Explore the vast range of titles available.

The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl- into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl- channels in their basolateral membrane. Disrupting barttin/Cl- channel function impaired liquid absorption, and overexpressing barttin/Cl- channels increased absorption. Together, apical CFTR and basolateral barttin/Cl- channels provide an electrically conductive pathway for Cl- flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption.

The airway surface liquid (ASL) plays a crucial role in lung defense mechanisms, and its composition and volume are regulated by the airway epithelium. The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in a rare airway epithelial cell type called an ionocyte. Recently, we demonstrated that ionocytes can increase liquid absorption through apical CFTR and basolateral barttin/chloride channels, while airway secretory cells mediate liquid secretion through apical CFTR channels and basolateral NKCC1 transporters. Th2-driven (IL-4/IL-13) airway diseases, such as asthma, cause goblet cell metaplasia, accompanied by increased mucus production and airway secretions. In this study, we investigate the effect of IL-13 on chloride and liquid transport performed by ionocytes. IL-13 treatment of human airway epithelia was associated with reduced epithelial liquid absorption rates and increased ASL volume. Additionally, IL-13 treatment reduced the abundance of CFTR-positive ionocytes and increased the abundance of CFTR-positive secretory cells. Increasing ionocyte abundance attenuated liquid secretion caused by IL-13. Finally, CFTR-positive ionocytes were less common in asthma and chronic obstructive pulmonary disease and were associated with airflow obstruction. Our findings suggest that loss of CFTR in ionocytes contributes to the liquid secretion observed in IL-13-mediated airway diseases.

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.

The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication. We also show that homology-directed recombination of the HIVCAR gene expression cassette into the CCR5 locus enhances suppression of replicating virus compared with HIVCAR expression alone. This work demonstrates that HIV immunotherapy utilizing potent bNAb-based single-chain variable fragments fused to second-generation CAR signaling domains, delivered directly into the CCR5 locus of T cells by homology-directed gene editing, is feasible and effective. This strategy has the potential to target HIV-infected cells in HIV-infected individuals, which might help in the effort to cure HIV. Rawlings, Wagner, and colleagues show that T cells expressing chimeric antigen receptors based on HIV-neutralizing antibodies can selectively clear HIV-infected cells in culture and demonstrate that the use of gene editing to protect therapeutic T cells from HIV infection can improve their efficacy.

Mantle-derived serpentinites have been detected at magma-poor rifted margins and above subduction zones, where they are usually produced by fluids released from the slab to the mantle wedge. Here we show evidence of a new class of serpentinite diapirs within the external subduction system of the Calabrian Arc, derived directly from the lower plate. Mantle serpentinites rise through lithospheric faults caused by incipient rifting and the collapse of the accretionary wedge. Mantle-derived diapirism is not linked directly to subduction processes. The serpentinites, formed probably during Mesozoic Tethyan rifting, were carried below the subduction system by plate convergence; lithospheric faults driving margin segmentation act as windows through which inherited serpentinites rise to the sub-seafloor. The discovery of deep-seated seismogenic features coupled with inherited lower plate serpentinite diapirs, provides constraints on mechanisms exposing altered products of mantle peridotite at the seafloor long time after their formation. Understanding subduction zone mechanics and resulting volcanism remains challenging. Here, the authors present seismic reflection profiles from the Mediterranean Sea where serpentinite diapirs are present on the external subduction system of the Calabrian Arc and may be linked to recent volcanism at Etna.

