Inhibiting anti-angiogenic VEGF165b activates a miR-17-20a-Calcipressin-3 pathway that revascularizes ischemic muscle in peripheral artery disease.

BACKGROUND: VEGF165a increases the expression of the microRNA-17-92 cluster, promoting developmental, retinal, and tumor angiogenesis. We have previously shown that VEGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity. In ischemic macrophages (Møs), VEGF165b inhibits VEGFR1 to induce S100A8/A9 expression, which drives M1-like polarization. Our current study aims to determine whether VEGF165b inhibition promotes perfusion recovery by regulating the microRNA(miR)-17-92 cluster in preclinical PAD. METHODS: Femoral artery ligation and resection was used as a preclinical PAD model. Hypoxia serum starvation (HSS) was used as an in vitro PAD model. VEGF165b was inhibited/neutralized by an isoform-specific VEGF165b antibody. RESULTS: Here, we show that VEGF165b-inhibition induces the expression of miR-17-20a (within miR-17-92 (miR-17-18a-19a-19b-20a-92) cluster) in HSS-ECs and HSS-Møs vs. respective normal and/or isotype-matched IgG controls to enhance perfusion recovery. Consistent with the bioinformatics analysis that revealed RCAN3 as a common target of miR-17 and miR-20a, Argonaute-2 pull-down assays showed decreased miR-17-20a expression and higher RCAN3 expression in the RNA-induced silencing complex of HSS-ECs and HSS-Møs vs. respective controls. Inhibiting miR-17-20a induced RCAN3 levels to decrease ischemic angiogenesis and promoted M1-like polarization to impair perfusion recovery. Finally, using STAT3 inhibitors, S100A8/A9 silencers, and VEGFR1-deficient ECs and Møs, we show that VEGF165b-inhibition activates the miR-17-20a-RCAN3 pathway independent of VEGFR1-STAT3 or VEGFR1-S100A8/A9 in ischemic-ECs and ischemic-Møs respectively. CONCLUSIONS: Our data revealed a hereunto unrecognized therapeutic 'miR-17-20a-RCAN3' pathway in the ischemic vasculature that is VEGFR1-STAT3/S100A8/A9 independent and is activated only upon VEGF165b-inhibition in PAD.

Therapies that can grow new blood vessels in the ischemic muscle are necessary to restore blood flow and provide relief to patients with peripheral artery disease (PAD). We have previously shown that blocking VEGF₁₆₅b, a small protein involved in the regulation of regenerating blood vessels, promotes the growth of new blood vessels in the ischemic muscle. However, the mechanism by which this occurs is not clear. Here, we build on this existing knowledge and show the complex processes driving the growth of new blood vessels, which will help to supply blood to the ischemic muscle and provide therapeutic relief from PAD.

Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test. ETHICS AND DISSEMINATION: The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT04901169.

A Clinicoepidemiological Study of Cutaneous and Systemic Comorbidities of Seborrheic Dermatitis in Adolescent and Adult Females.

Background Seborrheic dermatitis is the most common, chronic inflammatory skin condition which is confined to the scalp, nasolabial folds, and regions rich in sebaceous glands for which no definitive cause has been found. Although the disease is more common, the comorbidities associated with it have not been studied in detail. This study aims to assess the prevalence of seborrheic dermatitis and its associated cutaneous and systemic comorbidities in adolescent and adult patients. Methodology This cross-sectional study was performed among 451 adolescent and adult female patients who visited the Department of Dermatology, Venereology, and Leprosy of R. Laxminarayanappa Jalappa Hospital and Research Centre, Kolar. Patients having symptoms such as scaly patches, inflamed skin, and stubborn dandruff were diagnosed with seborrheic dermatitis and included in the study. A detailed history was collected for assessing other cutaneous disorders. Results Out of the 451 female participants, 87% belonged to the age group of 21-30 years, with 60.9% having cutaneous and 28.3% having systemic comorbidities. Acne (13.3%) and diabetes mellitus (13.1%) were the most common cutaneous and systemic associated comorbidities, respectively. Conclusions Comorbidities of seborrheic dermatitis were more commonly seen in adult female patients, Some of the common cutaneous comorbidities were acne, alopecia areata, and folliculitis. Systemic comorbidities included diabetes, obesity, and hypertension. However, all of these comorbidities were not statistically significant.

Real-world implementation of normothermic machine perfusion: A detailed analysis of intraoperative and early postoperative impact.

