Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy.

T-cell-engaging bispecific antibodies (T-BsAb) have produced impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that a complex interplay between immune cells and tumor cells is implicated in the mechanism of action and therefore, understanding immune regulatory mechanisms might provide a clue for how to improve the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In a preclinical model of myeloma, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-B-cell maturation antigen (BCMA) T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to the production of interleukin-10 and inhibition of T-BsAb-mediated CD8 T-cell responses. The activation of Treg cells was also seen in bone marrow samples from myeloma patients after ex vivo treatment with T-BsAb, further supporting that T-BsAb have an impact on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, this information suggests that therapy-induced activation of Treg cells critically regulates anti-tumor immunity elicited by T-BsAb therapy, with important implications for improving the efficacy of such treatment.

Harnessing the cytotoxic granule exocytosis to augment the efficacy of T-cell-engaging bispecific antibody therapy.

T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be established, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This approach reveals interleukin (IL)-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characterization strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cytotoxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.

Disruptions to HIV services due to the COVID pandemic in the USA: a state-level stakeholder perspective.

BACKGROUND: The United States envisions a 90% reduction in HIV infections by 2030. However, the COVID-19 pandemic disrupted the HIV continuum and disproportionately affected access to social and health services for people at the highest vulnerability. This study shows how stakeholders in the State of Michigan handled disruptions and their key recommendations. As a case study, this study adds to the literature about preparedness for future pandemics. METHODS: We interviewed 33 statewide Michigan HIV/AIDS Council members-practitioners, researchers, and community representatives, guiding service planning, improvement, and resource allocations, measuring group cohesiveness using a tested scale. We measured group cohesiveness as a proxy for how individual opinions reflected those of the Council as a group. We used qualitative questions to assess: (1) how the COVID-19 pandemic disrupted HIV prevention; (2) how disruptions were handled; and (3) recommendation to help address disruptions now and in the future. Using thematic analysis, we coded the interviews. RESULTS: We found a high degree of cohesiveness. Participants agreed that the pandemic disrupted HIV prevention services (e.g., HIV testing, PrEP education, referrals to primary care, etcetera) offered by community organizations, hospital clinics, and health departments across the state. In response, they developed online and curbside services to maintain HIV services, abate social isolation, and address structural issues like lack of food and public transportation. We organized results in four categories: (1) HIV service disruptions (e.g., "Housing for women and children who are fleeing a legal situation"); (2) Responses to disruptions (e.g., "Some of them, we would say, hey, weather permitting, we'll come out to your car"); (3) Minoritized groups disproportionately affected (e.g., "Especially in my community, to get people if there's ever a vaccine, Black people are going to be the last people to take it"); and (4) Recommendations (below). CONCLUSIONS: The pandemic unsettled and further exacerbated every aspect of HIV service provision. The main recommendation was to overhaul communication systems between government and organizations offering HIV services to mitigate disruptions and improve the chances of achieving a 90% reduction.

Health-related quality of life of adult and adolescent patients living with alopecia areata in Australia.

INTRODUCTION: To understand the experiences of adolescent and adult patients living with alopecia areata (AA) in Australia regarding symptom severity and the impact on psychosocial well-being and work/classroom productivity. MATERIALS AND METHODS: A cross-sectional online patient survey among adolescent and adult patients diagnosed with AA was recruited via the Australia Alopecia Areata Foundation. Patient-reported outcomes were also assessed. RESULTS: A total of 337 patients (49 adolescents; 288 adults), with a mean ± standard deviation age of 14.7 ± 1.55 and 38.9 ± 13.31 years for adolescents and adults, respectively, were included. In the group with extensive hair loss (Scalp Hair Assessment Patient-Reported Outcome, categories 3 + 4, n = 172), we observed higher emotional symptom and activity limitation scores (Alopecia Areata Patient Priority Outcomes, emotional symptoms: adults 2.5 ± 1.03, adolescents 2.2 ± 1.15; activity limitations: adults 1.4 ± 1.15, adolescents 1.2 ± 0.99). Additionally, in adults, the Alopecia Areata Symptom Impact Scale global score was 4.0 ± 2.10 (symptoms subscale score 4.1 ± 1.91; interference subscale scores 3.8 ± 2.73). Hospital Anxiety and Depression Scale scores were high across participants, irrespective of hair loss extent (adults: anxiety 9.2 ± 3.85, depression 6.6 ± 3.95; adolescents: anxiety 9.7 ± 4.65, depression 5.2 ± 3.59). Work and classroom productivity were substantially impaired due to AA, with 70.5% of adults and 57.1% of adolescents reporting activity impairment, and overall work/classroom impairment reported at 39.2% and 44.9%, respectively. CONCLUSIONS: AA impacts the physical, emotional and psychosocial well-being of both adult and adolescent patients. More extensive hair loss more profoundly impacts those living with AA. Patients may benefit from patient-centred care approaches addressing the impact of hair loss on mental and emotional well-being, daily activities and work productivity.

