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J Andrew Woods,1 James S Wheeler,1 Christopher K Finch,2 Nathan A Pinner3 1School of Pharmacy, Wingate University, Wingate, NC, USA; 2Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA; 3Harrison School of Pharmacy, Auburn University, Auburn, AL, USA Background: Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease that affects an estimated 10% of the world's population over the age of 40 years. Worldwide, COPD ranks in the top ten for causes of disability and death. Given the significant impact of this disease, it is important to note that acute exacerbations of COPD (AECOPD) are by far the most costly and devastating aspect of disease management. Systemic steroids have long been a standard for the treatment of AECOPD; however, the optimal strategy for dosing and administration of these medications continues to be debated. Objective: To review the use of corticosteroids in the treatment of acute exacerbations of COPD. Materials and methods: Literature was identified through PubMed Medline (1950–February 2014) and Embase (1950–February 2014) utilizing the search terms corticosteroids, COPD, chronic bronchitis, emphysema, and exacerbation. All reference citations from identified publications were reviewed for possible inclusion. All identified randomized, placebo-controlled trials, meta-analyses, and systematic reviews evaluating the efficacy of systemic corticosteroids in the treatment of AECOPD were reviewed and summarized. Results: The administration of corticosteroids in the treatment of AECOPD was assessed. In comparison to placebo, systemic corticosteroids improve airflow, decrease the rate of treatment failure and risk of relapse, and may improve symptoms and decrease the length of hospital stay. Therefore, corticosteroids are recommended by all major guidelines in the treatment of AECOPD. Existing literature suggests that low-dose oral corticosteroids are as efficacious as high-dose, intravenous corticosteroid regimens, while minimizing adverse effects. Recent data suggest that shorter durations of corticosteroid therapy are as efficacious as the traditional treatment durations currently recommended by guidelines. Conclusion: Systemic corticosteroids are efficacious in the treatment of AECOPD and considered a standard of care for patients experiencing an AECOPD. Therefore, systemic corticosteroids should be administered to all patients experiencing AECOPD severe enough to seek emergent medical care. The lowest effective dose and shortest duration of therapy should be considered. Keywords: chronic obstructive pulmonary disease, exacerbation

Prolonged intense exercise causes immunosuppression, whereas moderate-intensity exercise improves immune function and potentially reduces risk and severity of respiratory viral infections. Here, based on available evidence, we present a model whereby moderate exercise-induced increases in stress hormones reduce excessive local inflammation and skew the immune response away from a TH1 and toward a TH2 phenotype, thus improving outcomes after respiratory viral infections. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: Arterial stiffening with aging causes early return of reflected arterial pressure waves from peripheral arteries and augmentation of these waves on incident aortic pressure waves. The purpose of this study was to examine the relationship between pressure wave reflection and augmentation from peripheral arteries and peripheral sympathetic vasomotion in young and older men. METHODS: Thirty males (15 young, 15 older) participated in this cross-sectional study. Radial artery applanation tonometry was used to derive aortic pressure wave reflection time (Deltat; index of aortic stiffness) and augmentation index (AIx; index of wave reflection intensity). Low frequency (LF) power attained from spectral decomposition of beat-to-beat systolic blood pressure (SBPLF) variability was used as an estimate of sympathetic vasomotor modulation. RESULTS: SBPLF power was higher in older vs younger men (8.0+/-0.9 vs 4.5+/-0.5 mmHg2, p<0.05). Older men had higher AIx (24.0+/-1.8% vs -11.6+/-2.3%, p<0.05) and lower Deltat (138.1+/-1.9 ms vs 185.8+/-5.9 ms, p<0.05) compared with younger males. When ANCOVA was performed with SBPLF power as the covariate, the group differences in AIx75 and Deltat were preserved. Results from multiple regression revealed that, after entering age into the model, SBPLF power was not a significant correlate of AIx or Deltat, accounting for a non-significant 1.2% and 1.1% of the variance, respectively. CONCLUSIONS: These findings suggest that increased blood pressure variability with aging is not related to age-associated increases in aortic stiffness or wave reflection. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that Taiji practice may improve immune function. This study was intended to examine whether 5 months of moderate Taiji and Qigong (TQ) practice could improve the immune response to influenza vaccine in older adults. Fifty older adults (mean age 77.2 +/- 1.3 years) participated in this study (TQ N = 27; wait-list control [CON] N = 23). Baseline pre-vaccine blood samples were collected. All subjects then received the 2003-2004 influenza vaccine during the first week of the intervention. Post-vaccine blood samples were collected 3, 6 and 20 weeks post-intervention for analysis of anti-influenza hemagglutination inhibition (HI) titers. We found a significant (p < 0.05) increase in the magnitude and duration of the antibody response to influenza vaccine in TQ participants when compared to CON. The vaccination resulted in a 173, 130, and 109% increase in HI titer at 3, 6, and 20 weeks post-vaccine, respectively, in the TQ group compared to 58, 54, and 10% in CON. There was a significant between group difference at 3 and 20 weeks post-vaccine and at 20 weeks the TQ group had significantly higher titers compared to the pre-vaccine time point, whereas the CON group did not. A higher percentage of TQ subjects also responded to the influenza A strains with a protective (> 40HI) antibody response (37% TQ vs. 20% CON for the H1N1 strain and 56% TQ vs. 45% CON for the H3N2 strain), but the differences between groups were not statistically significant. Traditional TQ practice improves the antibody response to influenza vaccine in older adults, but further study is needed to determine whether the enhanced response is sufficient to provide definitive protection from influenza infection. [ABSTRACT FROM AUTHOR]

