Factors influencing maternal death surveillance and review implementation in Dodoma City, Tanzania. A qualitative case study.

Background: With 295 000 maternal deaths in 2017, 94% in low- and middle-income countries, maternal death is a matter of global public health concern. To address it, Maternal Death Surveillance and Response (MDSR) strategy was introduced in 2013 by the World Health Organization. With a reported maternal mortality ratio of 556:100000 per live births, Tanzania adopted the strategy in 2015. Studies are needed to understand factors influencing the implementation of MDSR in this specific setting. Aims and Objectives: The study aimed to assess the processes influencing MDSR implementation in Dodoma city council. Methods: A qualitative case study was conceptualized according to the Consolidated Framework for Implementation Research, focusing on implementation process domain. Members of MDSR committees were enrolled by purposeful sampling in the five health centres in Dodoma where the strategy was fully implemented and functional. In-depth interviews were conducted with key informants concerning the implementation processes influencing MDSR. Saturation was reached with the 15th respondent. Qualitative inductive content analysis was used to analyse data. Results: The inclusiveness in participatory planning process, stakeholders' readiness and accountability and collective learning were acknowledged as factors positively influencing the implementation of MDSR strategy by respondents. The interaction and alignment of influential factors were essential for successful implementation. Conclusions: MDSR implementation is positively influenced by factors that interact and converge in the building of a learning health system, to increase knowledge through practice and improve practice through knowledge. Further studies are needed to analyse the influence of additional factors at different levels of implementation to fully understand and empower the MDSR implementation network, and to better target the goal of closing the knowledge to practice loop.

Arterial stiffness assessment in coronary microvascular dysfunction and heart failure with preserved ejection fraction: An initial report from the WISE-CVD continuation study.

Background: Heart failure with preserved ejection fraction (HFpEF) is the most common cardiac complication in patients with coronary microvascular dysfunction (CMD), yet its underlying pathways remain unclear. Aortic pulse-wave velocity (aPWV) is an indicator of large artery stiffness and a predictor for cardiovascular disease. However, aPWV in CMD and HFpEF is not well characterized and may provide understanding of disease progression. Methods: Among participants without obstructive coronary artery disease, we evaluated 51 women with suspected CMD and 20 women and men with evidence of HFpEF. All participants underwent aPWV measurement (SphygmoCor, Atcor Medical) with higher aPWV indicating greater vascular stiffness. Cardiac magnetic resonance imaging (CMRI) assessed left ventricular (LV) ejection fraction, CMD via myocardial perfusion reserve index (MPRI), and ventricular remodeling via LV mass-volume ratio. . Statistical analysis was performed using Wilcoxon rank sum tests, Pearson correlations and linear regression analysis. Results: Compared to the suspected CMD group, the HFpEF participants were older (65 ± 12 vs 56 ± 11 yrs., p = 0.002) had higher BMI (31.0 ± 4.3 vs 27.8 ± 6.7 kg/m2, p = 0.013), higher aPWV (10.5 ± 2.0 vs 8.0 ± 1.6 m/s, p = 0.05) and lower MPRI (1.5 ± 0.3 vs1.8 ± 0.3, p = 0.02), but not remodeling. In a model adjusted for cardiovascular risk factors, the HFpEF group had a lower LVEF (estimate -4.78, p = 0.0437) than the suspected CMD group. Conclusions: HFpEF participants exhibit greater arterial stiffness and lower myocardial perfusion reserve, with lower LVEF albeit not remodeling, compared to suspected CMD participants. These findings suggest arterial stiffness may contribute to progression from CMD to HFpEF. Prospective work is needed and ongoing.

Parasite Burden of Trypanosoma cruzi in Whole Blood and Buffy Coat Determined by Real-Time PCR in Individuals with Chronic Chagas Disease.