Critical Dialogue and Capacity-Building Projects Reduced Alcohol and Substance Use in a Randomized Clinical Trial Among Formerly Incarcerated Men.

Background: Rates of alcohol and/or substance use (ASU) among residents of predominantly Black and marginalized communities are similar to ASU rates in White communities. Yet ASU has worse consequences in predominantly Black and marginalized communities (e.g., higher incarceration). Objective: We randomized participants to one of 16 intervention conditions using a 24 full factorial design to optimize a multilevel intervention reducing ASU among 602 formerly incarcerated men with substance-use-disorders (SUD). Candidate intervention components included (1) critical dialogue (CD; six weekly 2-hour-long group sessions vs. no CD sessions), (2) Quality of Life Wheel (QLW; six weekly 1-hour-long group sessions vs. no QLW sessions), (3) capacity building projects (CBP; six weekly 1-hour-long group sessions vs. no CBP sessions), and (4) delivery by a trained peer versus licensed facilitators. Outcome was percentage of days in which participants used alcohol, cocaine, opioid, and/or cannabis in previous 30 days. Results: Intent-to-treat analysis did not meet a priori component selection criteria due to low intervention attendance. After controlling for intervention group attendance (percentage of sessions attended), peer-delivered CD and CBP produced statistically and clinically significant main and interaction effects in ASU over 5 months. Per the multiphase optimization strategy framework, we selected peer-delivered CD and CBP for inclusion as the optimized version of the intervention with a cost of US$1,380 per 10 individuals. No adverse intervention effects occurred. Conclusion: CD and CBP were identified as the only potentially effective intervention components. Future research will examine strategies to improve attendance and test the optimized intervention against standard of care in a randomized-controlled-trial.

Human milk oligosaccharides promote intestinal epithelium regeneration independent of the microbiota during necrotizing enterocolitis.

PURPOSE: Necrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota. METHODS: Broad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5-9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids. RESULTS: HMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth. CONCLUSION: This study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC.

Use of research electronic data capture (REDCap) in a sequential multiple assignment randomized trial (SMART): a practical example of automating double randomization.

BACKGROUND: Adaptive interventions are often used in individualized health care to meet the unique needs of clients. Recently, more researchers have adopted the Sequential Multiple Assignment Randomized Trial (SMART), a type of research design, to build optimal adaptive interventions. SMART requires research participants to be randomized multiple times over time, depending upon their response to earlier interventions. Despite the increasing popularity of SMART designs, conducting a successful SMART study poses unique technological and logistical challenges (e.g., effectively concealing and masking allocation sequence to investigators, involved health care providers, and subjects) in addition to other challenges common to all study designs (e.g., study invitations, eligibility screening, consenting procedures, and data confidentiality protocols). Research Electronic Data Capture (REDCap) is a secure, browser-based web application widely used by researchers for data collection. REDCap offers unique features that support researchers' ability to conduct rigorous SMARTs. This manuscript provides an effective strategy for performing automatic double randomization for SMARTs using REDCap. METHODS: Between January and March 2022, we conducted a SMART using a sample of adult (age 18 and older) New Jersey residents to optimize an adaptive intervention to increase COVID-19 testing uptake. In the current report, we discuss how we used REDCap for our SMART, which required double randomization. Further, we share our REDCap project XML file for future investigators to use when designing and conducting SMARTs. RESULTS: We report on the randomization feature that REDCap offers and describe how the study team automated an additional randomization that was required for our SMART. An application programming interface was used to automate the double randomizations in conjunction with the randomization feature provided by REDCap. CONCLUSIONS: REDCap offers powerful tools to facilitate the implementation of longitudinal data collection and SMARTs. Investigators can make use of this electronic data capturing system to reduce errors and bias in the implementation of their SMARTs by automating double randomization. TRIAL REGISTRATION: The SMART study was prospectively registered at Clinicaltrials.gov; registration number: NCT04757298, date of registration: 17/02/2021.