During the 1970s, the Energy Utilization Index (EUI) was introduced in terms of the annual rate of energy used per unit of floor area in site-specific buildings. It indicates energy but not total resource use effectiveness of design alternatives compared to baseline values (i.e., targets). Because of increasing concerns about indoor and outdoor emissions from carbon-based products and processes, an analogous “Carbon Index” (CI) is here introduced as a cradle-tograve design tool for evaluating the performance of design alternatives in terms of carbon emitted throughout the five stages of a building’s lifespan: siting, design, construction, operations, and demolition/recycling. This CI is expressed as equivalent mass of CO2 per unit floor area (CO2e). At each stage, this CI is determined as the sum-of-products of two factors: 1) “Primary Factors” (PF), scalars that are defined and quantified by the designer; and 2) “Carbon Impact Factors” (CIF), which are standardized 2x1 matrices that characterize the PFs in terms of “embodied” CO2e emissions in the materials, assemblies, and equipment that are installed in the building, and as CO2e emissions that are released during the “operations” of the building. This design tool is posited to foster more accurate calculations of carbon emissions for design alternatives.

Pyoderma Gangrenosum is a severe ulcerative disease with a great need for novel therapies. A major barrier to the development of novel therapies is a lack of understanding of disease pathogenesis. We present the results of a proof-of-concept open label clinical trial of IL-23p19 antagonism with Tildrakizumab ion Pyoderma Gangrenosum. Gene expression analysis identified pro-inflammatory genes associated with interferon responses and dendritic cell activity including IFI27, XBP1, SAA1 LGALS3 and STAT3 significantly downregulated in lesional tissue after 12 weeks of therapy. Immunohistochemistry confirmed reduction in IL-17A and IL-17 F positive cells as well as reduction in TNF-a, C5a and IL-1B positive cells in week 12 samples compared to baseline. Significant reduction in serum inflammation was observed via serum proteomics, with IL-8, IL-6, and CASP-8 levels reduced comparable to healthy controls at Week 12. Clinical outcomes demonstrated significant reduction in ulcer size, pain, itch and quality of life outcomes in line with the molecular findings. Differential expression of key inflammatory cytokines such as IL-8, CXCL5, PD-L1, SPP1 and MMP1 were observed in tissue and serum when stratified by clinical responders and non-responders. This data provides insights into the clinical relevance of alterations in molecular markers in pyoderma gangrenosum and the potential for the identification of clinically relevant biomarkers of disease activity., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Together with addressing social determinants of health, culturally safe healthcare provision is essential for closing the health outcomes gap experienced by Aboriginal and Torres Strait Islander (Indigenous) Australians. Rural placements potentially provide students of the health professions with opportunities to enhance their knowledge and skills regarding cultural safety. We used rural placements data systematically collected from allied health students, including commencement- and end-of-placement questionnaire responses, to investigate the determinants of confidence in working with Indigenous people., Methods: The study comprised data from all students who provided survey data at both commencement and end of their first placement directly supervised by the administering University Department of Rural Health during the period 2019-2022. Five-point ordered responses to the question 'How confident do you feel about working with Aboriginal people?' were used to assess student and placement-related determinants of confidence (Confident/Very confident versus other) at baseline and increased confidence (≥ 1 point) during the placement using crude and adjusted multivariable robust Poisson regression., Results: Participating students (N = 489) were from diverse allied health disciplines (including pharmacy n = 94, 19.2%; chiropractic n= 66, 13.5%; physiotherapy n= 65, 13.3%; social work n = 59, 12.1%; and occupational therapy 58, 11.9%). Confidence in dealing with Aboriginal people was lower at commencement among females compared with males (adjusted relative risk [aRR] 0.65; 95% confidence interval [CI] 0.53-0.80), and higher among students of Australian rural origin compared with others (aRR 1.49; CI 1.22-1.83) and those who reported previous experience working with Indigenous people compared with those reporting none (aRR 1.40; CI 1.14-1.72). Placement attributes associated with increased confidence working with Indigenous people between placement commencement and end were interaction with Indigenous people within the placement (aRR 2.32; CI 1.24-4.34), placement model reflecting more structured academic supervision (aRR 1.18; CI 1.02-1.37), and placement length (aRR per additional day 1.002; CI 1.001-1.004). These associations were robust to modelling that accounted for a ceiling effect on increased confidence., Conclusions: While influenced by students' demographic attributes and prior experiences, confidence of allied health students in working with Indigenous people is enhanced during rural placements, particularly through direct contact with Indigenous people., (© 2024. The Author(s).)

