Assessing Functional Vasodilation in the Gracilis Collateral Arteriole

Peripheral arterial occlusive disease (PAOD) involves arterial occlusion due to the formation of atherosclerotic plaques. It is suggested that intermittent claudication, the most frequent clinical presentation of PAOD, is caused by impaired vasodilation. Current treatments for PAOD are not directed at improving vascular reactivity and are often insufficient. Stimulating arteriogenesis in collateral arterioles has therapeutic potential for PAOD, but because arterioles are the primary site of blood flow resistance, it is important that these treatments do not impair collateral vasodilation. Before this can be evaluated, the effects of arteriogenesis on collateral function must be studied in untreated collaterals. There is impaired functional vasodilation at the collateral stem following collateral enlargement in the mouse hindlimb ischemia model. In order to determine if a similar impairment occurs at the collateral midzone, visualization of the gracilis collateral arteriole must be improved. In this study, we tested the hypotheses that FITC-dextran injected into the intravascular space would allow visualization of the gracilis collateral arteriole using epifluorescence, and that a trans-illumination device placed deep to the gracilis muscle would allow visualization of the arteriole by backlighting the midzone. Both of these methods allowed for clear visualization of the gracilis vasculature. Additionally, the placement of the trans-illumination device did not affect vasodilation in the upstream feed artery, suggesting that collateral reactivity would also remain unaltered by the device. In future studies, both of these visualization techniques will be employed to assess functional vasodilation in the midzone of the gracilis collateral arteriole in both unoperated animals and those with ligation-induced ischemia

The Impacts of Arterial Occlusion, Sex, and Exercise on Arteriogenesis and Functional Vasodilation

The most frequent clinical presentation of peripheral arterial occlusive disease (PAOD) is intermittent claudication, which may be caused by impaired vasodilation. Patients demonstrate both local and systemic impairments in vasodilation, but as the collateral circulation is the primary site of resistance to the ischemic zone, impaired collateral vasodilation would have the greatest potential to induce claudication. Collateral function following arterial occlusion is not well defined, but immature collaterals may demonstrate impaired vasodilation in animal models, although this is potentially improved with exercise training. Furthermore, as females exhibit poorer physical function with ischemia and less improvement with therapeutic exercise, there appears to be a sexually dimorphic response to PAOD, warranting a comparison in collateral vasodilation between sexes. In this study, the femoral artery was ligated to induce chronic ischemia in sedentary and exercise-trained mice, and at 7 or 28 days post-surgery, the diameter of the gracilis collateral arteriole was measured at rest and after gracilis muscle contraction using intravital microscopy. No major sex differences were observed in any group. At day 7, both the resting and dilated diameters were increased, while vascular reactivity was minimal. By day 28, resting diameter decreased while maximal diameter was unchanged, causing an increase in functional vasodilation. Exercise training also improved vasodilation by decreasing collateral resting diameter. These results are consistent with reported trends in endothelium-dependent and smooth muscle-dependent vasodilation, which are impaired in immature vessels and improved with maturation and exercise, but the significance of the observed variations in resting diameter remains unclear. Large resting diameters at day 7 could be due to a loss of sympathetic tone or the proliferative and non-contractile state of smooth muscle cells, while decreased resting diameters at day 28 could indicate that a smooth muscle contractile phenotype has been restored, or that the gracilis collateral is no longer the primary collateral. However, the further research is required to determine the functional relevance of collateral resting diameter and its importance in the ischemic limb circulation

The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis

Assessment of the patient, health system, and population eff ects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach

Background Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm. Methods We used an integrated model to assess the eff ects of diff erent algorithms of Xpert MTB/RIF and lightemitting diode (LED) fl uorescence microscopy in Tanzania. To understand the eff ects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the eff ects and cost-eff ectiveness of diff erent diagnostic options. Findings Among the diagnostic options considered, we identifi ed three strategies as cost eff ective in Tanzania. Full scale-up of Xpert would have the greatest population-level eff ect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-eff ectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104–265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fl uorescence microscopy is the next most eff ective strategy with an ICER of$45 (95% CrI 25–74), followed by LED fl uorescence microscopy with an ICER of $29 (6–59). Compared with same-day LED fl uorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a followon test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania. Interpretation For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-eff ective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation

How best to capture the impact of complementary therapies in palliative care: A systematic review to identify and assess the appropriateness and validity of multi-domain tools

