Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation.

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

Assessing the Strategies That Children's Hospitals Adopt to Engage the Social Determinants of Health in US Cities.

CONTEXT: There is growing evidence that social factors contribute disproportionately to health outcomes in the United States as compared with health care services. As a result, nonprofit hospitals are incorporating strategies to address social needs into their Internal Revenue Service (IRS)-mandated community benefit work. Much of the research base on this subject, however, has focused on the efforts of adult-serving hospitals. OBJECTIVE: The aim of this study was to determine whether communities surrounding children's hospitals are unique with regard to social needs and categorize how children's hospitals are addressing social needs in their IRS-mandated community benefit work. METHODS: Using county-level health and economic data, we compared community characteristics of children's hospital counties with the national average. We then coded and analyzed the community benefit reports of all nonprofit children's hospitals in the United States to categorize the different strategies that hospitals adopt to address social needs. RESULTS: Children's hospitals (N = 168) serve communities with greater social needs than the national average. In terms of community benefit investments, children's hospitals were more likely to identify social needs in their community health needs assessment than adult-serving hospitals, but still less than half identified or addressed 1 or more social needs. Children's hospitals were more likely to adopt interventions that address broader population health rather than strategies that focus on clinical services or children and adolescents in particular. CONCLUSIONS: Pediatric health care institutions have a profound opportunity to reduce health disparities by altering the social environments in which children develop. Policy makers and scholars should provide support and resources to increase community benefit investments in this area.

Medical pluralism in maternal health-seeking behavior of rural women in Southern Ecuador.

In rural Ecuador pregnant women face complex challenges navigating the terrain between traditional and biomedical maternal health care services. Semi-structured interviews were conducted in three rural communities in Southern Ecuador that have presented active Chagas disease transmission with women who were pregnant or have given birth within the last five years. This study was conducted to identify and understand the experiences of mothers in these communities and the decisions they make to maintain the wellness of themselves and their children. The researchers recorded women's maternal health stories, analyzed their access to maternal health care, and explored factors influencing their birth location preferences and health seeking behaviors. The researchers found that women in this region are utilizing medical pluralism to sustain maternal health and the well-being of their children.

Availability of Evidence-Based Diabetes Programs in U.S. Children's Hospitals.

Diabetes affects Americans across the lifespan requiring individual and community-level interventions for prevention and management. Nonprofit hospitals are required to address community health needs under current tax law. The study objective was to assess what strategies children's hospitals implemented in prevention and care of diabetes and determine how many hospitals used evidence-based strategies. We identified the most recent Children's Hospital Needs Assessments and implementation strategies for each hospital. Data were thematically coded. Twenty-nine of the 233 U.S. children's hospitals addressed diabetes in their community benefit investments. Of the 130 hospital programs, 48 (37%) aligned with the DSMES framework. Programs focused on prevention (32%), healthy eating (18%), education (15%), physical activity (12%), quality improvement (11%), and self-management (5%). Most children's hospital interventions (85%) did not state a focus on reducing health disparities and none addressed problem solving or diabetes technology. Minimal hospitals are using evidence-based programming for diabetes management and are not targeting health disparities which undercuts their efforts. Hospitals are not adopting structural evidence-based approaches, missing key opportunities to implement strategies shown to reduce diabetes prevalence and lower A1c. This study suggests that children's hospitals need improvement in their diabetes programming to better serve their communities.

Spontaneous Pneumothorax in a Patient with Systemic Lupus Erythematosus and Recent Infection with Coronavirus.

A 50-year-old woman with a history of systemic lupus erythematosus and a recent infection with COVID-19 presented to the emergency department with acute shortness of breath twice in 10 days. She was diagnosed with myopericarditis attributed to COVID-19 infection (first admission), and chest X-ray revealed a small left-sided pneumothorax, pericardial effusion (second admission), with no mediastinal shift or other signs of tension. Computed tomography confirmed these results and revealed a few small cysts in the right lung. An echocardiogram demonstrated normal heart anatomy and filling dynamics. The patient was diagnosed with simple pneumothorax and ongoing myopericarditis managed with colchicine, ibuprofen, and low-dose prednisolone. The patient responded to treatment and was discharged. Pneumothorax association with COVID-19 is reported in a small number of publications, but the association is less clear with SLE. Our patient may have been predisposed to developing pneumothorax after COVID-19 infection due to her existing connective tissue disorder.