BACKGROUND: Outcome data for the great majority of liver normothermic machine perfusion (NMP) cases derive from the strict confines of clinical trials. Detailed specifics regarding the intraoperative and early postoperative impact of NMP on reperfusion injury and its sequelae during real-world use of this emerging technology remain largely unavailable. METHODS: We analyzed transplants performed in a 3-month pilot period during which surgeons invoked commercial NMP at their discretion. Living donor, multi-organ, and hypothermic machine perfusion transplants were excluded. RESULTS: Intraoperatively, NMP (n = 24) compared to static cold storage (n = 25) recipients required less peri-reperfusion bolus epinephrine (0 vs. 60 µg; p < .001) and post-reperfusion fresh frozen plasma (2.5 vs. 7.0 units; p = .0069), platelets (.0 vs. 2.0 units; p = .042), and hemostatic agents (0% vs. 24%; p = .010). Time from incision to venous reperfusion did not differ (3.6 vs. 3.1; p = .095) but time from venous reperfusion to surgery end was shorter for NMP recipients (2.3 vs. 2.8 h; p = .0045). Postoperatively, NMP recipients required fewer red blood cell (1.0 vs. 4.0 units; p = .0083) and fresh frozen plasma (4.0 vs. 7.0 units; p = .046) transfusions, had shorter intensive care unit stays (33.5 vs. 58.4 h; p = .012), and experienced less early allograft dysfunction according to both the Model for Early Allograft Function Score (3.4 vs. 5.0; p = .0047) and peak AST within 10 days of transplant (619 vs. 1,181 U/L; p = .036). Liver acceptance for the corresponding recipient was conditional on NMP use for 63% (15/24) of cases. CONCLUSION: Real-world NMP use was associated with significantly lower intensity of reperfusion injury and intraoperative and postoperative care that may translate into patient benefit.

The Association of Depression, Loneliness, and Internet Addiction Levels in Male Bachelor of Medicine, Bachelor of Surgery (MBBS) Students With Androgenetic Alopecia Male Pattern Baldness in a Medical College in Kolar, India.

Introduction The genetically determined progressive process that causes a gradual conversion of terminal hair into vellus hair is known as androgenetic alopecia (AGA). AGA male pattern baldness is very common among male medical students whose self-image is severely deteriorated by AGA and this affects the quality of their professional career. Hence, the assessment of the association of depression, loneliness, and internet addiction levels of male Bachelor of Medicine, Bachelor of Surgery (MBBS) students with AGA male pattern baldness is essential to improving academic and professional performance. Aims and objectives The aim of this study is to evaluate the effects of AGA male pattern baldness and its severity on depression, loneliness, and internet addiction levels of male medical students in Kolar. Materials and methods This questionnaire-based cross-sectional study was conducted among 100 male MBBS students from Sri Devaraj Urs Medical College in Kolar with AGA male pattern baldness of varying grades. The participants were selected through simple random sampling from July 2022 to November 2022 with their prior informed consent. Students' AGA severity was evaluated clinically using the Norwood-Hamilton Classification. Their levels of depression, loneliness, and internet addiction were assessed using the standardized Beck Depression Inventory (BDI) scale, University of Carolina Los Angeles - Loneliness Scale (UCLA-LS), and Young Internet Addiction Test - Short Form (YIAT-SF), respectively, and one-way analysis of variance (ANOVA) was used to ascertain the statistical significance between the means of BDI, UCLA-LS, and YIAT-SF with the severity of AGA. Chi-square/Fisher Exact test was used to find the significance of study parameters on a categorical scale between two or more groups. Significance was assessed at a 5% level of significance. Results The mean of BDI (17.38, 25.11, 34.62, 41.25, 51.00), UCLA-LS (18.72,27.51,36.69,43.5,49.00), and YIAT-SF (20.51, 31.77, 50.31, 60.25, 72.00) scores in each of the AGA grades from Grade I to Grade V in our study showed that these scores increase along with an increase in the severity of AGA and are statistically significant. The frequency distribution of male medical students with varied degrees of AGA and the level of depression, loneliness, and internet addiction levels assessed by the BDI, UCLA-LS, and YIAT-SF showed a robust and statistically significant association between the severity of AGA and the severity of depression, loneliness, and internet addiction levels. Conclusion The current study showed that there is a statistically significant association of depression, loneliness, and internet addiction levels in male MBBS students with AGA male pattern baldness.