BACKGROUND: Complementary therapies are widely used in palliative care settings. Qualitative research found that people with advanced disease report a range of physical and psychological benefits from complementary therapies, however evidence of their effectiveness from clinical trials is inconclusive. This may be because trials are limited by use of inappropriate outcome measures. AIMS: To identify tools which capture the impact of massage, reflexology and aromatherapy in people with advanced disease. We (1) identified multi-domain tools used to evaluate these therapies in populations with any chronic health condition and (2) assessed whether tools were valid and psychometrically robust in populations with advanced disease. DESIGN: A two-stage systematic review was conducted using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines (PROSPERO: CRD42020161199). DATA SOURCES: Six databases were searched (August 2021). Study methodological quality, tool psychometric properties and evidence quality were assessed. A global comparison score was generated. RESULTS: Stage 1: 66 trials using 40 different multi-domain tools were identified. Stage 2: Of these tools, we identified papers for seven tools regarding development or validation in advanced disease populations. The majority of psychometric data were inconsistent or inconclusive. Data were mostly of low quality due to methodological issues. CONCLUSION: Of the tools identified, 'Functional Assessment of Cancer Therapy - General' appears to be the most suitable alternative tool against COMSIN criteria, for trials of massage, reflexology and aromatherapy in palliative care. Further tool validation is required before firm recommendations can be made. Co-development of a core outcome set could ensure relevant domains are assessed

Long Term Therapy with Lenalidomide in a patient with POEMS Syndrome

Lenalidomide is an effective therapy against malignant plasma cells and a potent agent against proinflammatory and proangiogenic cytokines. The use of lenalidomide in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein with plasma cells, skin changes) has been reported, but its benefit in long-term use is not well established. A 55-year-old man with POEMS and debilitating polyneuropathy was treated with lenalidomide and dexamethasone followed by maintenance lenalidomide. He remains in haematologic remission and in complete recovery of functional status 3.5 years after diagnosis. This case supports the long-term use of lenalidomide in patients with POEMS syndrome

The Reproducibility of Lists of Differentially Expressed Genes in Microarray Studies

Reproducibility is a fundamental requirement in scientific experiments and clinical contexts. Recent publications raise concerns about the reliability of microarray technology because of the apparent lack of agreement between lists of differentially expressed genes (DEGs). In this study we demonstrate that (1) such discordance may stem from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion, the lists become much more reproducible, especially when fewer genes are selected; and (3) the instability of short DEG lists based on P cutoffs is an expected mathematical consequence of the high variability of the t-values. We recommend the use of FC ranking plus a non-stringent P cutoff as a baseline practice in order to generate more reproducible DEG lists. The FC criterion enhances reproducibility while the P criterion balances sensitivity and specificity

Towards elimination of mother-to-child transmission of HIV: performance of different models of care for initiating lifelong antiretroviral therapy for pregnant women in Malawi (Option B+).

INTRODUCTION: Malawi introduced a new strategy to improve the effectiveness of prevention of mother-to-child HIV transmission (PMTCT), the Option B+ strategy. We aimed to (i) describe how Option B+ is provided in health facilities in the South East Zone in Malawi, identifying the diverse approaches to service organization (the "model of care") and (ii) explore associations between the "model of care" and health facility-level uptake and retention rates for pregnant women identified as HIV-positive at antenatal (ANC) clinics. METHODS: A health facility survey was conducted in all facilities providing PMTCT/antiretroviral therapy (ART) services in six of Malawi's 28 districts to describe and compare Option B+ service delivery models. Associations of identified models with program performance were explored using facility cohort reports. RESULTS: Among 141 health facilities, four "models of care" were identified: A) facilities where newly identified HIV-positive women are initiated and followed on ART at the ANC clinic until delivery; B) facilities where newly identified HIV-positive women receive only the first dose of ART at the ANC clinic, and are referred to the ART clinic for follow-up; C) facilities where newly identified HIV-positive women are referred from ANC to the ART clinic for initiation and follow-up of ART; and D) facilities serving as ART referral sites (not providing ANC). The proportion of women tested for HIV during ANC was highest in facilities applying Model A and lowest in facilities applying Model B. The highest retention rates were reported in Model C and D facilities and lowest in Model B facilities. In multivariable analyses, health facility factors independently associated with uptake of HIV testing and counselling (HTC) in ANC were number of women per HTC counsellor, HIV test kit availability, and the "model of care" applied; factors independently associated with ART retention were district location, patient volume and the "model of care" applied. CONCLUSIONS: A large variety exists in the way health facilities have integrated PMTCT Option B+ care into routine service delivery. This study showed that the "model of care" chosen is associated with uptake of HIV testing in ANC and retention in care on ART. Further patient-level research is needed to guide policy recommendations

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants