSCT.

Loss of flavin-containing monooxygenase 3 modulates dioxin-like polychlorinated biphenyl 126-induced oxidative stress and hepatotoxicity.

Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in adipose tissue and have been linked to cardiometabolic disorders, including fatty liver disease. The toxicity of these compounds is associated with activation of the aryl hydrocarbon receptor (Ahr), leading to the induction of phase I metabolizing enzyme cytochrome P4501a1 (Cyp1a1) and the subsequent production of reactive oxygen species (ROS). Recent research has shown that DLPs can also induce the xenobiotic detoxification enzyme flavin-containing monooxygenase 3 (FMO3), which plays a role in metabolic homeostasis. We hypothesized whether genetic deletion of Fmo3 could protect mice, particularly in the liver, where Fmo3 is most inducible, against PCB 126 toxicity. To test this hypothesis, male C57BL/6 wild-type (WT) mice and Fmo3 knockout (Fmo3 KO) mice were exposed to PCB 126 or vehicle (safflower oil) during a 12-week study, at weeks 2 and 4. Various analyses were performed, including hepatic histology, RNA-sequencing, and quantitation of PCB 126 and F2-isoprostane concentrations. The results showed that PCB 126 exposure caused macro and microvesicular fat deposition in WT mice, but this macrovesicular fatty change was absent in Fmo3 KO mice. Moreover, at the pathway level, the hepatic oxidative stress response was significantly different between the two genotypes, with the induction of specific genes observed only in WT mice. Notably, the most abundant F2-isoprostane, 8-iso-15-keto PGE2, increased in WT mice in response to PCB 126 exposure. The study's findings also demonstrated that hepatic tissue concentrations of PCB 126 were higher in WT mice compared to Fmo3 KO mice. In summary, the absence of FMO3 in mice led to a distinctive response to dioxin-like pollutant exposure in the liver, likely due to alterations in lipid metabolism and storage, underscoring the complex interplay of genetic factors in the response to environmental toxins.

Prevalence and predictors of risk factors for cardiovascular diseases among women aged 15-49 years across urban and rural India: findings from a nationwide survey.

BACKGROUND: Women's health is usually looked upon in terms of their reproductive health. However, cardio-vascular diseases are one of the leading causes of death and disability among women, globally as well as in India. Risk factors of today can be disease of tomorrow. Gradience in level of epidemiological transition is observed across different states. The study aims to estimate the national and regional prevalence, and sociodemographic determinants of biological and behavioural risk factors for cardiovascular diseases. MATERIALS AND METHODS: The present study was conducted among women in the age group of 15 to 49 years using nationally representative sample from fifth round National Family Health Survey in India. The data analysis in the current study included 7,24,115 women in the age group of 15 to 49 years. SPSS version 20 was used for the purpose of analysis. Weighted prevalence was computed for the studied behavioral and biological (dependent variable) risk factors using women specific weights as provided in the dataset. Binary logistic regression model was employed to calculate the adjusted odds ratio (OR) with the corresponding 95% confidence interval (CI) to study the sociodemographic determinants (independent variables) of these risk factors. RESULTS: Highest prevalent risk factor for cardiovascular diseases was reported to be central obesity (78.2%), followed by overweight/obesity (23.9%), oral contraceptive use (13.4%), raised blood pressure (11.8%), raised blood sugar (8.6%), tobacco use (4.0%), and alcohol use (0.7%). Higher odds of all the studied risk factors were reported with increasing age. All of the studied risk factors, except for alcohol consumption [OR (95%CI): 0.9 (0.8-0.96)], had higher odds in rural areas compared to urban areas. Compared to other castes, the odds of tobacco [OR (95% CI): 2.01 (1.91-2.08)] and alcohol consumption [OR (95% CI): 5.76 (5.12-6.28)], and raised blood pressure [OR (95% CI): 1.07(1.04-1.11)] was significantly higher among the people belonging to schedule tribe. CONCLUSION AND RECOMMENDATION: The present study highlights the state-wise disparities in the burden and predictors of risk factors for cardio-vascular diseases among women of reproductive age. The study provides insights to these disparities, and focuses on the need of tailoring the disease prevention and control measures suiting to the local needs.