Can we lower the platelet threshold of ≥ 50 × 109/L for performing a lumbar puncture safely in patients with hematological malignancies?

Lumbar punctures (LP) are routinely used to administer intrathecal chemotherapy for children and adults with hematologic malignancies. The current guidelines suggest a platelet threshold of ≥ 50 × 109/L prior to LP for intrathecal chemotherapy (ITC). This can be challenging in patients with hematological malignancies who are thrombocytopenic. We conducted a retrospective chart review of 900 LPs for ITC and compared adverse events in patients with a platelet count of ≥ 50 × 109/L and < 50 × 109/L. Cohort 1 included 682 LPs (75.8%) with a pre-procedure platelet count ≥ 50 × 109/L, and cohort 2 included 218 LPs (24.2%) with a pre-procedure platelet count < 50 × 109/L. Cohort 2 was further subdivided into pre-procedure platelet counts of 41 × 109/L-49 × 109/L (n = 43), 31 × 109/L-40 × 109/L (n = 77), 21 × 109/L-30 × 109/L (n = 84), and 11 × 109/L-20 × 109/L (n = 14). Among 900 LP procedures, a pre-procedure platelet count < 50 × 109/L did not demonstrate a higher rate of post-procedure adverse events (6.5% vs 6.8%, p = 0.8237). When cohort 2 was further stratified, the cohort with a pre-procedure platelet count of 21 × 109/L-30 × 109/L had the highest percentage of complications from LP (9.5%) and the highest rates of traumatic taps with observed LP RBC count > 200 (35.7%, p = 0.0015). The rate of red blood cells (RBC) in the CSF was significantly higher in the group with platelets < 50 × 109/L with observed LP RBC count ≥ 200 (31.2% vs 20.5%, p = 0.0016), ≥ 500 (27.1% vs 14.6%, p < 0.0001), and ≥ 1000 (23% vs 11.6%, p < 0.0001). No instances of epidural hematomas were seen. We found no significant difference in bleeding complications between patients undergoing LPs for ITC with a platelet count above or below 50 × 109/L.

A Deception Study to Avoid Recall Bias Confirms Similar Scores for 3 Validated Questionnaires in the Office or Over the Phone in Women With or Without Urinary Incontinence.

PURPOSE: With increasing telehealth technology, confirming the validity of non-office administration of questionnaires intended for office use only is important. We studied 3 validated questionnaires: the Urinary Distress Inventory 6-Short Form, the International Incontinence 7-Short Form, and a quality of life survey using a deception model. MATERIALS AND METHODS: Following Institutional Review Board approval and power calculations, these 3 questionnaires were prospectively administered in women with and without incontinence by phone and then again in person about 2 weeks later. To avoid recall bias, participants were not informed of the study over the phone. After completing their office visit questionnaire scores, they were told about the study and invited to consent for comparison of their phone and in-person questionnaire scores. Non-English speakers and those with an active urinary tract infection, with impaired mental competency, or on a fluid diet were excluded. RESULTS: From June to September 2021, 86 women, including 40 incontinent (30-85 years old) and 46 control (30-85 years old), with similar demographic parameters met all study criteria. Of the 14 questions studied, only 2, ie, Question 1 on the Urinary Distress Inventory 6-Short Form (P = .033) and Question 7 on the International Incontinence 7-Short Form (P = .036), showed rather minimal but statistically significant differences in scores. For incontinent women, only Question 7 on the International Incontinence 7-Short Form (P = .012) showed a significant score difference. CONCLUSIONS: The 3 questionnaire scores were overall comparable when obtained over the phone or during office visits. Women with incontinence, who may otherwise be lost to follow-up or only reachable by telehealth calls, can benefit from the remote administration of these 3 questionnaires.

Acute Kidney Injury in Pregnancies Complicated by Late-Onset Preeclampsia with Severe Features.