Necrotizing enterocolitis: recent advances in treatment with translational potential.

Necrotizing enterocolitis (NEC) is one of the most prevalent and devastating gastrointestinal disorders in neonates. Despite advances in neonatal care, the incidence and mortality due to NEC remain high, highlighting the need to devise novel treatments for this disease. There have been a number of recent advancements in therapeutic approaches for the treatment of NEC; these involve remote ischemic conditioning (RIC), stem cell therapy, breast milk components (human milk oligosaccharides, exosomes, lactoferrin), fecal microbiota transplantation, and immunotherapy. This review summarizes the most recent advances in NEC treatment currently underway as well as their applicability and associated challenges and limitations, with the aim to provide new insight into the paradigm of care for NEC worldwide.

Argon inhalation attenuates systemic inflammation and rescues lung architecture during experimental neonatal sepsis.

PURPOSE: Neonatal sepsis is a systemic inflammatory infection common in premature infants and a leading cause of mortality. Argon is an emerging interest in the field of noble gas therapy. Neonates with severe sepsis are frequently mechanically ventilated creating an opportunity for inhalation therapy. We aimed to investigate argon inhalation as a novel experimental therapy in neonatal sepsis. METHODS: Sepsis was established in C57BL/6 neonatal mice by a lipopolysaccharide intraperitoneal injection on postnatal day 9. Septic pup mice were exposed to room air as well as non-septic controls. In the argon group, septic pup mice were exposed to argon (70% Ar, 30% O2) for 6 h in a temperature-controlled environment. RESULTS: At 6 h, survival was significantly enhanced when septic mice received argon compared to septic controls. Serum profiles of cytokine release were significantly attenuated as well as lung architecture restored. CONCLUSIONS: Our findings suggest that argon inhalation as a novel treatment for neonatal sepsis, reducing mortality and counteracting the acute systemic inflammatory response in the blood and preserving the architecture of the lung. This research can contribute to a paradigm shift in the treatment and outcome of neonates with sepsis.

Bovine milk-derived exosomes attenuate NLRP3 inflammasome and NF-κB signaling in the lung during neonatal necrotizing enterocolitis.

PURPOSE: Necrotizing enterocolitis (NEC), an inflammatory intestinal disease common in premature infants, has been associated with the development of lung damage. Toll-like receptor 4 has been shown to regulate inflammation in the NEC lungs, however, other important inflammatory mechanisms have not been thoroughly investigated. In addition, we reported that milk-derived exosomes were able to attenuate intestinal injury and inflammation in experimental NEC. This study aims to (i) investigate the role of the NLRP3 inflammasome and NF-κB pathway in regulating lung damage during experimental NEC; and (ii) evaluate the therapeutic potential of bovine milk exosomes in reducing lung inflammation and injury during NEC. METHODS: NEC was induced by gavage feeding of hyperosmolar formula, hypoxia, and lipopolysaccharide administration in neonatal mice from postnatal days 5-9. Exosomes were obtained by ultracentrifugation of bovine milk and administered during each formula feed. RESULTS: The lung of NEC pups showed increased inflammation, tissue damage, NLRP3 inflammasome expression, and NF-κB pathway activation, which were attenuated upon exosome administration. CONCLUSION: Our findings suggest that the lung undergoes significant inflammation and injury following experimental NEC which are attenuated by bovine milk-derived exosomes. This emphasizes the therapeutic potential of exosomes not just on the intestine but also on the lung.

The sanctity of life: The role of purity in attitudes towards abortion and euthanasia.

Although abortion and euthanasia are highly contested issues at the heart of the culture war, the moral foundations underlying ideological differences on these issues are mostly unknown. Given that much of the extant debate is framed around the sanctity of life, we argued that the moral foundation of purity/sanctity-a core moral belief that emphasises adherence to the "natural order"-would mediate the negative relationship between conservatism and support for abortion and euthanasia. As hypothesised, results from a nation-wide random sample of adults in New Zealand (N = 3360) revealed that purity/sanctity mediated the relationship between conservatism and opposition to both policies. These results demonstrate that, rather than being motivated by a desire to reduce harm, conservative opposition to pro-choice and end-of-life decisions is (partly) based on the view that ending a life, even if it is one's own, violates God's natural design and, thus, stains one's spiritual purity.