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

ObjectiveThis study aimed to investigate potential missed diagnoses of acute rheumatic fever and rheumatic heart disease during hospital-based care among persons subsequently identified with these conditions.MethodsThis retrospective cohort study used linked emergency department and inpatient administrative records from Queensland, Northern Territory, South Australia, and New South Wales during 2003-2018 (varying between jurisdictions by completeness of data) of all persons first identified with acute rheumatic fever or rheumatic heart disease while aged 8-24years. Using coded discharge diagnoses from the preceding 3years, we identified presentations (e.g. joint pains or heart murmur without specific identified cause) that potentially mimic and thereby represent a missed opportunity to detect acute rheumatic fever or rheumatic heart disease. Sociodemographic factors associated with experiencing ≥1 mimic diagnoses were investigated using multivariable logistic regression models.ResultsAmong 1855 persons, 65 (3.5%) (using narrow diagnostic inclusions) and 146 (7.9%) (with broad inclusions) experienced ≥1 mimic diagnosis. Joint disorders predominated. Mimics categorised as 'high-likelihood' (most specific) were more frequent among persons subsequently diagnosed as young adults (18-24years) than as children (8-12years) (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.34-4.47), and those from low-risk ethnic groups (including Australian-born non-Indigenous persons) compared with Aboriginal and Torres Strait Islander peoples (OR 2.44, 95% CI 1.02-5.85).ConclusionMissed opportunities to detect acute rheumatic fever and rheumatic heart disease continue to occur in Australian hospitals, and present disproportionately among persons from demographic groups considered to be at low risk, suggesting the need for enhanced clinical suspicion in these groups.

Gut inflammation can trigger neuroinflammation and is linked to mood disorders. Microbiota-derived short-chain fatty acids (SCFAs) can modulate microglia, yet the mechanism remains elusive. Since microglia do not express free-fatty acid receptor (FFAR)2, but intestinal epithelial cells (IEC) and peripheral myeloid cells do, we hypothesized that SCFA-mediated FFAR2 activation within the gut or peripheral myeloid cells may impact microglia inflammation. To test this hypothesis, we developed a tamoxifen-inducible conditional knockout mouse model targeting FFAR2 exclusively on IEC and induced intestinal inflammation with dextran sodium sulfate (DSS), a well-established colitis model. Given FFAR2's high expression in myeloid cells, we also investigated its role by selectively deleting it in these populations of cells. In an initial study, male and female wild-type mice received 0 or 2% DSS for 5d and microglia were isolated 3d later to assess inflammatory status. DSS induced intestinal inflammation and upregulated inflammatory gene expression in microglia, indicating inflammatory signaling via the gut-brain axis. Despite the lack of significant effects of sex in the intestinal phenotype, male mice showed higher microglial inflammatory response than females. Subsequent studies using FFAR2 knockout models revealed that FFAR2 expression in IECs or immune myeloid cells did not affect DSS-induced colonic pathology (i.e. clinical and histological scores and colon length), or colonic expression of inflammatory genes. However, FFAR2 knockout led to an upregulation of several microglial inflammatory genes in control mice and downregulation in DSS-treated mice, suggesting that FFAR2 may constrain neuroinflammatory gene expression under healthy homeostatic conditions but may permit it during intestinal inflammation. No interactions with sex were observed, suggesting sex does not play a role on FFAR2 potential function in gut-brain communication in the context of colitis. To evaluate the role of FFAR2 activated by microbiota-derived SCFAs, we employed the same knockout and DSS models adding fermentable dietary fiber (0 or 2.5% inulin for 8 wks). Despite no genotype or fiber main effects, contrary to our hypothesis, inulin feeding augmented DSS-induced inflammation and signs of colitis, suggesting context-dependent effects of fiber. These findings highlight microglial involvement in colitis-associated neuroinflammation and advance our understanding of FFAR2's role in the gut-brain axis. Although not integral, we observed that the role of FFAR2 differs between homeostatic and inflammatory conditions, underscoring the need to consider different inflammatory conditions and disease contexts when investigating the role of FFAR2 and SCFAs in the gut-brain axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Cardiovascular disease contributes significantly to disease burden among many Indigenous populations. However, data on stroke incidence in Indigenous populations are sparse. We aimed to investigate what is known of stroke incidence in Indigenous populations of countries with a very high Human Development Index (HDI), locating the research in the broader context of Indigenous health., Methods: We identified population-based stroke incidence studies published between 1990 and 2022 among Indigenous adult populations of developed countries using PubMed, Embase, and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with fewer than 10 Indigenous people, or not covering a 35- to 64-year minimum age range. Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. We assessed quality using "gold standard" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for reporting of Indigenous health research. An Indigenous Advisory Board provided oversight for the study., Results: From 13,041 publications screened, 24 studies (19 full-text articles, 5 abstracts) from 7 countries met the inclusion criteria. Age-standardized stroke incidence rate ratios were greater in Aboriginal and Torres Strait Islander Australians (1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), compared with respective non-Indigenous populations. Studies had substantial heterogeneity in design and risk of bias. Attack rates, male-female rate ratios, and time trends are reported where available. Few investigators reported Indigenous stakeholder involvement, with few studies meeting any of the CONSIDER criteria for research among Indigenous populations., Discussion: In countries with a very high HDI, there are notable, albeit varying, disparities in stroke incidence between Indigenous and non-Indigenous populations, although there are gaps in data availability and quality. A greater understanding of stroke incidence is imperative for informing effective societal responses to socioeconomic and health disparities in these populations. Future studies into stroke incidence in Indigenous populations should be designed and conducted with Indigenous oversight and governance to facilitate improved outcomes and capacity building., Registration Information: PROSPERO registration: CRD42021242367.