Elder Mistreatment Documentation by Prehospital Clinicians: An Analysis of the National Emergency Medical Services Information System Database.

OBJECTIVES: Elder mistreatment (EM), encompassing abuse and neglect, is a significant public health issue, affecting up to 10% of community-dwelling older adults annually. Elder mistreatment is a growing concern with a higher prevalence in institutional settings and substantial associated healthcare costs. Prehospital clinicians (PHCs) such as emergency medical technicians and paramedics are uniquely positioned to detect and report EM during their interactions with older adults in their homes. The objective of the study is to describe the rate and characteristics of EM documented by PHCs using the National Emergency Medical Services Information System (NEMSIS) database. METHODS: This study analyzed data from NEMSIS, which includes standardized information about PHC emergency response encounters across the United States. In 2018, 22,532,890 activations were included from 9,599 agencies in 43 states and US territories. Elder mistreatment was identified using specific International Classification of Diseases (ICD) codes related to EM. Demographic data, injury location, and associated physical findings were also examined. RESULTS: Out of 9,605,522 EMS encounters for patients aged ≥60, EM was coded in 1,765 encounters (0.02%). Most EM cases were listed as the cause of injury (64%), followed by the clinician's first impression (25.4%). Physical abuse was the most common type of mistreatment reported (20.8%), followed by sexual abuse (18.2%), neglect (9.7%), and psychological/emotional abuse (0.34%). The median age of patients with documented EM was 72, and 62.3% were female. The most common anatomic locations of injuries were the lower extremities, head, and upper extremities. CONCLUSIONS: Despite the high prevalence of EM, PHCs infrequently document EM in their encounters with older adults. Additional training and comprehensive protocols are needed to improve the identification and reporting of EM, mainly elder neglect. Empowering PHCs through education and protocol development can significantly impact the detection and intervention of EM.

Direct benefit transfer for nutritional support of patients with TB in India-analysis of national TB program data of 3.7 million patients, 2018-2022.

BACKGROUND: Patients with TB have additional nutritional requirements and thus additional costs to the household. Ni-kshay Poshan Yojana(NPY) is a Direct Benefit Transfer (DBT) scheme under the National Tuberculosis Elimination Programme(NTEP) in India which offers INR 500 monthly to all notified patients with TB for nutritional support during the period of anti-TB treatment. Five years after its implementation, we conducted the first nationwide evaluation of NPY. METHODS: In our retrospective cohort study using programmatic data of patients notified with TB in nine randomly selected Indian states between 2018 and 2022, we estimated the proportion of patients who received at least one NPY instalment and the median time to receive the first instalment. We determined the factors associated (i) with non-receipt of NPY using a generalised linear model with Poisson family and log link and (ii) with time taken to receive first NPY benefit in 2022 using quantile regression at 50th percentile. RESULTS: Overall, 3,712,551 patients were notified between 2018 and 2022. During this period, the proportion who received at least one NPY instalment had increased from 56.9% to 76.1%. Non-receipt was significantly higher among patients notified by private sector (aRR 2.10;2.08,2.12), reactive for HIV (aRR 1.69;1.64,1.74) and with missing/undetermined diabetic status (aRR 2.02;1.98,2.05). The median(IQR) time to receive the first instalment had reduced from 200(109,331) days in 2018 to 91(51,149) days in 2022. Patients from private sector(106.9;106.3,107.4days), those with HIV-reactive (103.7;101.8,105.7days), DRTB(104.6;102.6,106.7days) and missing/undetermined diabetic status (115.3;114,116.6days) experienced longer delays. CONCLUSIONS: The coverage of NPY among patients with TB had increased and the time to receipt of benefit had halved in the past five years. Three-fourths of the patients received at least one NPY instalment, more than half of whom had waited over three months to receive the first instalment. NTEP has to focus on timely transfer of benefits to enable patients to meet their additional nutritional demands, experience treatment success and avoid catastrophic expenditure.

Siravedha and Knee Osteoarthritis: A Case Report.