The objective of this study was to compare, by qPCR, the circulating blood parasite load of Trypanosoma cruzi in the buffy coat, and in whole blood mixed with boiled and unboiled guanidine hydrochloride-EDTA buffer, of individuals with chronic ChD. The concentration and purity of DNA were evaluated in a Nanodrop Denovix DS-11FX Series Spectrophotometer (DeNovix Inc., Wilmington, NC, USA). The parasite load was determined with the Taqman® qPCR system using a Stratagene Mx3000P thermocycler (Agilent Technologies, Santa Clara, CA, USA) with Cruzi 1 and Cruzi 2 satellite primers. Student's t-test with Bonferroni correction, Chi-squared (χ2) tests and Spearman's correlation coefficient were applied. The concentration and purity of DNA were higher in the buffy coat. Parasite DNA was detected and quantifiable in the three types of samples in seven patients, without statistically significant differences in the parasite load obtained. Higher correlations were found between the total DNA concentrations and the parasite loads obtained in the samples of the buffy coat.

An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Effects of adolescent methylphenidate administration on methamphetamine conditioned place preference in an animal model of attention-deficit/hyperactivity disorder: Examination of potential sex differences.

BACKGROUND: Individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with a substance use disorder; however, the effects of long-term psychostimulant treatment on addiction are mixed. Preclinical studies are useful for further elucidating the relationship between ADHD and addiction-like behaviors, but these studies have focused on male subjects only. The goal of the current study was to determine if early-life administration of methylphenidate (MPH) augments methamphetamine (METH) conditioned place preference (CPP) and/or potentiates reinstatement of CPP in both male and female rats. METHODS: Male and female spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) received either MPH (1.5mg/kg; p.o.) or vehicle (1.0ml/kg) during adolescence (postnatal day [PND] ~29-57). Two weeks after cessation of MPH treatment, rats were tested for METH CPP (1.0mg/kg or 2.0mg/kg; s.c.). Rats were then given extinction sessions. Once rats met extinction criteria, they were tested for reinstatement of CPP following a priming injection of METH (0.25mg/kg; s.c.). RESULTS: All groups developed METH CPP, except vehicle-treated SHR males and vehicle-treated WKY females conditioned with the higher dose of METH (2.0mg/kg). Female SHRs treated with MPH showed greater reinstatement of METH CPP compared to female SHRs treated with vehicle. Adolescent MPH treatment did not augment the locomotor-stimulant effects of METH in adulthood. CONCLUSIONS: These results demonstrate the importance of considering biological sex when prescribing psychostimulant medications for ADHD as long-term MPH administration may increase the risk of continued drug use in females with ADHD following a period of abstinence.

Toxicity assessment of CeO2 and CuO nanoparticles at the air-liquid interface using bioinspired condensational particle growth.

CeO2 and CuO nanoparticles (NPs) are used as additives in petrodiesel to enhance engine performance leading to reduced diesel combustion emissions. Despite their benefits, the additive application poses human health concerns by releasing inhalable NPs into the ambient air. In this study, a bioinspired lung cell exposure system, Dosimetric Aerosol in Vitro Inhalation Device (DAVID), was employed for evaluating the toxicity of aerosolized CeO2 and CuO NPs with a short duration of exposure (≤10 min vs. hours in other systems) and without exerting toxicity from non-NP factors. Human epithelial A549 lung cells were cultured and maintained within DAVID at the air-liquid interface (ALI), onto which aerosolized NPs were deposited, and experiments in submerged cells were used for comparison. Exposure of the cells to the CeO2 NPs did not result in detectable IL-8 release, nor did it produce a significant reduction in cell viability based on lactate dehydrogenase (LDH) assay, with a marginal decrease (10%) at the dose of 388 µg/cm2 (273 cm2/cm2). In contrast, exposure to CuO NPs resulted in a concentration dependent reduction in LDH release based on LDH leakage, with 38% reduction in viability at the highest dose of 52 µg/cm2 (28.3 cm2/cm2). Cells exposed to CuO NPs resulted in a dose dependent cellular membrane toxicity and expressed IL-8 secretion at a global dose five times lower than cells exposed under submerged conditions. However, when comparing the ALI results at the local cellular dose of CuO NPs to the submerged results, the IL-8 secretion was similar. In this study, we demonstrated DAVID as a new exposure tool that helps evaluate aerosol toxicity in simulated lung environment. Our results also highlight the necessity in choosing the right assay endpoints for the given exposure scenario, e.g., LDH for ALI and Deep Blue for submerged conditions for cell viability.

Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

Top of the podium, at what cost? injuries in female international elite climbers.

Objectives: Competitive sport climbing has made its way to the Olympic stage. This prestige has brought about route setting and training alterations which presumably affect injury epidemiology. Most of the climbing injury literature contains male climbers and lacks high performing athletes. Studies with both female and male climbers, rarely included separate analyses for performance level or sex. Therefore, injury concerns for elite female competitive climbers are impossible to discern. A former study examined the prevalence of amenorrhea in elite international female climbers (n = 114) and reported that 53.5% had at least one injury in the past 12 months, but injury details were excluded. This study's aim was to report these injury details and their associations with BMI, menstrual status and eating disorders of the cohort. Methods: Online survey was emailed to competitive female climbers recruited through the IFSC database between June and August 2021. Data was analyzed using Mann-Whitney U, χ2 and logistic regression. Results: 229 registered IFSC climbers opened the questionnaire and 114 (49.7%) provided valid responses. Respondents (mean ± SD; age = 22.9 ± 5 year) represented 30 different countries and more than half (53.5%, n = 61) reported an injury in the prior 12 months with the majority in shoulders (37.7%, n = 23) and fingers (34.4%, n = 21). Injury prevalence in climbers with amenorrhea was 55.6% (n = 10). BMI was not a significant predictor of injury risk (OR = 1.082, 95% CI: 0.89, 1.3; p = 0.440) while accounting for current ED over the past 12 months. However, the odds ratio for having an injury was doubled for those with an ED (OR = 2.129, 95% CI: 0.905, 5.010; p = 0.08). Conclusion: With over half reporting recent injuries (<12 months) mostly to shoulders and fingers, development of new strategies for injury prevention in competitive female climbers are warranted. In addition, climbers with disordered eating behaviors and/or menstrual disturbances might be more prone to injury. More research in this population is required. Suitable screening to prevent these health issues and proper monitoring of these athletes are paramount to long-term athlete success.

Bioinspired Hierarchical Carbon Structures as Potential Scaffolds for Wound Healing and Tissue Regeneration Applications.

Engineered bio-scaffolds for wound healing provide an attractive treatment option for tissue engineering and traumatic skin injuries since they can reduce dependence on donors and promote faster repair through strategic surface engineering. Current scaffolds present limitations in handling, preparation, shelf life, and sterilization options. In this study, bio-inspired hierarchical all-carbon structures comprising carbon nanotube (CNT) carpets covalently bonded to flexible carbon fabric have been investigated as a platform for cell growth and future tissue regeneration applications. CNTs are known to provide guidance for cell growth, but loose CNTs are susceptible to intracellular uptake and are suspected to cause in vitro and in vivo cytotoxicity. This risk is suppressed in these materials due to the covalent attachment of CNTs on a larger fabric, and the synergistic benefits of nanoscale and micro-macro scale architectures, as seen in natural biological materials, can be obtained. The structural durability, biocompatibility, tunable surface architecture, and ultra-high specific surface area of these materials make them attractive candidates for wound healing. In this study, investigations of cytotoxicity, skin cell proliferation, and cell migration were performed, and results indicate promise in both biocompatibility and directed cell growth. Moreover, these scaffolds provided cytoprotection against environmental stressors such as Ultraviolet B (UVB) rays. It was seen that cell growth could also be tailored through the control of CNT carpet height and surface wettability. These results support future promise in the design of hierarchical carbon scaffolds for strategic wound healing and tissue regeneration applications.

Sugarcane Straw as a Source of Arabinoxylans: Optimization and Economic Viability of a Two-Step Alkaline Extraction.