Background: Several studies have reported that marathon runners have a higher risk of upper respiratory tract infections (URTI) post marathon than non-exercising controls. However, other studies did not find a higher risk of URTI in the same participants before and after a marathon, precluding a conclusive consensus. Besides the between-subjects effects, another important confounding factor in these results is the different pre and post follow-up time to track URTI., Objectives: Identify by meta-analysis whether a marathon Running increases the risk of URTI, adjusting the follow-up time to track URTI., Data Sources: We searched for articles using MEDLINE (PubMed), Embase, Scopus, Web of Science, the Cochrane Library, and EBSCOhost, combining the marathon and respiratory infection descriptor synonyms, on 1st December 2022., Eligibility Criteria: The PICOS framework included human population, comparison between pre and post marathon running, of URTI symptoms (assessed from one to 4 weeks), in noncontrolled intervention studies., Data Synthesis: Because follow-up was longer before the marathon in many studies, we adjusted the number of subjects with infections before marathon to the equivalent post-marathon follow-up duration. There was 18% higher incidence of URTI post-marathon (OR 1.18 95%CI [1.05-1.33], p= 0.005) in a very consistent meta-analysis (I2 = 0%, p = 0.69), with no risk of publication bias (Egger test p-value = 0.82) for the 7 studies included. The main issues with quality of the studies were bias in measuring the outcome, bias in classification of intervention (participation in the marathon) and time-varying confounding (corrected for analysis), and therefore the quality of evidence was moderate (GRADE approach = 3)., Limitations: The need for follow-up time adjustment is a limitation, since the number of URTI recorded could be different if the original studies had used the same follow-up time pre and post marathon. The subjectivity of the URTI assessments is another limitation in this field., Conclusions: There is an increased risk of URTI post marathon running and research on this topic to understand mechanisms might support runners to find efficient interventions to reduce this risk., Protocol: Protocol registration on in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42022380991., (Copyright © 2016 International Society of Exercise and Immunology. All rights reserved.)

Mast cells have traditionally been associated with allergic inflammatory responses; however, they play important roles in cutaneous innate immunity and wound healing. The Hidradenitis Suppurativa tissue transcriptome is associated with alterations in innate immunity and wound healing-associated pathways; however, the role of mast cells in the disease is unexplored. We demonstrate that mast cell-associated gene expression (using whole tissue RNAseq) is upregulated, and in-silico cellular deconvolution identifies activated mast cells upregulated and resting mast cells downregulated in lesional tissue. Tryptase/Chymase positive mast cells (identified using IHC) localize adjacent to epithelialized tunnels, fibrotic regions of the dermis and at perivascular sites associated with Neutrophil Extracellular Trap formation and TNF-alpha production. Treatment with Spleen Tyrosine Kinase antagonist (Fostamatinib) reduces the expression of mast cell-associated gene transcripts, associated biochemical pathways and the number of tryptase/chymase positive mast cells in lesional hidradenitis suppurativa tissue. This data indicates that although mast cells are not the most abundant cell type in Hidradenitis Suppurativa tissue, the dysregulation of mast cells is paralleled with B cell/plasma cell inflammation, inflammatory epithelialized tunnels and epithelial budding. This provides an explanation as to the mixed inflammatory activation signature seen in HS, the correlation with dysregulated wound healing and potential pathways involved in the development of epithelialized tunnels., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Objective: Suicide is a leading cause of death in the United States. This has prompted the U.S. surgeon general to issue a report describing actionable items to reduce suicide rates, including a recommendation to increase the use of the caring letters intervention. This intervention involves mailing brief, nondemanding messages of care. As part of the Department of Veterans Affairs' (VA's) efforts to reduce suicide rates among veterans, a caring letters project was developed for veterans who contact the Veterans Crisis Line (VCL). This article describes the results of qualitative interviews conducted to better understand the experiences of veterans who received caring letters., Methods: Beginning in 2020, all identifiable veterans who used Veterans Health Administration services and contacted the VCL received nine letters over 1 year, along with a list of mental health resources. Semistructured interviews (N=23) were conducted, and content analysis was used to identify veterans' perspectives and suggestions for improving the intervention., Results: Sixteen men and seven women participated (mean age=53 years). Feedback varied, with most participants reporting that receiving caring letters had a positive impact and others noting aspects that could be improved to enhance the intervention's caring intent. Some also reported that the letters helped them engage with community resources and made them more likely to seek VA care., Conclusions: The caring letters intervention, received after contact with the VCL, was well received by participants. They described feeling appreciated, cared for, encouraged, and connected. The results of this study will inform future evaluation examining veteran outcomes., Competing Interests: Dr. Landes is a consultant for RAND and UTHealth Houston. Dr. Abraham is a consultant for Roche and Strategic Science and Technologies. Dr. Garrido has received grant funding from Arnold Ventures and the Commonwealth Foundation. The other authors report no financial relationships with commercial interests.

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS., Competing Interests: JWF has conducted advisory work for Janssen, Boehringer-Ingelheim, Pfizer, Kyowa Kirin, LEO Pharma, Regeneron, Chemocentryx, Abbvie and UCB, participated in trials for Pfizer, UCB, Boehringer-Ingelheim, Eli Lilly, CSL, Abbvie, Janssen, and received research support from Ortho Dermatologics and Sun Pharma and La Roche Posay. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Flora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Due to the increasing human life expectancy and limited supply of healthcare resources, strategies to promote healthy aging and reduce associated functional deficits are of public health importance. The gut microbiota, which remodels with age, has been identified as a significant contributor to the aging process that is modifiable by diet. Since prebiotic dietary components such as inulin have been shown to impart positive benefits with regards to aging, this study used C57Bl6 mice to investigate whether 8 weeks on a 2.5 % inulin enhanced AIN-93M 1 % cellulose diet could offset age-associated changes in gut microbiome composition and markers of colon health and systemic inflammation in comparison to a AIN 93M 1 % cellulose diet with 0 % inulin. Our results demonstrated that, in both age groups, dietary inulin significantly increased production of butyrate in the cecum and induced changes in the community structure of the gut microbiome but did not significantly affect systemic inflammation or other markers of gastrointestinal health. Aged mice had different and less diverse microbiomes when compared to adult mice and were less sensitive to inulin-induced microbiome community shifts, evidenced by longitudinal differences in differentially abundant taxa and beta diversity. In aged mice, inulin restored potentially beneficial taxa including Bifidobacterium and key butyrate producing genera (e.g. Faecalibaculum). Despite inducing notable taxonomic changes, however, the 2.5 % inulin diet reduced alpha diversity in both age groups and failed to reduce overall community compositional differences between age groups. In conclusion, a 2.5 % inulin enhanced diet altered gut microbiome α and β diversity, composition, and butyrate production in both adult and aged mice, with more potent effects on β diversity and greater number of taxa significantly altered in adult mice. However, significant benefits in age-associated changes in systemic inflammation or intestinal outcomes were not detected., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Family and domestic violence, encompassing diverse behaviours including physical, sexual, emotional and financial abuse, is endemic worldwide and has multiple adverse health and social consequences. Principal drivers include traditional gender values that disempower women. Changing these is a key prevention strategy. In Australia, high-quality national surveys provide data on public perspectives concerning family and domestic violence but may not capture community-level diversity. As part of a project for primary prevention family and domestic violence in outer regional Australia, our aims were to develop and administer a questionnaire-based survey suitable for the local community encompassing knowledge about, attitudes towards, and personal experiences of family and domestic violence, to describe and to investigate the theoretical (factor) structure and local socio-demographic predictors of responses, and to determine the extent to which the survey findings are locally distinctive., Methods: The online community survey for local residents (≥15 years), comprised items on respondents' sociodemographic characteristics plus questions abridged from pre-existing national instruments on knowledge about, attitudes towards, and personal experiences of family and domestic violence. Responses were rake-weighted to correct census-ascertained sample imbalance and investigated using exploratory factor analysis, with sociodemographic predictors determined using multiple linear regression and dominance analysis., Results: Among 914 respondents, males (27.0%), those from age-group extremes, and less-educated persons were underrepresented. Familiarity with diverse family and domestic violence behaviours was high among all subgroups. Poorer knowledge of the FDV behaviour continuum and attitudes supporting traditional gender roles and FDV were disproportionately evident among males, older respondents and those with lower education levels. Both the factor structure of extracted composite measures reflecting community perspectives and sociodemographic predictors of responses generally aligned with patterns evident in national data., Conclusions: Local reinforcement of existing nationwide findings on community understanding of and attitudes towards family and domestic violence provides salience for targeted interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Woods et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Microglia play a vital role maintaining brain homeostasis but can also cause persistent neuroinflammation. Short-chain fatty acids (SCFAs) produced by the intestinal microbiota have been suggested to regulate microglia inflammation indirectly by signaling through the gut-brain axis or directly by reaching the brain. The present work evaluated the anti-inflammatory effects of SCFAs on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber that is fermented by intestinal microbiota to produce SCFAs in vivo, and SCFAs applied to primary microglia in vitro. Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein. Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin. Additionally, when mice were fed inulin and injected i.p with LPS, the ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS. Similarly, in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production with the effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro. Whereas microglia expression of SCFA receptors Ffar2 or Ffar3 was not detected by single-cell RNA sequencing analysis, the SCFA transporters Mct1 and Mct4 were. Nevertheless, inhibiting monocarboxylate transporters on primary microglia did not interfere with the anti-inflammatory effects of SCFAs, suggesting that if SCFAs produced in the gut regulate microglia directly it is likely through an epigenetic mechanism following diffusion., (© 2023. The Author(s).)

Purpose: Endurance exercise alters the gut microbiome independently of diet. The extent to which gut microbes are responsible for physiologic adaptations to exercise training is unknown. The purpose of these experiments was to determine the role of gut microbes in performance and muscle adaptation to 6 wk of voluntary wheel running (VWR) in mice., Methods: We depleted microbes with broad-spectrum antibiotic (ABX) treatment and used germ-free (GF) mice to determine effects on adaptations to VWR. Male and female C57Bl/6 mice ( n = 56) were assigned to daily VWR or sedentary conditions. After the intervention, treadmill endurance and glucose tolerance were assessed, and gastrocnemius and soleus tissues were harvested and analyzed for citrate synthase (CS) enzyme activity and expression of exercise training-sensitive genes., Results: ABX treatment and GF status resulted in VWR volumes ~22% and 26% lower than controls, respectively. Analysis of variance revealed that, although VWR increased treadmill endurance, ABX had no effect. GF status significantly reduced treadmill performance in trained GF mice after training. VWR increased gastrocnemius CS enzyme activity in all groups, and ABX and GF status did not reduce the VWR effect. VWR also increased muscle expression of PGC1a, but this was not affected by ABX treatment., Conclusions: ABX treatment and GF status reduced VWR behavior but did not affect VWR-induced adaptations in endurance capacity, CS activity, or expression of muscle metabolic genes. However, GF status reduced endurance capacity. These data indicated that reducing microbes in adulthood does not inhibit endurance training adaptations in C57Bl/6 mice, but that GF mice possess a reduced responsiveness to endurance exercise training, perhaps because of a developmental defect associated with lack of microbes from birth., (Copyright © 2022 by the American College of Sports Medicine.)