Background: Knee osteoarthritis is a degenerative disease resulting from wear and tear of the articular cartilage. Siravedha is an Ayurvedic surgical procedure of therapeutic blood-letting to manage various diseases including painful musculoskeletal conditions. Case Report: A female patient aged 51 years came to the hospital in the outpatient department of Shalya Tantra (surgery) in the month of June, 2022. She had complaints of pain and swelling in her left knee for six months with difficulty in walking, squatting, and going up and down stairs. Diagnosis was made using the 2016 American College of Rheumatology criteria and knee radiographs. The patient was diagnosed with left knee osteoarthritis of grade II (Kellgren and Lawrence osteoarthritis grading). She was previously treated with non-steroidal anti-inflammatory drugs and physiotherapy in a private hospital with slight relief. Initially, only oral Ayurvedic medicines were prescribed for one month. The patient reported minimal relief in symptoms. All oral medications were stopped. After obtaining written consent and completing diagnostic labs, therapeutic blood-letting by Siravedha was planned and executed. The outcomes of treatment were assessed with the Knee Injury and Osteoarthritis Outcome Score, goniometric readings, and findings of knee radiographs. Result and Discussion: Marked improvement was observed in range of motion of the knee joint and also in the Knee Injury and Osteoarthritis Outcome Scores with a positive impact on quality of life. Sustainability of relief in the follow-up period is suggestive of the fact that Siravedha has a role in alleviating the symptoms and progression of the ailment. Conclusion: Siravedha was found to be effective in knee osteoarthritis in terms of reducing pain and improving range of motion obviating the need for oral medication. This case report provides the first ever evidence on efficacy of Siravedha in knee osteoarthritis and may also serve as a lead for future research.

Time-to-operation delays and in-hospital complications in operative facial trauma: A national analysis.

BACKGROUND: Management of facial fractures is variable. Understanding how time to operative management impacts outcomes can help standardize practice. METHODS: Retrospective analysis of the ACS Trauma Quality Improvement Program (TQIP) database between 2016 and 2019. Adult patients with operative facial fractures were isolated by ICD-10 procedure codes, and further stratified by fracture location, including the mandible, orbit, maxilla, zygoma, and frontal bone. Multivariable logistic regression was conducted to predict in-hospital complications (both surgical and systemic complications) adjusting for time-to-operation, comorbidities, fracture location, AIS, and demographics. RESULTS: 1678 patients with operative facial fractures were identified. The median time-to-operation was 2 days (IQR 1.0-2.0 days). Most patients only had one operative fracture (95 %) and orbital fracture was the most common (44 %). The overall complication rate was higher for those operated after 2 days compared to those operated between 1 and 2 days and within 24 h (2.8 % vs 0.6 % vs 0.7 %; p < 0.001). Patients who were operated on after 48 h exhibited an increased risk of any complication (OR 4.72, 95 % CI 1.49-16.6, p = 0.010) on multivariable models. CONCLUSION: Delays in the management of facial fractures are associated with more in-hospital complications. However, the incidence of short-term postoperative complications remains low. Injury characteristics are the primary predictor of delays in operation, however Hispanic patients independently experienced delays in care.

Transfemoral tricuspid valve replacement and one-year outcomes: the TRISCEND study.

BACKGROUND AND AIMS: For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes. METHODS: The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year. RESULTS: Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III-IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart Association class I or II was achieved in 93.3% (P < .001), Kansas City Cardiomyopathy Questionnaire score increased by 25.7 points (P < .001), and six-minute walk distance increased by 56.2 m (P < .001). All-cause mortality was 9.1%, and 10.2% of patients were hospitalized for heart failure. CONCLUSIONS: In an elderly, highly comorbid population with ≥moderate TR, patients receiving transfemoral EVOQUE transcatheter TV replacement had sustained TR reduction, significant increases in stroke volume and cardiac output, and high survival and low hospitalization rates with improved clinical, functional, and quality-of-life outcomes to one year. Funded by Edwards Lifesciences, TRISCEND ClinicalTrials.gov number, NCT04221490.

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T-follicular helper cells and germinal center B cells.

The Three Prime Repair EXonuclease I (TREX1) is critical for degrading post-apoptosis DNA. Mice expressing catalytically inactive TREX1 (TREX1 D18N) develop lupus-like autoimmunity due to chronic sensing of undegraded TREX1 DNA substrates, production of the inflammatory cytokines, and the inappropriate activation of innate and adaptive immunity. This study aimed to investigate Thelper (Th) dysregulation in the TREX1 D18N model system as a potential mechanism for lupus-like autoimmunity. Comparison of immune cells in secondary lymphoid organs, spleen and peripheral lymph nodes (LNs) between TREX1 D18N mice and the TREX1 null mice revealed that the TREX1 D18N mice exhibit a Th1 bias. Additionally, the T-follicular helper cells (Tfh) and the germinal celter (GC) B cells were also elevated in the TREX1 D18N mice. Targeting Bcl6, a lineage-defining transcription factor for Tfh and GC B cells, with a commercially available Bcl6 inhibitor, FX1, attenuated Tfh, GC, and Th1 responses, and rescued TREX1 D18N mice from autoimmunity. The study presents Tfh and GC B-cell responses as potential targets in autoimmunity and that Bcl6 inhibitors may offer therapeutic approach in TREX1-associated or other lupus-like diseases.

CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs.

Interleukin (IL)-10 is an important regulatory cytokine that can modulate excessive immune mediated injury. Several distinct cell types have been demonstrated to produce IL-10, including most recently CD8+ cytotoxic T lymphocytes (CTLs) responding to respiratory virus infection. Here we report that CD4+ T cell help in the form of IL-2 is required for IL-10 production by CTLs, but not for the induction of CTL effector cytokines. We show that IL-2 derived from CD4+ helper T cells cooperates with innate immune cell-derived IL-27 to amplify IL-10 production by CTLs through a Blimp-1-dependent mechanism. These findings reveal a previously unrecognized pathway that coordinates signals derived from innate and helper T cells to control the production of a regulatory cytokine by CTLs during acute viral infection.

Impact of mail-based continuous positive airway pressure initiation on treatment usage and effectiveness.

PURPOSE: In-person visits with a trained therapist have been standard care for patients initiating continuous positive airway pressure (CPAP). These visits provide an opportunity for hands-on training and an in-person assessment of mask fit. However, to improve access, many health systems are shifting to remote CPAP initiation with equipment mailed to patients. While there are potential benefits of a mailed approach, relative patient outcomes are unclear. Specifically, many have concerns that a lack of in-person training may contribute to reduced CPAP adherence. To inform this knowledge gap, we aimed to compare treatment usage after in-person or mailed CPAP initiation. METHODS: Our medical center shifted from in-person to mailed CPAP dispensation in March 2020 during the COVID-19 pandemic. We assembled a cohort of patients with newly diagnosed obstructive sleep apnea (OSA) who initiated CPAP in the months before (n = 433) and after (n = 186) this shift. We compared 90-day adherence between groups. RESULTS: Mean nightly PAP usage was modest in both groups (in-person 145.2, mailed 140.6 min/night). We did not detect between-group differences in either unadjusted or adjusted analyses (adjusted difference - 0.2 min/night, 95% - 27.0 to + 26.5). CONCLUSIONS: Mail-based systems of CPAP initiation may be able to improve access without reducing CPAP usage. Future work should consider the impact of mailed CPAP on patient-reported outcomes and the impact of different remote setup strategies.

Momentum-resolved superconducting energy gaps of Sr2RuO4 from quasiparticle interference imaging.