Sugarcane processing produces a significant amount of byproducts in the form of straw and bagasse, which are rich in cellulose, hemicellulose, and lignin. This work aims to provide a valorization approach to sugarcane straw by optimizing a two-step alkaline extraction of arabinoxylans by a response surface methodology to evaluate a potential industrial-scale production. Sugarcane straws were delignified using an alkaline-sulfite pretreatment, followed by alkaline extraction and precipitation of arabinoxylan, a two-step process optimized using a response surface methodology. A KOH concentration of (2.93-17.1%) and temperature (18.8-61.2 °C) were chosen as independent variables, and the arabinoxylan yield (%) as a response variable. The model application shows that KOH concentration, temperature, and the interaction between both independent variables are significant in extracting arabinoxylans from straw. The best-performing condition was further characterized by FTIR, DSC, and chemical and molecular weight evaluation. The straws arabinoxylans presented high purities levels, ca. 69.93%, and an average molecular weight of 231 kDa. The overall estimated production cost of arabinoxylan from straw was 0.239 €/g arabinoxylan. This work demonstrates a two-step alkaline extraction of the arabinoxylans method, as well as their chemical characterization and economic viability analysis, that can be used as a model for industrial scale-up production.

Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved. Objective: To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance. Design, Setting, and Participants: In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021. Main Outcomes and Measures: Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery. Results: Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001). Conclusions and Relevance: In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

Self-Reported Early and Later Life Weight and the Risk of All-Cause Mortality in Older Adults.

OBJECTIVES: The extent to which body weight in early adulthood is associated with late-life mortality risk is unclear. This study aimed to determine the association between body mass index (BMI) in early adulthood (at 18 years of age) and older age (70 years and over), and the risk of mortality in later life. DESIGN: Secondary analysis of the ASPREE Longitudinal Study of Older Persons (ALSOP). SETTING, PARTICIPANTS: Data were from 14,853 relatively healthy community-dwelling Australians aged ≥ 70 years when enrolled in the study. MEASUREMENTS: Self-reported weight at age ≥ 70 years and recalled weight at age 18 years were collected at ALSOP study baseline. Height was measured with a stadiometer and was used for calculation of BMI at both timepoints. BMI at each timepoint was defined as: underweight, normal weight, overweight and obese. Individuals were categorised into one of five 'lifetime' BMI groups: normal weight (BMI between 18.5 and 24.9 at both times), overweight (25.0-29.9 at either or both times), obesity to non-obese (≥30.0 at age 18 and <30.0 ≥ 70 years), non-obese to obesity (<30.0 at age 18 and ≥30.0 at age ≥ 70 years), and early and later life obesity (≥30.0 at both times). RESULTS: During a median 4.7 years follow-up, 715 deaths occurred. Obesity at 18 years, but not in older age (p=0.44), was significantly associated with the risk of mortality in later life, even after accounting for current health status (HR: 2.35, 95% CI: 1.53-3.58, p<0.001). Compared with participants with normal BMI at both time points, being obese at both time points was associated with increased mortality risk (HR=1.99, 95% CI: 1.04-3.81, p=0.03), and the risk was even greater for individuals who were obese at 18 years but were no longer obese in older age (HR=2.92, 95% CI: 1.65-5.16, p<0.001), in fully adjusted models. Participants who were normal weight at 18 years and were obese in later life, did not have an increased mortality risk (p=0.78). CONCLUSIONS: Obesity in early adulthood, and obesity in both early and later life, were associated with increased mortality risk in later life. This highlights the importance of preventing obesity in early adulthood and maintaining a normal weight over an adult lifespan.

TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer.

Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.

The eyes speak when the mouth cannot: Using eye movements to interpret omissions in primary progressive aphasia.