Caring Letters is recommended in multiple best practice guidelines; however, the Caring Letters intervention has not been widely implemented. The process of tracking, scheduling, and mailing letters for multiple patients over many months may represent a significant barrier for busy clinicians. This evaluation examined whether the use of centralized administrative support (Centralized Caring Letters; CCL) was associated with increased utilization of the intervention. These procedures were tested in the Department of Veterans Affairs (VA) Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program. In REACH VET, VA clinicians are routinely asked to consider Caring Letters as one option for veterans identified as at-risk. In this evaluation, clinicians at two VA facilities were offered assistance in the tracking, preparation, mailing, and documentation of Caring Letters for veterans they chose to enroll in CCL. The utilization of Caring Letters increased more than 14-fold after CCL was implemented. In the year that preceded CCL, 3% of REACH VET veterans were sent Caring Letters at the two sites; this increased to 43% of cases after the implementation of CCL (45% at Site 1 and 41% at Site 2). In qualitative interviews with providers, clinicians described Caring Letters as beneficial and stated that the centralized features of the program were helpful. Caring Letters were discontinued for 30% of enrolled veterans, often because of a bad address (9% of enrolled) or relocation (8% of enrolled). Although there are barriers for the use of Caring Letters, CCL was associated with a very large increase in the use of Caring Letters. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Altered gut microbiota composition has been observed in individuals with hidradenitis suppurutiva (HS) and many other inflammatory diseases, including obesity, type 1 and type 2 diabetes. Here, we addressed whether adalimumab, a systemic anti-inflammatory therapy, may impact the microbiota biochemical profile, particularly on beneficial metabolites such as short-chain fatty acids (SCFAs). We conducted an observational single-arm pilot trial to assess gut microbiota composition by 16S rRNA gene sequence analysis and to detect metabolite signatures by gas chromatography in stool samples from participants with HS prior to and 12 weeks after commencing adalimumab therapy. HS individuals that better responded to adalimumab treatment showed a shift in the composition and function of the gut microbiota with significantly increased SCFA acetate and propionate compared to age, gender and BMI-matched healthy controls. A positive correlation was observed between propionate with Prevotella sp and Faecalibacterium prausnitsii. Increased SCFAs, changes in gut microbiota composition, function and metabolic profile following 12 weeks of adalimumab suggest that targeting SCFAs may be considered a potential biomarker to be evaluated as a complementary protective factor or as a diagnostically relevant signal in HS., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Objective: To describe the design, implementation, and plans to evaluate the Veterans Crisis Line (VCL) Caring Letters intervention., Data Sources: Veterans with VCL contact and VHA service utilization., Study Design: Caring Letters is an evidence-based post-acute care suicide prevention intervention in which brief messages are mailed to individuals at high risk of suicide repeatedly over time to communicate that people care about them and are concerned for their well-being. An effectiveness-implementation hybrid type 1 trial using the RE-AIM evaluation framework is underway to examine the use of Caring Letters with veterans who contact the VCL. A team of suicide prevention subject matter experts, researchers, and operational partners from the VCL will evaluate the effects of Caring Letters on clinical outcomes and Department of Veterans Affairs - Veterans Health Administration (VHA) clinical utilization rates and examine facilitators and barriers to implementing the Caring Letters campaign., Data Collection Methods: Veterans who contact the VCL are linked with national administrative VHA data. Semi-structured interviews were conducted as part of a qualitative formative evaluation., Principal Findings: In the first 12 months of the intervention, Caring Letters have been sent to over 100,000 veterans with VCL contact (over 500,000 letters mailed). A formative qualitative evaluation early in implementation revealed a variety of positive veteran perspectives on the intervention., Conclusions: Partnered program design and evaluation with a high level of stakeholder engagement and participant feedback can result in a rigorous and feasible evaluation plan that improves implementation processes and produces actionable results. The initial results of this evaluation will be used to better inform care in the VHA and, specifically, the VCL., (© 2022 Health Research and Educational Trust.)