A Systematic Review of the safety of non-TNF inhibitor biologic and targeted synthetic drugs in rheumatic disease in pregnancy.

INTRODUCTION: Despite increasing evidence to support safe use of tumour necrosis factor inhibitors (TNFi) and other biologic disease modifying anti-rheumatic drugs (bDMARDs) during pre-conception/pregnancy, there remains a paucity of evidence regarding the safety and compatibility of other non-TNFi and novel targeted synthetic (ts)DMARDs during pre-conception/pregnancy. Therefore, we conducted a systematic review to determine the compatibility of these drugs in pre-conception, during pregnancy and post-partum period. METHOD: Databases including; EMBASE, Pubmed (MEDLINE), and Cochrane were searched up to 23rd October 2020 to find relevant peer-reviewed papers, using keywords including; rheumatic disease, pregnancy, conception/pre-conception, lactation/breastfeeding, childhood and vaccination/infection, and commonly prescribed non-TNFi drugs and tsDMARDs. RESULTS: Our search yielded 1483 papers that were screened independently by two authors, and 109 full-text papers were eligible for final analysis. These studies reported 1291 maternal pregnancies exposed to non-TNFi bDMARDs and tsDMARDs with known outcomes, including 721 live births, 219 spontaneous miscarriages and 27 congenital abnormalities. Paternal exposures in 174 pregnancies had reassuring outcomes. A total of 48 breastfed infants were exposed to non-TNFi bDMARDs and no adverse events reported upon long-term follow-up. Fifteen infants exposed to bDMARDs received normal vaccination regimes, including live vaccines, and had normal developmental outcomes, without any complications or infections. CONCLUSION: Overall, the findings are reassuring and do not suggest a cause for any major concerns or an increased risk of adverse pregnancy outcomes for maternal or paternal exposures to non-TNFi bDMARDs or tsDMARDs. There were no major concerns for breastfeeding exposures to non-TNFi bDMARDs.

Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence.

There is limited evidence relating to the impact of disease modifying anti-rheumatic drugs (DMARDs) upon male fertility and peri-conception paternal exposure in men with rheumatic disease. Therefore, we conducted a systematic review of available evidence to update information on this subject and guide paternal counselling. A systematic search of PubMed and Embase was carried out up to September 2017, to find relevant peer-reviewed papers, using keywords for fertility/spermatogenesis/conception, men, and disease modifying or biologic drugs commonly prescribed in patients with rheumatic disease. The search yielded 724 papers, and the titles/abstracts were screened independently by 2 authors, duplicates removed and 233 potentially relevant papers selected for full text review. A total of 84 papers were included in the final analysis which covered the impact on fertility of over 611 male exposures to relevant drugs, and over 5986 pregnancies conceived during paternal exposure to (or within 3 months of stopping) these drugs. Aside from the known adverse impact of cyclophosphamide and sulfasalazine on spermatogenesis, overall there was no firm evidence of harm to fertility or pregnancy outcomes with paternal exposure to anti-TNF therapies, abatacept, rituximab, azathioprine, cyclosporine A, hydroxychloroquine, leflunomide, methotrexate or mycophenolate mofetil. There was no evidence found pertaining to the effects of male exposure to IVIG, tacrolimus, golimumab, anakinra or belimumab on fertility or pregnancy outcomes. These results provide further reassurance as to the safety of many DMARDs for men trying to conceive and will be useful when counselling men about risks of anti-rheumatic drugs to fertility and pregnancies, and following accidental conception.

Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Establishment in severe combined immunodeficiency mice of subrenal capsule xenografts and transplantable tumor lines from a variety of primary human lung cancers: potential models for studying tumor progression-related changes.