Though it may seem simple, object naming is a complex multistage process that can be impaired by lesions at various sites of the language network. Individuals with neurodegenerative disorders of language, known as primary progressive aphasias (PPA), have difficulty with naming objects, and instead frequently say "I don't know" or fail to give a vocal response at all, known as an omission. Whereas other types of naming errors (paraphasias) give clues as to which aspects of the language network have been compromised, the mechanisms underlying omissions remain largely unknown. In this study, we used a novel eye tracking approach to probe the cognitive mechanisms of omissions in the logopenic and semantic variants of PPA (PPA-L and PPA-S). For each participant, we identified pictures of common objects (e.g., animals, tools) that they could name aloud correctly, as well as pictures that elicited an omission. In a separate word-to-picture matching task, those pictures appeared as targets embedded among an array with 15 foils. Participants were given a verbal cue and tasked with pointing to the target, while eye movements were monitored. On trials with correctly-named targets, controls and both PPA groups ceased visual search soon after foveating the target. On omission trials, however, the PPA-S group failed to stop searching, and went on to view many foils "post-target". As further indication of impaired word knowledge, gaze of the PPA-S group was subject to excessive "taxonomic capture", such that they spent less time viewing the target and more time viewing related foils on omission trials. In contrast, viewing behavior of the PPA-L group was similar to controls on both correctly-named and omission trials. These results indicate that the mechanisms of omission in PPA differ by variant. In PPA-S, anterior temporal lobe degeneration causes taxonomic blurring, such that words from the same category can no longer be reliably distinguished. In PPA-L, word knowledge remains relatively intact, and omissions instead appear to be caused by downstream factors (e.g., lexical access, phonological encoding). These findings demonstrate that when words fail, eye movements can be particularly informative.

Telemedicine for Neurosurgery Consultations at a Pituitary Center of Excellence: Patient Preference and Willingness to Proceed with Surgery.

Objective The purpose of this study was to evaluate pituitary tumor patient satisfaction with telemedicine, patient preference for telemedicine, potential socioeconomic benefit of telemedicine, and patients' willingness to proceed with surgery based on a telemedicine visit alone. Method In total, 134 patients who had pituitary surgery and a telemedicine visit during the coronavirus disease 2019 (COVID-19) pandemic (April 23, 2020-March 4, 2021) were called to participate in a 13-part questionnaire. Chi-square, ANOVA, and Wilcoxon Rank Sum tests were used to determine significance. Result Of 134 patients contacted, 90 responded (67%). Ninety-five percent were "satisfied" or "very satisfied" with their telemedicine visit, with 62% stating their visit was "the same" or "better" than previous in-person appointments. Eighty-two percent of the patients rated their telemedicine visit as "easy" or "very easy." On average, patients saved 150 minutes by using telemedicine compared with patient reported in-person visit times. Seventy-seven percent of patients reported the need to take off from work for in-person visits, compared with just 12% when using telemedicine. Forty-nine percent of patients preferred in-person visits, 34% preferred telemedicine, and 17% had no preference. Fifty percent of patients said they would feel comfortable proceeding with surgery based on a telemedicine visit alone. Patients with both initial evaluation and follow-up conducted via telemedicine were more likely to feel comfortable proceeding with surgery based on a telemedicine visit alone compared with patients who had only follow-up telemedicine visits ( p = 0.051). Conclusion Many patients are satisfied with telemedicine visits and feel comfortable proceeding with surgery based on a telemedicine visit alone. Telemedicine is an important adjunct to increase access to care at a Pituitary Center of Excellence.

