Microbiota dynamics in a randomized trial of gut decontamination during allogeneic hematopoietic cell transplantation.

BACKGROUNDGut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on gut microbiome composition and the incidence of aGVHD in HCT patients.METHODSWe randomized 20 patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).RESULTSThe 2 arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at 2 weeks post-HCT (genus, P = 0.8; species, P = 0.44) or aGVHD incidence (P = 0.58). Immune reconstitution of T cell and B cell subsets was similar between groups. Five patients in the no-GD arm had 8 BSI episodes versus 1 episode in the GD arm (P = 0.09). The BSI-causing pathogens were traceable to the gut in 7 of 8 BSI episodes in the no-GD arm, including Staphylococcus species.CONCLUSIONWhile GD did not differentially affect Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens.TRIAL REGISTRATIONClinicalTrials.gov NCT02641236.FUNDINGNIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, and Stanford Maternal & Child Health Research Institute.

Impact of the COVID-19 Pandemic on Chronic Disease Care in India, China, Hong Kong, Korea, and Vietnam.

This study aims to provide evidence on how the COVID-19 pandemic has impacted chronic disease care in diverse settings across Asia. Cross-sectional surveys were conducted to assess the health, social, and economic consequences of the pandemic in India, China, Hong Kong, Korea, and Vietnam using standardized questionnaires. Overall, 5672 participants with chronic conditions were recruited from five countries. The mean age of the participants ranged from 55.9 to 69.3 years. A worsened economic status during the COVID-19 pandemic was reported by 19% to 59% of the study participants. Increased difficulty in accessing care was reported by 8% to 24% of participants, except Vietnam: 1.6%. The worsening of diabetes symptoms was reported by 5.6% to 14.6% of participants, except Vietnam: 3%. In multivariable regression analyses, increasing age, female participants, and worsened economic status were suggestive of increased difficulty in access to care, but these associations mostly did not reach statistical significance. In India and China, rural residence, worsened economic status and self-reported hypertension were statistically significantly associated with increased difficulty in access to care or worsening of diabetes symptoms. These findings suggest that the pandemic disproportionately affected marginalized and rural populations in Asia, negatively affecting population health beyond those directly suffering from COVID-19.

Computational Fluid Dynamics Simulations to Predict False Lumen Enlargement After Surgical Repair of Type-A Aortic Dissection.

We aim to use computational fluid dynamics to investigate the hemodynamic conditions that may predispose to false lumen enlargement in this patient population. Nine patients who received surgical repairs of their type-A aortic dissections between 2017-2018 were retrospectively identified. Multiple contrast-enhanced post-operative CT scans were used to construct 3D models of aortic geometries. Computational fluid dynamics simulations of the models were run on a high-performance computing cluster using SimVascular - an open-source simulation package. Physiological pulsatile flow conditions (4.9 L/min) were used at the aortic true lumen inlet, and physiological vascular resistances were applied at the distal vascular ends. Exploratory analyses showed no correlation between rate of false lumen growth and blood pressure, immediate post-op aortic diameter, or the number of fenestrations (p = 0.2). 1-year post-operative CT scans showed a median false lumen growth rate of 4.31 (3.66, 14.67) mm/year Median (Interquartile range) peak systolic, mid-diastolic, and late diastolic velocity magnitudes were 0.90 (1.40); 0.10 (0.16); and 0.06 (0.06) cm/s respectively. Spearman's ranked correlations between fenestration velocity and 1-year false lumen growth rates were found to be statistically significant: Velocity magnitude at peak systolic (p = 0.025; rho = 0.75), mid diastolic (p = 0.025; rho = 0.75) and late diastolic phases of the cardiac cycle (p = 0.006; rho = 0.85). We have shown that false lumen growth is strongly correlated to fenestration flow velocity, which has potential implications for post-operative surveillance and risk stratification.

The Impact of Catastrophic Medical Insurance in China: A five-year patient-level panel study.