Purpose Populations most affected by obesity are not reflected in the patients who undergo bariatric surgery. Gaps in the referral system have been studied, but there is a lack of literature investigating obstacles patients encounter after first contact with bariatric surgery clinics. We aim to identify patient populations at risk for attrition during bariatric surgery evaluation and determine patient reported barriers to bariatric surgical care. Materials and Methods This study was a single institution, retrospective, mixed methods study from 2012 to 2021 comparing patients who underwent bariatric surgery to those that withdrew. Surveys were performed of patients who withdrew, collecting information on patient knowledge, expectations, and barriers. Results This study included 5982 patients evaluated in bariatric surgery clinic. Those who attained bariatric surgery (38.8%) were more likely to be White (81.2 vs. 75.6%, p <0.001), married (48.5 vs. 44.1%, p =0.004), and employed full time (48.2 vs. 43.8%, p =0.01). They were less likely to live in an area with low income (37.1 vs. 40.7%, p =0.01) or poverty (poverty rate 15.8 vs. 17.4, p <0.001). Of the 280 survey respondents, fear of complications, length of insurance approval process, and wait time between evaluation and surgery were the most reported barriers. Conclusion Patients who undergo bariatric surgery were more likely to be White, married, employed full time, and reside in more resourced environments which is not reflective of communities most affected by obesity. The complexity of insurance coverage requirements was a major barrier to bariatric surgery and should be a focus of future healthcare reform. Graphical Abstract

Purpose Ventricular–arterial (V–A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). Methods After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. Results Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l −1 ), arterial d P /d t max (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms −1 ), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p  < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg −1  min −1 , p  < 0.05). Conclusions HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V–A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.

This study aimed to evaluate the effects of a 4-week social, emotional and ethical learning online training (SEELOT) on public school teachers’ stress, well-being, social-emotional learning literacy, positive and negative emotions, attention, motivation, and frustration, and to assess the impact on their classes and personal lives. During the Covid-19 pandemic, teachers from public schools in Brazil ( N  = 333) were invited to participate and were divided into two groups: an active group (SEELOT) and a waiting-list group (WLC). They were evaluated before and after one month. A robust trimmed means ANOVA was used for data analysis. The SEELOT group showed improvements in their well-being, attention, motivation, and frustration, and decreased their stress levels compared to the WLC group. Additionally, a subset of the active group participated in semi-structured interviews and reported developing new skills and knowledge related to human values, emotional management, and the ability to handle the challenges of education.

Background Risk-adjustment (RA) models are used to account for severity of illness in comparing patient outcomes across hospitals. Researchers specify covariates as main effects, but they often ignore interactions or use stratification to account for effect modification, despite limitations due to rare events and sparse data. Three Agency for Healthcare Research and Quality (AHRQ) hospital-level Quality Indicators currently use stratified models, but their variable performance and limited interpretability motivated the design of better models. Methods We analysed patient discharge de-identified data from 14 State Inpatient Databases, AHRQ Healthcare Cost and Utilization Project, California Department of Health Care Access and Information, and New York State Department of Health. We used hierarchical group lasso regularisation (HGLR) to identify first-order interactions in several AHRQ inpatient quality indicators (IQI) - IQI 09 (Pancreatic Resection Mortality Rate), IQI 11 (Abdominal Aortic Aneurysm Repair Mortality Rate), and Patient Safety Indicator 14 (Postoperative Wound Dehiscence Rate). These models were compared with stratum-specific and composite main effects models with covariates selected by least absolute shrinkage and selection operator (LASSO). Results HGLR identified clinically meaningful interactions for all models. Synergistic IQI 11 interactions, such as between hypertension and respiratory failure, suggest patients who merit special attention in perioperative care. Antagonistic IQI 11 interactions, such as between shock and chronic comorbidities, illustrate that naïve main effects models overestimate risk in key subpopulations. Interactions for PSI 14 suggest key subpopulations for whom the risk of wound dehiscence is similar between open and laparoscopic approaches, whereas laparoscopic approach is safer for other groups. Model performance was similar or superior for composite models with HGLR-selected features, compared to those with LASSO-selected features. Conclusions In this application to high-profile, high-stakes risk-adjustment models, HGLR selected interactions that maintained or improved model performance in populations with heterogeneous risk, while identifying clinically important interactions. The HGLR package is scalable to handle a large number of covariates and their interactions and is customisable to use multiple CPU cores to reduce analysis time. The HGLR method will allow scholars to avoid creating stratified models on sparse data, improve model calibration, and reduce bias. Future work involves testing using other combinations of risk factors, such as vital signs and laboratory values. Our study focuses on a real-world problem of considerable importance to hospitals and policy-makers who must use RA models for statutorily mandated public reporting and payment programmes.