Medication Safety in Dialysis Care.

The outpatient dialysis setting presents unique challenges in the medication process. Dialysis staff conduct all steps in the medication process, including transcribing and verifying orders, preparing and administering medications, and monitoring for therapeutic and adverse effects. When addressing best medication practices, consideration should be given to education and resources provided to staff. This article explores the multiple strategies taken by a national dialysis network to support clinical staff and improve patient safety.

Ion Transporter Gene Families as Physiological Targets of Natural Selection During Salinity Transitions in a Copepod.

Salinity is a key factor that structures biodiversity on the planet. With anthropogenic change, such as climate change and species invasions, many populations are facing rapid and dramatic changes in salinity throughout the globe. Studies on the copepod Eurytemora affinis species complex have implicated ion transporter gene families as major loci contributing to salinity adaptation during freshwater invasions. Laboratory experiments and population genomic surveys of wild populations have revealed evolutionary shifts in genome-wide gene expression and parallel genomic signatures of natural selection during independent salinity transitions. Our results suggest that balancing selection in the native range and epistatic interactions among specific ion transporter paralogs could contribute to parallel freshwater adaptation. Overall, these studies provide unprecedented insights into evolutionary mechanisms underlying physiological adaptation during rapid salinity change.

Intestinal epithelial tight junctions and permeability can be rescued through the regulation of endoplasmic reticulum stress by amniotic fluid stem cells during necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases affecting premature infants. It has been shown that NEC is associated with disrupted intestinal barrier and dysregulated endoplasmic reticulum (ER)-stress response. It has also been shown that stem cells derived from amniotic fluid (AFSC) rescued intestinal injury in experimental NEC. Herein, we hypothesized that the beneficial effects of AFSC in the injured intestine are due to the restoration of intestinal barrier function. We evaluated intestinal barrier function using an ex vivo intestinal organoid model of NEC. We found that AFSC restored the expression and localization of tight junction proteins in intestinal organoids, and subsequently decreased epithelial permeability. AFSC rescued tight junction expression by inducing a protective ER stress response that prevents epithelial cell apoptosis in injured intestinal organoids. Finally, we validated these results in our experimental mouse model of NEC and confirmed that AFSC induced sustained ER stress and prevented intestinal apoptosis. This response led to the restoration of tight junction expression and localization, which subsequently reduced intestinal permeability in NEC pups. These findings confirm that intestinal barrier function is disrupted during NEC intestinal injury, and further demonstrate the disruption can be reversed by the administration of AFSC through the activation of the ER stress pathway. This study provides insight into the pathogenesis of NEC and highlights potential therapeutic targets for the treatment of NEC.

Amniotic fluid stem cell administration can prevent epithelial injury from necrotizing enterocolitis.

BACKGROUND: Stem cell therapy has been proven to rescue intestinal injury and stimulate intestinal regeneration in necrotizing enterocolitis (NEC). Specifically, stem cells derived from amniotic fluid (AFSCs) and mesenchymal stem cells (MSCs) derived from bone marrow have shown promising results in the treatment of experimental NEC. This study aims to examine the effects of AFSCs and MSCs on the prevention of intestinal injury during experimental NEC. METHODS: Supernatants from AFSC and MSC cultures were collected to perform proteomic analysis. Prior to NEC induction, mice received intraperitoneal injections of phosphate-buffered saline (PBS), 2 × 106 AFSCs, or 2 × 106 MSCs. RESULTS: We found that AFSCs grew faster than MSCs. Proteomic analysis indicated that AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. Administering AFSCs before NEC induction decreased NEC severity and mucosal inflammation. Intestinal proliferation and endogenous stem cell activation were increased after AFSC administration. However, administering MSCs before NEC induction had no beneficial effects. CONCLUSIONS: This study demonstrated that AFSCs and MSCs have different protein release profiles. AFSCs can potentially be used as a preventative strategy for neonates at risk of NEC, while MSCs cannot be used. IMPACT: AFSCs and MSCs have distinct protein secretory profiles, and AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. AFSCs are unique in transiently enhancing healthy intestinal epithelial cell growth, which offers protection against the development of experimental NEC. The prevention of NEC via the administration of AFSCs should be evaluated in infants at great risk of developing NEC or in infants with early signs of NEC.

Comparison of pelvic incidence measurement using lateral x-ray, standard ct versus ct with 3d reconstruction.

PURPOSE: Pelvic incidence (PI) is a position independent parameter used to quantify spinopelvic sagittal balance. PI is generally measured on lateral radiographs, but more recent studies have suggested better accuracy with standard CT scans versus three-dimensional (3D) CT scans. This study compares PI obtained from lateral XR, standard CT scan and CT scan with 3D reconstruction. METHODS: A total of 77 subjects with lateral XRs of the pelvis or lumbosacral spine and CT scans of the pelvis were randomly selected. Pelvic incidence on lateral XRs, standard CT scans and CT scans utilizing multiplanar reconstruction were measured and compared using intraclass correlation coefficients (ICC). PI was also measured on serial images in 28 individuals using the same imaging modality within 3 years and evaluated using ICC. RESULTS: Mean ± SD of PI measurements on XR, standard CT and CT with 3D reconstruction were 56° ± 13°, 53° ± 12° and 53° ± 12°, respectively, demonstrating a small but significant elevation of PI measurement on XR (P < 0.001). ICC values demonstrated a higher correlation between standard CT and 3D CT (ICC 0.986), compared to XR and standard CT (ICC 0.934) and XR and 3D CT (ICC 0.937). PI measurements on repeated imaging of the same individual also demonstrated that both CT methods produced more consistent measurements (ICC 0.986 for standard CT, 0.981 for 3D CT, 0.935 for XR). CONCLUSION: Although standard XR does provide a high level of reliability, it appears to slightly overestimate PI. CT scans do provide increased reliability, with no additional benefit of 3D reconstructions over standard CT.

Clinical Features of Patients Presenting to the Emergency Department With Cardiovascular Adverse Reactions After COVID-19 mRNA Vaccination.

BACKGROUND: Since the implementation of the nationwide coronavirus disease 2019 (COVID-19) vaccination campaign, emergency departments (EDs) have had an increasing number of patients reporting postvaccination cardiovascular adverse effects. We investigated the clinical features of patients who visited the ED for cardiovascular adverse reactions after COVID-19 mRNA vaccination. METHODS: We conducted a retrospective observational study in two EDs. Patients with cardiovascular adverse reactions after COVID-19 mRNA vaccination who visited EDs between June 1, 2021, and October 15, 2021, were selected. The clinical data of these patients were collected by reviewing medical records. RESULTS: Among 683 patients, 426 (62.4%) were female. The number of patients in their 20s was the highest (38.9% of males, 28.2% of females) (P < 0.001). More patients visited the ED for adverse reactions following the first vaccine dose than following the second dose (67.6% vs. 32.2%). Chief complaints were chest pain/discomfort (74.4%), dyspnea (14.3%) and palpitation (11.3%). The final diagnosis was a nonspecific cause (63.1%), and 663 (97.1%) patients were discharged from the ED. The admission rate was higher in males than in females (3.9% vs. 1.9%). Myocarditis was diagnosed in four males, who showed mild clinical progression and were discharged within 5 hospital days. CONCLUSION: Most patients who visited the ED with cardiovascular adverse reactions were discharged from the ED, but some were admitted for other medical diseases as well as adverse vaccine reactions. Therefore, further surveillance and a differential diagnosis of cardiovascular adverse events after COVID-19 mRNA vaccination should be considered by emergency physicians.

Graduate medical education-led continuous assessment of burnout and learning environments to improve residents' wellbeing.

BACKGROUND: Promoting residents' wellbeing and decreasing burnout is a focus of Graduate Medical Education (GME). A supportive clinical learning environment is required to optimize residents' wellness and learning. OBJECTIVE: To determine if longitudinal assessments of burnout and learning environment as perceived by residents combined with applying continuous quality Model for Improvement and serial Plan, Do, Study, Act (PDSA) cycles to test interventions would improve residents' burnout. METHODS: From November 2017 to January 2020, 271 GME residents in internal medicine, general surgery, psychiatry, emergency medicine, family medicine and obstetrics and gynecology, were assessed over five cycles by Maslach Burnout Inventory (MBI), and by clinical learning environment factors (which included personal/social relationships, self-defined burnout, program burnout support, program back-up support, clinical supervision by faculty, and sleep difficulties). The results of the MBI and clinical learning environment factors were observed and analyzed to determine and develop indicated Institutional and individual program interventions using a Plan, Do, Study, Act process with each of the five cycles. RESULTS: The response rate was 78.34%. MBI parameters for all GME residents improved over time but were not statistically significant. Residents' positive perception of the clinical supervision by faculty was significantly and independently associated with improved MBI scores, while residents' self-defined burnout; and impaired personal relations perceptions were independently significantly associated with adverse MBI scores on liner regression. For all GME, significant improvements improved over time in residents' perception of impaired personal relationships (p < 0.001), self-defined burnout (p = 0.013), program burn-out support (p = 0.002) and program back-up support (p = 0.028). For the Internal Medicine Residency program, there were statistically significant improvements in all three MBI factors (p < 0.001) and in clinical learning environment measures (p = 0.006 to < 0.001). Interventions introduced during the PDSA cycles included organization-directed interventions (such as: faculty and administrative leadership recruitment, workflow interventions and residents' schedule optimization), and individual interventions (such as: selfcare, mentoring and resilience training). CONCLUSION: In our study, for all GME residents, clinical learning environment factors in contrast to MBI factors showed significant improvements. Residents' positive perception of the clinical learning environment was associated with improved burnout measures. Residents in separate programs responded differently with one program reaching significance in all MBI and clinical learning environment factors measured. Continuous wellbeing assessment of all GME residents and introduction of Institutional and individual program interventions was accomplished.

Remote ischemic conditioning causes CD4 T cells shift towards reduced cell-mediated inflammation.

PURPOSE: Necrotizing enterocolitis (NEC) is a gastrointestinal disease in neonates that is associated with immune-mediated intestinal inflammation. Remote ischemic conditioning (RIC) applied to a limb has been shown to be protective against experimental NEC. In this study, we explore the immune cell-mediated response involved in NEC and the immunomodulatory effects of RIC in an experimental mouse model of the disease. METHODS: NEC was induced in C57BL/6 mice (ethical approval #58119) pups on postnatal day5 (p5) using gavage hyperosmolar formula, lipopolysaccharide, and hypoxia. RIC consisted of 4 cycles of 5 min ischemia followed by 5 min reperfusion of the right hindlimb during NEC induction on p6 and p8. Breastfed mice were used as control. The mice were sacrificed on p9, with ileal tissue evaluated for inflammatory cytokines and by characterization of T-cell populations. RESULTS: NEC mice had increased number of CD4+ cells indicating an accumulation of T-cells in the mesenchyme of the NEC ileum. Compared to control, NEC pups had upregulated expression pro-inflammatory cytokines (GATA3, IFNγ, IL1ß, IL6, IL17, IL22, and TNFα) and reduced anti-inflammatory cytokine (TGFß). In NEC, there was also a shift in the balance of Treg/Th17 cells towards Th17. Compared to NEC alone, RIC during the course of NEC resulted in reduction of pro-inflammatory cytokines (GATA3, IFNγ, IL1ß, IL6, IL17, IL22, and TNFα), increase in anti-inflammatory cytokine TGFß and concomitant shift back of Th17 cells towards Treg cells. CONCLUSION: In experimental NEC, remote ischemic conditioning reduces the production of pro-inflammatory markers and increases the production of anti-inflammatory markers. In addition, during NEC, RIC reverses the imbalance of Treg/Th17 providing support for its effect on cell-mediated inflammation. RIC is a non-invasive physical maneuver that can have a significant beneficial effect in reducing the inflammation seen in NEC.

Testing a digitally distributed method to recruit a network of community organizations to fight the consequences of the drug epidemic: A study in 13 American states.

To mitigate the opioid epidemic, a concerted effort to educate, prevent, diagnose, treat, and engage residents is required. In this study, a digitally distributed method to form a large network of organizations was tested with 99 counties in regions with high vulnerability to hepatitis C virus (HCV). The method involved a cascade of contacts going from email to phone calls, to videoconferencing and measuring the number of contacts required, amount of time taken, and the proportion of success at recruiting at least one community organization per county. A recruitment period of 5 months and 2118 contact attempts led to the recruitment of organizations from 73 out of our 99 target counties. Organizations belonging to health departments required more attempts and time to recruit but ultimately enrolled at higher rates than did other organizations such as coalitions and agencies. Organizations from counties more (vs. less) vulnerable to HCV outbreaks required more attempts to recruit and, using multiple recruitment methods (e.g., emails, phone calls, and Zoom meetings), improved enrollment success. Overall, this method proved to be successful at remotely engaging a large-scale network of communities with different levels of risk within a large geographic region.