OBJECTIVE: Acute kidney injury (AKI)-complicating pregnancy is used as a marker of severe maternal morbidity (SMM) and frequently associated with obstetric hypertensive disorders. We examined AKI in pregnancies complicated by late-onset preeclampsia with severe features (SPE) using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared outcomes of pregnancies with and without AKI and stratified by stage of disease. We further differentiated renal dysfunction at the time of admission and compared outcomes to those who developed AKI after admission. STUDY DESIGN: This was a retrospective cohort study of women with care established before 20 weeks and diagnosed with preeclampsia with severe features with delivery at ≥34 weeks. Women with chronic hypertension or suspected underlying renal dysfunction were excluded. KDIGO criteria were applied to stratify staging of renal disease. Demographics and perinatal outcomes were compared using Chi-square analysis and Wilcoxon's rank-sum test with p < 0.05 considered significant. RESULTS: From January 2015 through December 2019, a total of 3,515 women meeting study criteria were delivered. Of these, 517 (15%) women met KDIGO criteria for AKI at delivery with 248 (48%) having AKI at the time of admission and the remaining 269 (52%) after admission. Stratified by severity, 412 (80%) had stage 1 disease, 89 (17%) had stage II, and 16 (3%) had stage III. Women with AKI had higher rates of cesarean delivery (risk ratio [RR] = 1.3; 95% confidence interval [CI]: 1.17-1.44), postpartum hemorrhage (RR = 1.46; 95% CI: 1.29-1.66), and longer lengths of stay. Other associated outcomes included NICU admission (RR = 1.72; 95% CI: 1.19-2.48), 5-minute Apgar score ≤ 3 (RR = 5.11; 95% CI: 1.98-13.18), and infant length of stay. CONCLUSION: Of women with late preterm SPE, 15% were found to have AKI by KDIGO criteria. The majority (80%) of AKI was stage I disease, and approximately half of the cases were present by the time of admission. KEY POINTS: · AKI was found in 15% of our cohort with 80% stage I disease.. · Half of the cases of AKI were present on admission.. · Few adverse perinatal outcomes are associated with AKI..

Efficacy of antimicrobial intravesical treatment for uncomplicated recurrent urinary tract infections: a systematic review.

INTRODUCTION AND HYPOTHESIS: Intravesical antimicrobials (IVA) provide a localized modality of treatment for recurrent urinary tract infections (rUTIs). Owing to the sporadic use of these treatments, we conducted a systematic review on the efficacy of IVA in the management of uncomplicated rUTIs. METHODS: A systematic review was conducted for all English language articles from inception to April 2021 utilizing the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards with the following databases: PubMed, OVID Embase, Biomed Central, and Scopus. References were cross-examined for further articles. Risk of bias was assessed in the articles included using the Cochrane and Joanna Briggs Institute tools. RESULTS: The initial search resulting in 476 titles led to 15 full-text articles. Of the 13 in the final review (2 RCTs), 3 used gentamicin and 10 used hyaluronic acid IVA. These included 764 participants, mostly women, with a mean age range of 27-80 (median: 53.1). There was a reduction in UTI frequency in 12 out of 13 studies, with 10 studies showing a statistically significant decrease. Dosages of 80 mg of gentamicin per instillation and both 40 mg and 800 mg of hyaluronic acid per instillation were found to be effective in reducing the frequency of UTIs in most studies. Eleven participants reported gentamicin-resistant infections after IVA treatment. Despite high levels of bias in selected categories, the 13 studies were designated to be of high quality for inclusion. CONCLUSIONS: The IVAs gentamicin and hyaluronic acid with chondroitin sulphate demonstrated efficacy in the management of uncomplicated rUTIs, mostly in women.

Defining Valid Activity Monitor Data: A Multimethod Analysis of Weight-Loss Intervention Participants' Barriers to Wear and First 100 Days of Physical Activity.

Despite the popularity of commercially available wearable activity monitors (WAMs), there is a paucity of consistent methodology for analyzing large amounts of accelerometer data from these devices. This multimethod study aimed to inform appropriate Fitbit wear thresholds for physical activity (PA) outcomes assessment in a sample of 616 low-income, majority Latina patients with obesity enrolled in a behavioral weight-loss intervention. Secondly, this study aimed to understand intervention participants' barriers to Fitbit use. We applied a heart rate (HR) criterion (≥10 h/day) and a step count (SC) criterion (≥1000 steps/day) to 100 days of continuous activity monitor data. We examined the prevalence of valid wear and PA outcomes between analytic subgroups of participants who met the HR criterion, SC criterion, or both. We undertook qualitative analysis of research staff notes and participant interviews to explore barriers to valid Fitbit data collection. Overall, one in three participants did not meet the SC criterion for valid wear in Weeks 1 and 13; however, we found the SC criterion to be more inclusive of participants who did not use a smartphone than the HR criterion. Older age, higher body mass index (BMI), barriers to smartphone use, device storage issues, and negative emotional responses to WAM-based self-monitoring may predict higher proportions of invalid WAM data in weight-loss intervention research.