With increasing age, microglia shift toward a pro-inflammatory phenotype that may predispose individuals to neurodegenerative disease. Because fiber fermentation in the colon produces bioactive short-chain fatty acids (SCFAs; e.g., acetate, butyrate, and propionate) that signal through the gut-brain axis, increasing dietary fiber may prevent or reverse age-related dysregulation of microglia. Adult (3-4 months old) and aged (23-24 months old) male and female mice were given ad libitum access to a modified AIN-93M diet with 1% cellulose or the same diet with 2.5 or 5.0% inulin for 8 weeks. Several adult and aged male mice fed 0 or 5% inulin were randomly selected for whole brain single-cell RNA sequencing (scRNA-seq) and differential gene expression analysis to classify brain microglia according to gene expression profile; and identify additional genetic markers of aging as possible targets for dietary interventions. Microglia were isolated from remaining mice and expression of selected aging-, inflammatory-, and sensome-related genes was assessed by Fluidigm as was the ex vivo secretion of tumor necrosis factor-alpha (TNF-α). SCFAs were measured in samples collected from the cecum. Microglia from adult and aged mice segregated into distinct phenotypes according to their gene expression profile. In aged mice, a considerably greater proportion of the population of microglia was identified being "activated" and a considerably smaller proportion was identified being "quiescent." These findings using whole brain scRNA-seq were largely corroborated using highly purified microglia and Fluidigm analysis to assess a selected panel of genes. Aged mice compared to adults had lower levels of SCFA's in cecum. Dietary inulin increased SCFAs in cecum and mostly restored microglial cell gene expression and TNF-α secretion to that seen in adults. Sex differences were observed with females having lower levels of SCFAs in cecum and increased neuroinflammation. Overall, these data support the use of fiber supplementation as a strategy to counterbalance the age-related microglial dysregulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vailati-Riboni, Rund, Caetano-Silva, Hutchinson, Wang, Soto-Díaz, Woods, Steelman and Johnson.)

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with high rates of hospitalizations, costs, and morbidity. Therefore, hospitalists and the multidisciplinary team (hospital team) need to take a proactive approach to ensure patients are effectively managed from hospital admission to postdischarge. Comprehensive screening and diagnostic testing of patients at admission will enable an accurate diagnosis of COPD exacerbations, and severity, as well as other factors that may impact the length of hospital stay. Depending on the exacerbation severity and cause, pharmacotherapies may include short-acting bronchodilators, systemic corticosteroids, and antibiotics. Oxygen and/or ventilatory support may benefit patients with demonstrable hypoxemia. In preparation for discharge, the hospital team should ensure that patients receive the appropriate maintenance therapy, are counseled on their medications including inhalation devices, and proactively discuss smoking cessation and vaccinations. For follow-up, effective communication can be achieved by transferring discharge summaries to the primary care physician via an inpatient case manager. An inpatient case manager can support both the hospitalist and the patient in scheduling follow-up appointments, sending patient reminders, and confirming that a first outpatient visit has occurred. A PubMed search (prior to 26 January 2021) was conducted using terms such as: COPD, exacerbation, hospitalization. This narrative review focuses on the challenges the hospital team encounters in achieving optimal outcomes in the management of patients with COPD exacerbations. Additionally, we propose a novel simplified algorithm that may help the hospital team to be more proactive in the diagnosis and management of patients with COPD exacerbations.

Purpose: A case of delayed statin associated autoimmune myopathy (SAAM) is presented along with review of clinical findings and treatment strategies., Summary: A 54 year old male presented with proximal extremity weakness, difficulty ambulating, and dysphagia. Symptoms began when restarting atorvastatin 40 mg daily for a recent NSTEMI, following 10 years of statin use, interrupted after diagnosis of NASH. Relevant labs included CK of 13,618 IU/L, ALT/ AST of 568/407 IU/L, while additional liver, renal, and toxicology tests were normal. Following treatment response to prednisone 40 mg daily for 3 days, outpatient testing for anti-HMGCR antibodies was ordered.Twelve days from discharge, the patient was readmitted for myalgia and dysphagia, CK = 6042 IU/L, ALT/AST = 360/112 IU/L, and positive anti-HMGCR antibodies. Newly diagnosed with SAAM, symptoms improved with methylprednisolone and intravenous immunoglobulin (IVIG), continuing outpatient as daily prednisone and monthly IVIG. Four days later, the patient relapsed with worsened weakness and dysphagia, CK = 5812 IU/L, and ALT/AST = 647/337 IU/L. After response to methylprednisolone and rituximab, the patient was discharged on a corticosteroid taper, biweekly rituximab, and monthly IVIG. Two weeks later, a final admission involved a syncopal episode and fall, with a CK = 1461 IU/L. Treatment included IVIG, rituximab, and corticosteroid taper, which lead to remission for greater than 6 months., Conclusion: Statin associated autoimmune myopathy occurred when restarting atorvastatin, following 10 years of statin use. Clinical findings and positive anti-HMGCR antibodies confirmed the diagnosis. Recurrent relapses required triple combination therapy including addition of rituximab to achieve remission.

Transitions in care, such as discharge from an emergency department (ED), are periods of increased risk for suicide and effective interventions that target these periods are needed. Caring Contacts is an evidence-based suicide prevention intervention that targets transitions, yet it has not been widely implemented. This pilot study adapted Caring Contacts for a Department of Veterans Affairs (VA) ED setting and population, created an implementation toolkit, and piloted implementation and evaluation of effectiveness. To inform adaptation, qualitative interviews were conducted with stakeholders. Data were used by an advisory board comprised of stakeholders, experts, and veterans to make adaptations and develop an implementation planning guide to delineate steps needed to implement. Key decisions about how to adapt Caring Contacts included recipients, author, content, and the schedule for sending. Pilot implementation occurred at one VA ED. Caring Contacts involved sending patients at risk of suicide brief, non-demanding expressions of care. Program evaluation of the pilot used a type 2 hybrid effectiveness-implementation design to both pilot an implementation strategy and evaluate effectiveness of Caring Contacts. Evaluation included qualitative interviews with veteran patients during implementation. VA electronic health records were used to evaluate VA service utilization in the 6-month periods immediately before and after veterans were delivered their first Caring Contact. Hundred and seventy-five veterans were mailed Caring Contacts and the facility continued adoption after the pilot. Participants were positive about the intervention and reported feeling cared about and connected to VA as a result of receiving Caring Contacts. This project developed an implementation planning process that successfully implemented Caring Contacts at one site. This can be used to further implement Caring Contacts at additional VA or community EDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Landes, Jegley, Kirchner, Areno, Pitcock, Abraham, McBain, Singh, Bollinger, Painter, Woods, Curtis, Jones, Matarazzo, Reger and Comtois.)

Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4. Complexes 1 and 2 showed greater photocytotoxicity than 4 when irradiated with 420 nm light (A2780 cell line IC50 values: 2.7 and 3.7 μM) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 μM). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pKa(H2O) of 5.13 for the free carboxylate group was determined for 1, corresponding to an overall negative charge during biological experiments, which crucially, did not appear to impede cellular accumulation and photocytotoxicity.

Background and Aims: Despite known Indigenous health and socioeconomic disadvantage in countries with a Very High Human Development Index, data on the incidence of stroke in these populations are sparse. With oversight from an Indigenous Advisory Board, we will undertake a systematic review of the incidence of stroke in Indigenous populations of developed countries or regions, with comparisons between Indigenous and non-Indigenous populations of the same region, though not between different Indigenous populations. Methods: Using PubMed, OVID-EMBASE, and Global Health databases, we will examine population-based incidence studies of stroke in Indigenous adult populations of developed countries published 1990-current, without language restriction. Non-peer-reviewed sources, studies including <10 Indigenous People, or with insufficient data to determine incidence, will be excluded. Two reviewers will independently validate the search strategies, screen titles and abstracts, and record reasons for rejection. Relevant articles will undergo full-text screening, with standard data extracted for all studies included. Quality assessment will include Sudlow and Warlow's criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and the CONSIDER checklist for Indigenous research. Results: Primary outcomes include crude, age-specific and/or age-standardized incidence of stroke. Secondary outcomes include overall stroke rates, incidence rate ratio and case-fatality. Results will be synthesized in figures and tables, describing data sources, populations, methodology, and findings. Within-population meta-analysis will be performed if, and where, methodologically sound and comparable studies allow this. Conclusion: We will undertake the first systematic review assessing disparities in stroke incidence in Indigenous populations of developed countries. Data outputs will be disseminated to relevant Indigenous stakeholders to inform public health and policy research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Handling Editor declared a past co-authorship with two of the authors, AD and MP., (Copyright © 2021 Balabanski, Dos Santos, Woods, Thrift, Kleinig, Suchy-Dicey, Siri, Boden-Albala, Krishnamurthi, Feigin, Buchwald, Ranta, Mienna, Zavaleta, Churilov, Burchill, Zion, Longstreth, Tirschwell, Anand, Parsons, Brown, Warne, Harwood and Katzenellenbogen.)

Objectives: Anticipation and prompt relief of symptoms among patients with a life-limiting illness is a core element of palliative care. Indigenous Australians commonly encounter cultural barriers in healthcare that may impair outcomes. The Palliative Care Outcomes Collaboration collects patient care data for the purposes of continuous quality improvement and benchmarking, with each recorded care episode divided into phases that reflect a patient's condition. We aimed to investigate differences between Indigenous and non-Indigenous patients in the occurrence and duration of 'unstable' phases (which indicate unanticipated deterioration in a patient's condition or circumstances), and determine attainment of the relevant benchmark (resolution of unstable phases in ≤3 days in 90% of cases) for both groups., Design: Cohort study., Setting: Australia-wide hospital-based and community-based specialist palliative care (1 January 2010 to 30 June 2015)., Participants: 139 556 (1502 Indigenous and 138 054 non-Indigenous) adult patients., Outcome Measures: Indigenous and non-Indigenous patients were compared on (1) the risk of a phase being categorised as unstable, (2) the duration of unstable phases, and (3) the risk of unstable phases being prolonged (>3 days). Crude and adjusted estimates were produced from three-level robust Poisson regression and complementary log-log discrete time survival models., Results: Unstable phases occurred with similar frequency overall among Indigenous and non-Indigenous patients (adjusted relative risks 1.06; 95% CI 1.00 to 1.11; not significant after correction for multiple comparisons). The duration and risk of prolongation of unstable phases were similar in both patient groups, with no significant differences evident among subgroups. The benchmark was not met for either Indigenous or non-Indigenous patients (unstable phase duration >3 days in 24.3% vs 25.5%; p=0.398)., Conclusions: Despite well-documented shortcomings of healthcare for Indigenous Australians, there is no clear evidence of greater occurrence or prolongation of unanticipated problems among Indigenous patients accessing specialist palliative care services in hospital or the community., Competing Interests: Competing interests: CEJ is a PCOC chief investigator and receives funding to support the collection of data from palliative care services that participate in PCOC. CEJ is a member of the PCOC Executive Directors Group that approves release of data to researchers, but was excluded from the approval process in this instance in view of the potential for competing interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)