Background: In an effort to provide greater financial protection from the risk of large medical expenditures, China has gradually added catastrophic medical insurance (CMI) to the various basic insurance schemes. Tongxiang, a rural county in Zhejiang province, China, has had CMI since 2000 for their employee insurance scheme, and since 2014 for their resident insurance scheme. Methods: Compiling and analysing patient-level panel data over five years, we use a difference-in-difference approach to study the effect of the 2014 introduction of CMI for resident insurance beneficiaries in Tongxiang. In our study design, resident insurance beneficiaries are the treatment group, while employee insurance beneficiaries are the control group. Findings: We find that availability of CMI significantly increases medical expenditures among resident insurance beneficiaries, including for both inpatient and outpatient spending. Despite the greater financial protection, out-of-pocket expenditures increased, in part because patients accessed treatment more often at higher-level hospitals. Interpretation: Better financial coverage for catastrophic medical expenditures led to greater access and expenditures, not only for inpatient admissions-the category that most often leads to catastrophic expenditures-but for outpatient visits as well. These patterns of expenditure change with CMI may reflect both enhanced access to a patient's preferred site of care as well as the influence of incentives encouraging more care under fee-for-service payment. Funding: Stanford University's Freeman Spogli Institute for International Studies' Policy Implementation Lab and a Shorenstein Asia Pacific Research Center faculty research award provided funding for this project. Chinese translation of the abstract (Appendix 1).

Patient experiences and perceptions of chronic disease care during the COVID-19 pandemic in India: a qualitative study.

OBJECTIVE: People with chronic conditions are known to be vulnerable to the COVID-19 pandemic. This study aims to describe patients' lived experiences, challenges faced by people with chronic conditions, their coping strategies, and the social and economic impacts of the COVID-19 pandemic. DESIGN, SETTING AND PARTICIPANTS: We conducted a qualitative study using a syndemic framework to understand the patients' experiences of chronic disease care, challenges faced during the lockdown, their coping strategies and mitigators during the COVID-19 pandemic in the context of socioecological and biological factors. A diverse sample of 41 participants with chronic conditions (hypertension, diabetes, stroke and cardiovascular diseases) from four sites (Delhi, Haryana, Vizag and Chennai) in India participated in semistructured interviews. All interviews were audio recorded, transcribed, translated, anonymised and coded using MAXQDA software. We used the framework method to qualitatively analyse the COVID-19 pandemic impacts on health, social and economic well-being. RESULTS: Participant experiences during the COVID-19 pandemic were categorised into four themes: challenges faced during the lockdown, experiences of the participants diagnosed with COVID-19, preventive measures taken and lessons learnt during the COVID-19 pandemic. A subgroup of participants faced difficulties in accessing healthcare while a few reported using teleconsultations. Most participants reported adverse economic impact of the pandemic which led to higher reporting of anxiety and stress. Participants who tested COVID-19 positive reported experiencing discrimination and stigma from neighbours. All participants reported taking essential preventive measures. CONCLUSION: People with chronic conditions experienced a confluence (reciprocal effect) of COVID-19 pandemic and chronic diseases in the context of difficulty in accessing healthcare, sedentary lifestyle and increased stress and anxiety. Patients' lived experiences during the pandemic provide important insights to inform effective transition to a mixed realm of online consultations and 'distanced' physical clinic visits.

Patient-Specific Computational Fluid Dynamics Reveal Localized Flow Patterns Predictive of Post-Left Ventricular Assist Device Aortic Incompetence.

BACKGROUND: Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem. METHODS: Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients' aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver. RESULTS: The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm2 [95% CI, -0.51 to 1.85]; P=0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, -0.07 to 0.019]; P=0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm2; mean difference [95% CI, 0.15-0.39]; P<0.001), whereas oscillatory shear index was not significantly different between both groups (95% CI, -0.009 to 0.001; P=0.17). CONCLUSIONS: Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.

Use of patient-specific computational models for optimization of aortic insufficiency after implantation of left ventricular assist device.

OBJECTIVE: Aortic incompetence (AI) is observed to be accelerated in the continuous-flow left ventricular assist device (LVAD) population and is related to increased mortality. Using computational fluid dynamics (CFD), we investigated the hemodynamic conditions related to the orientation of the LVAD outflow in these patients. METHOD: We identified 10 patients with new aortic regurgitation, and 20 who did not, after LVAD implantation between 2009 and 2018. Three-dimensional models of patients' aortas were created from their computed tomography scans. The geometry of the LVAD outflow graft in relation to the aorta was quantified using azimuth angles (AA), polar angles (PAs), and distance from aortic root. The models were used to run CFD simulations, which calculated the pressures and wall shear stress (rWSS) exerted on the aortic root. RESULTS: The AA and PA were found to be similar. However, for combinations of high values of AA and low values of PA, there were no patients with AI. The distance from aortic root to the outflow graft was also smaller in patients who developed AI (3.39 ± 0.7 vs 4.07 ± 0.77 cm, P = .04). There was no significant difference in aortic root pressures in the 2 groups. The rWSS was greater in AI patients (4.60 ± 5.70 vs 2.37 ± 1.20 dyne/cm2, P < .001). Qualitatively, we observed a trend of greater perturbations, regions of high rWSS, and flow eddies in the AI group. CONCLUSIONS: Using CFD simulations, we demonstrated that patients who developed de novo AI have greater rWSS at the aortic root, and their outflow grafts were placed closer to the aortic roots than those patients without de novo AI.

Cloning and expression of koala (Phascolarctos cinereus) liver cytochrome P450 reductase.

The cloning, expression and characterization of hepatic NADPH-cytochrome P450 reductase (CPR) from koala (Phascolarctos cinereus) is described. Two 2059 bp koala liver CPR cDNAs, designated CPR1 and CPR2, were cloned by reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. The koala CPR cDNAs encode proteins of 678 amino acids and share 85% amino acid sequence identity to human CPR. Transfection of the koala CPR cDNAs into Cos-7 cells resulted in the expression of proteins, which were recognized by a goat-antihuman CPR antibody. The koala CPR1 and 2 cDNA-expressed enzymes catalysed cytochrome c reductase at the rates of 4.9 +/- 0.5 and 2.6 +/- 0.4 nmol/min/mg protein (mean +/- SD, n = 3), respectively which were comparable to that of rat CPR cDNA-expressed enzyme. The apparent Km value for CPR activity in koala liver microsomes was 11.61 +/- 6.01 microM, which is consistent with that reported for rat CPR enzyme. Northern analysis detected a CPR mRNA band of approximately 2.6 kb. Southern analysis suggested a single PCR gene across species. The present study provides primary molecular data regarding koala CPR1 and CPR2 genes in this unique marsupial species.

"One day I might find myself HIV-positive like her": audience involvement and identification with role models in an entertainment-education radio drama in Botswana.

Entertainment-education programs promote health and development goals throughout the world. This study looks specifically at a radio serial drama designed to provide behavioral role models for HIV prevention and reproductive health in Botswana as part of the behavior-change strategy, Modeling and Reinforcement to Combat HIV/AIDS (MARCH). The purpose of this qualitative study is to elucidate regular listeners' involvement and identification with three different types of fictional characters in the drama. Regular listeners were interviewed using a semi-structured guide; 31 interviews were analyzed to assess respondents' reactions to three female characters. The findings suggest that characters designed to be "negative," "positive," and "transitional" (i.e., moving from negative to positive) role models were generally perceived as such and that the type of behavior modeled influenced whether a character was perceived to be transitional or positive. Audience members discussed the implications of specific behaviors by contrasting the different character types. Although characters modeled behaviors within distinct but interrelated storylines, the respondents spontaneously compared characters' ways of confronting similar dilemmas across storylines, suggesting that listeners perceived the drama as a unified whole rather than as a series of parallel stories. The use of more than one transitional character for each behavioral objective might be beneficial for improving audience identification with agents of behavior change by providing several models to which the audience can relate.

Absence of type 1 11beta-hydroxysteroid dehydrogenase enzyme in koala liver.

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) interconvert 11beta-hydroxysteroids such as cortisol into 11-oxosteroids such as cortisone. In most mammals, 11beta-HSD 1 is expressed predominantly in the liver and is active in both the oxidative (cortisol to cortisone) and dehydrogenase (cortisone to cortisol) directions, whilst 11beta-HSD 2 is expressed predominantly in the kidney and functions as a pure oxidative enzyme. We have investigated 11beta-HSD 1 activity in the Australian koala (Phascolarctos cinereus) and have found no activity (either reductive or oxidative) in hepatic microsomes. Immunoblot analysis of koala hepatic microsomes, using an 11beta-HSD 1 antibody raised against the mouse enzyme, failed to identify immunoreactive protein. Reverse transcriptase-polymerase chain reaction (RT-PCR) of koala liver mRNA and genomic PCR using primers designed against highly conserved regions of 11beta-HSD 1 nucleotide sequences were also negative. Furthermore, Southern and Northern blot analysis of koala genomic DNA and mRNA, respectively, confirmed that the koala lacks the 11beta-HSD 1 gene and gene transcript. These results support the fact that the lack of hepatic 11beta-HSD 1 activity in the koala is due to the absence of the 11beta-HSD 1 gene, and this absence is novel among mammalian species studied to date.