Frailty and Effects of a Multidomain Physical Rehabilitation Intervention Among Older Patients Hospitalized for Acute Heart Failure: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Frailty is common among older patients with acute decompensated heart failure (ADHF) and is associated with worse quality of life (QOL) and a higher risk of clinical events. Frailty can also limit recovery and response to interventions. In the Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a 3-month innovative, early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and QOL (vs usual care) in older patients with ADHF. Objective: To evaluate whether baseline frailty modified the benefits of the physical rehabilitation intervention among patients with ADHF enrolled in the REHAB-HF trial and to assess the association between changes in frailty with the risk of adverse clinical outcomes on follow-up. Design, Setting, and Participants: This prespecified secondary analysis of the REHAB-HF trial, a multicenter randomized clinical trial, included 337 patients 60 years and older hospitalized for ADHF. Patients were enrolled from September 17, 2014, through September 19, 2019. Participants were stratified across baseline frailty strata as assessed using modified Fried criteria. Data were analyzed from July 2021 to September 2022. Interventions: Physical rehabilitation intervention or attention control. Main Outcomes and Measures: Primary outcome was the Short Physical Performance Battery (SPPB) score at 3 months. Clinical outcomes included all-cause hospitalization or mortality at 6 months. Results: This prespecified secondary analysis included 337 participants; 181 (53.7%) were female, 167 (49.6%) were Black, and the mean (SD) age was 72 (8) years. A total of 192 (57.0%) were frail and 145 (43.0%) were prefrail at baseline. A significant interaction was observed between baseline frailty status and the treatment arm for the primary trial end point of overall SPPB score, with a 2.6-fold larger improvement in SPPB with intervention among frail patients (2.1; 95% CI, 1.3-2.9) vs prefrail patients (0.8; 95% CI, -0.1 to 1.6; P for interaction = .03). Trends consistently favored a larger intervention effect size, with significant improvement among frail vs prefrail participants for 6-minute walk distance, QOL, and the geriatric depression score, but interactions did not achieve significance. Conclusions and Relevance: In this prespecified secondary analysis of the REHAB-HF trial, patients with ADHF with worse baseline frailty status had a more significant improvement in physical function in response to an innovative, early, transitional, tailored, multidomain physical rehabilitation intervention than those who were prefrail. Trial Registration: Clinical Trials.gov Identifier: NCT02196038.

Iatrogenic arteriovenous fistula in an infant mimicking an arteriovenous malformation.

We report the case of a 12-month-old infant who presented with progressive lower limb enlargement associated with erythema mimicking an arteriovenous malformation. Computed tomography confirmed an arteriovenous fistula (AVF) between the deep femoral artery and the common femoral vein. This case describes the unique clinical and imaging findings of iatrogenic AVF and contrasts them with other congenital vascular entities.

Evaluation of Human Performance Aiding Live Synthetically Engineered Bacteria in a Gut-on-a-Chip.

Synbiotics are a new class of live therapeutics employing engineered genetic circuits. The rapid adoption of genetic editing tools has catalyzed the expansion of possible synbiotics, exceeding traditional testing paradigms in terms of both throughput and model complexity. Herein, we present a simplistic gut-chip model using common Caco2 and HT-29 cell lines to establish a dynamic human screening platform for a cortisol sensing tryptamine producing synbiotic for cognitive performance sustainment. The synbiotic, SYN, was engineered from the common probiotic E. coli Nissle 1917 strain. It had the ability to sense cortisol at physiological concentrations, resulting in the activation of a genetic circuit that produces tryptophan decarboxylase and converts bioavailable tryptophan to tryptamine. SYN was successfully cultivated within the gut-chip showing log-phase growth comparable to the wild-type strain. Tryptophan metabolism occurred quickly in the gut compartment when exposed to 5 µM cortisol, resulting in the complete conversion of bioavailable tryptophan into tryptamine. The flux of tryptophan and tryptamine from the gut to the vascular compartment of the chip was delayed by 12 h, as indicated by the detectable tryptamine in the vascular compartment. The gut-chip provided a stable environment to characterize the sensitivity of the cortisol sensor and dynamic range by altering cortisol and tryptophan dosimetry. Collectively, the human gut-chip provided human relevant apparent permeability to assess tryptophan and tryptamine metabolism, production, and transport, enabled host analyses of cellular viability and pro-inflammatory cytokine secretion, and succeeded in providing an efficacy test of a novel synbiotic. Organ-on-a-chip technology holds promise in aiding traditional therapeutic pipelines to more rapidly down select high potential compounds that reduce the failure rate and accelerate the opportunity for clinical intervention.