PURPOSE: Lung cancer is a biologically diverse disease and relevant models reflecting its diversity would facilitate the improvement of existing therapies. With a view to establishing such models, we developed and evaluated xenografts of a variety of human lung cancers. EXPERIMENTAL DESIGN: Using nonobese diabetic/severe combined immunodeficiency mice, subrenal capsule xenografts were generated from primary lung cancer tissue, including moderately and poorly differentiated squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, large cell undifferentiated carcinoma, and carcinosarcoma. After 4 to 12 weeks, xenografts were harvested for serial transplantation and comparison with the original tissue via histologic, chromosomal, and cytogenetic analyses. RESULTS: Xenografts were successfully established. H&E staining showed that xenografts retained major histologic features of the original cancers. Immunohistochemistry and fluorescence in situ hybridization confirmed the human origin of the tumor cells and development in xenografts of murine supportive stroma. Four transplantable lines were developed from rapidly growing tumors (>5 generations), i.e., a small cell lung carcinoma, large cell undifferentiated carcinoma, pulmonary carcinosarcoma, and squamous cell carcinoma. Analyses including spectral karyotyping, comparative genomic hybridization, and fluorescence in situ hybridization, revealed that the xenografts were genetically similar to the original tumors, showing chromosomal abnormalities consistent with karyotypic changes reported for lung cancer. CONCLUSIONS: The subrenal capsule xenograft approach essentially provides a living tumor bank derived from patient material and a means for isolating and expanding specific cell populations. The transplantable tumor lines seem to provide good models for studying various aspects of tumor progression and a platform for developing novel therapeutic regimens, with the possibility of patient-tailored therapies.

Chronic hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is traditionally divided on clinical grounds into acute, subacute, and chronic stages. Most biopsy specimens come from patients in the subacute stage, in which there is a relatively mild, usually peribronchiolar, chronic interstitial inflammatory infiltrate, accompanied in most cases by poorly formed interstitial granulomas or isolated giant cells. However, the pathologic features in the chronic, ie, fibrotic stage, are poorly defined in the literature. These features are important to recognize because the chronic stage of HP is often associated with a poor prognosis. We reviewed 13 cases of chronic HP. Where information was available, exposures to the sensitizing agent had generally occurred over a long period of time. Three patterns of fibrosis were seen: 1) predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci resembling, microscopically, usual interstitial pneumonia (UIP); 2) relatively homogeneous linear fibrosis resembling fibrotic nonspecific interstitial pneumonia (NSIP); and 3) irregular predominantly peribronchiolar fibrosis. In some instances, mixtures of the UIP-like and peribronchiolar patterns were found. In all cases, the presence of scattered poorly formed granulomas, or isolated interstitial giant cells, or sometimes only Schaumann bodies indicated the correct diagnosis. In 7 cases, areas of typical subacute HP were present as well. High-resolution CT scans showed variable patterns ranging from severe fibrosis, in some instances with an upper zone predominance, to predominantly ground glass opacities with peripheral reticulation. We conclude that, at the level of morphology, chronic HP may closely mimic UIP or fibrotic NSIP. If no areas of subacute HP are evident, the presence of isolated giant cells, poorly formed granulomas, or Schaumann bodies is crucial to arriving at the correct diagnosis, and the finding of peribronchiolar fibrosis may be helpful. Despite the presence of extensive fibrosis, some patients responded to removal from exposure and steroid therapy.

Diffuse lung cysts in lymphoid interstitial pneumonia: high-resolution CT and pathologic findings.

Lymphoid interstitial pneumonia is part of a spectrum of pulmonary lymphoproliferative disorders that range from benign, small, and airway-centered cellular infiltrates (follicular bronchiolitis, nodular lymphoid hyperplasia) to low-grade malignant lymphoma. Most of the cases occur in patients with underlying autoimmune disease or immunodeficiency. The characteristic high-resolution computed tomography findings consist of diffuse ground-glass opacities, ill-defined centrilobular nodules, bronchovascular thickening, interlobular septal thickening, and scattered thin-walled cysts. The cysts may be seen in up to 80% of the patients and are typically few in number and measure less than 3 cm in diameter. This case illustrates extensive cysts as the predominant high-resolution computed tomography finding of idiopathic lymphoid interstitial pneumonia in a 64-year-old man who underwent unilateral lung transplant. Such extensive cystic disease and lung transplantation treatment has not been previously described.