Sr2RuO4 has long been the focus of intense research interest because of conjectures that it is a correlated topological superconductor. It is the momentum space (k-space) structure of the superconducting energy gap [Formula: see text] on each band i that encodes its unknown superconducting order parameter. However, because the energy scales are so low, it has never been possible to directly measure the [Formula: see text] of Sr2RuO4 Here, we implement Bogoliubov quasiparticle interference (BQPI) imaging, a technique capable of high-precision measurement of multiband [Formula: see text] At T = 90 mK, we visualize a set of Bogoliubov scattering interference wavevectors [Formula: see text] consistent with eight gap nodes/minima that are all closely aligned to the [Formula: see text] crystal lattice directions on both the α and ß bands. Taking these observations in combination with other very recent advances in directional thermal conductivity [E. Hassinger et al., Phys. Rev. X 7, 011032 (2017)], temperature-dependent Knight shift [A. Pustogow et al., Nature 574, 72-75 (2019)], time-reversal symmetry conservation [S. Kashiwaya et al., Phys. Rev B, 100, 094530 (2019)], and theory [A. T. Rømer et al., Phys. Rev. Lett. 123, 247001 (2019); H. S. Roising, T. Scaffidi, F. Flicker, G. F. Lange, S. H. Simon, Phys. Rev. Res. 1, 033108 (2019); and O. Gingras, R. Nourafkan, A. S. Tremblay, M. Côté, Phys. Rev. Lett. 123, 217005 (2019)], the BQPI signature of Sr2RuO4 appears most consistent with [Formula: see text] having [Formula: see text] [Formula: see text] symmetry.

PIMT Controls Insulin Synthesis and Secretion through PDX1.

Pancreatic beta cell function is an important component of glucose homeostasis. Here, we investigated the function of PIMT (PRIP-interacting protein with methyl transferase domain), a transcriptional co-activator binding protein, in the pancreatic beta cells. We observed that the protein levels of PIMT, along with key beta cell markers such as PDX1 (pancreatic and duodenal homeobox 1) and MafA (MAF bZIP transcription factor A), were reduced in the beta cells exposed to hyperglycemic and hyperlipidemic conditions. Consistently, PIMT levels were reduced in the pancreatic islets isolated from high fat diet (HFD)-fed mice. The RNA sequencing analysis of PIMT knockdown beta cells identified that the expression of key genes involved in insulin secretory pathway, Ins1 (insulin 1), Ins2 (insulin 2), Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Kcnn1 (potassium calcium-activated channel subfamily N member 1), Rab3a (member RAS oncogene family), Gnas (GNAS complex locus), Syt13 (synaptotagmin 13), Pax6 (paired box 6), Klf11 (Kruppel-Like Factor 11), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1) was attenuated due to PIMT depletion. PIMT ablation in the pancreatic beta cells and in the rat pancreatic islets led to decreased protein levels of PDX1 and MafA, resulting in the reduction in glucose-stimulated insulin secretion (GSIS). The results from the immunoprecipitation and ChIP experiments revealed the interaction of PIMT with PDX1 and MafA, and its recruitment to the insulin promoter, respectively. Importantly, PIMT ablation in beta cells resulted in the nuclear translocation of insulin. Surprisingly, forced expression of PIMT in beta cells abrogated GSIS, while Ins1 and Ins2 transcript levels were subtly enhanced. On the other hand, the expression of genes, PRIP/Asc2/Ncoa6 (nuclear receptor coactivator 6), Pax6, Kcnj11, Syt13, Stxbp1 (syntaxin binding protein 1), and Snap25 (synaptosome associated protein 25) associated with insulin secretion, was significantly reduced, providing an explanation for the decreased GSIS upon PIMT overexpression. Our findings highlight the importance of PIMT in the regulation of insulin synthesis and secretion in beta cells.

A Rare Case of True Pancreatic Cyst.

Pancreatic cysts can be true or pseudocysts. True pancreatic cysts in children are rare clinical entities. We present a 23-month-old boy with a cystic lesion in the distal body and tail of the pancreas which on histopathology was found to be a rare true congenital simple cyst of the pancreas.

Gall Bladder Duplication with Choledochal Cyst: A Rare Entity.

A 4-year-old male child presented with complaints of abdominal pain and vomiting along with yellowish discoloration of the eyes. Investigations were suggestive of acute pancreatitis and double gall bladder (GB) with dilated common bile duct (CBD) with intraluminal calculi and Type II choledochal cyst. He underwent surgical resection of double GB with dilated CBD with hepatico-docho-jejunostomy. On follow-up, the patient was asymptomatic. Our case highlights the importance of preoperative diagnosis to deal with increased operative difficulty and complications.