Effectiveness and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Patients With HIV-1 Infection and Ongoing Substance Use Disorder: The BASE Study

BACKGROUND: People with human immunodeficiency virus (HIV) and substance use disorder (PWH/SUD) are at higher risk of nonadherence to antiretroviral therapy. Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) exhibits high rates of efficacy with a favorable adverse event profile. The BASE study (NCT03998176) is a phase 4, single-arm study evaluating the effectiveness and safety of B/F/TAF among PWH/SUD. METHODS: Viremic (HIV RNA \u3e1000 copies/mL) PWH/SUD initiated B/F/TAF once daily for 48 weeks (W). The primary endpoint was proportion of participants with HIV RNA/mL at W24. Secondary endpoints were proportion of participants with HIV-1 RNA/mL at W48, safety, B/F/TAF adherence (dried blood spot [DBS] concentrations of emtricitabine triphosphate and tenofovir diphosphate [TFV-DP]), substance use (NIDA-ASSIST), and quality of life (SF-12). RESULTS: Forty-three participants were enrolled; 95% reported methamphetamine use. Median age was 38 (range, 21-62) years; 21% were female, 81% White, 14% Black, and 16% Hispanic. Thirty-two (74%) and 21 (49%) participants had HIV RNA/mL (intention-to-treat) at W24 and W48, respectively. Seven participants (16%) experienced confirmed virologic failure through W48; 1 developed emergent drug resistance (M184V). Fifteen participants (35%) experienced grade ≥3 adverse events. Five participants (12%) reported suicidal ideation; none resulted in discontinuation. Median DBS concentrations were representative of 5-6 doses/week (TFV-DP, 1603 fmol/punches). NIDA-ASSIST scores declined from baseline to W48 with methamphetamine use decreasing most (-7.9 points; -29%), and SF-12 physical/mental scores increased 1.2 and 7.6 points, respectively. CONCLUSIONS: B/F/TAF among a high-risk population of PWH/SUD resulted in an initial 72% viral suppression rate at W24 before dropping to 49% at W48 as retention declined. One participant developed emergent drug resistance (M184V)

Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease

Accumulating evidence suggests revascularization of peripheral arterial disease (PAD) limbs results in limited improvement in functional gait parameters, suggesting underlying locomotor system pathology. Spatial and temporal (ST) gait parameters are well studied in patients with PAD at baseline and are abnormal when compared to controls. The purpose of this study was to systematically review and critically analyze the available data on ST gait parameters before and after interventions. A full review of literature was conducted and articles were included which examined ST gait parameters before and after intervention (revascularization and exercise). Thirty-three intervention articles were identified based on 154 articles that evaluated ST gait parameters in PAD. Four articles fully assessed ST gait parameters before and after intervention and were included in our analysis. The systematic review of the literature revealed a limited number of studies assessing ST gait parameters. Of those found, results demonstrated the absence of improvement in gait parameters due to either exercise or surgical intervention.Our study demonstrates significant lack of research examining the effectiveness of treatments on ST gait parameters in patients with PAD. Based on the four published articles, ST gait parameters failed to significantly improve in patients with PAD following intervention

The Grizzly, February 4, 1983

Trouble at Cutillo\u27s: Frats Earn Reputation as Animals • Drinking Concerns Richter • Economics Council Sponsors Entrepreneur-Related Forum • President\u27s Corner • Wismer Tries Again • Pfacelift at Pfahler • Bear Blades Burnished Beat Wilmington Twice • Serendipity Celebration Features Films • Writing Center Welcomes Students • Who\u27s Who in Who\u27s Who? • Commentary: Speak Up for Coed Housing • Didja Ever Wonder • Wrestlers Earn Split • Lewis on Wall Street • Disruptive Fans Cause Flare-up at Widener • Top Individual Efforts Mark Gymnastics Team • Interview: Chupein Named to All-League Team • Lady Hoops Still Struggling • Men\u27s Basketball Find Road a Bit Bumpy • Swimmers Maul Terrors of Western Marylandhttps://digitalcommons.ursinus.edu/grizzlynews/1092/thumbnail.jp

Patient-reported Outcomes: the ICHOM Standard Set for Inflammatory Bowel Disease in Real-life Practice Helps Quantify Deficits in Current Care

BackgroundPatient reported outcome measures (PROMs) are key to documenting outcomes that matter most to patients and are increasingly important to commissioners of healthcare seeking value. We report the first series of the ICHOM Standard Set for Inflammatory Bowel Disease (IBD).MethodsPatients treated for ulcerative colitis (UC) or Crohn's disease (CD) in our centre were offered enrolment into the web-based TrueColours-IBD programme. Through this programme, email prompts linking to validated questionnaires were sent for symptoms, quality of life, and ICHOM IBD outcomes.ResultsThe first 1,299 consecutive patients enrolled (779 UC, 520 CD) were studied with median 270 days of follow up (IQR 116-504). 671 (52%) were female, mean age 42 years (sd 16), mean BMI 26 (sd 5.3). 483 (37%) were using advanced therapies at registration. Median adherence to fortnightly quality of life reporting and quarterly outcomes was 100% [IQR48-100%] and 100% [IQR75-100%], respectively. In the previous 12 months, prednisolone use was reported by 229 (29%) patients with UC vs. 81 (16%) with CD, p3 months. 174 (13%) patients reported an IBD-related intervention and 80 (6%) reported an unplanned hospital admission. There were high rates of fatigue (50%) and mood disturbance (23%).ConclusionOutcomes reported by patients illustrate the scale of the therapeutic deficit in current care. Proof of principle is demonstrated that PROM data can be collected continuously with little burden on healthcare professionals. This may become a metric for quality improvement programmes, or to compare outcomes

Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology

Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease

Accumulating evidence suggests revascularization of peripheral arterial disease (PAD) limbs results in limited improvement in functional gait parameters, suggesting underlying locomotor system pathology. Spatial and temporal (ST) gait parameters are well studied in patients with PAD at baseline and are abnormal when compared to controls. The purpose of this study was to systematically review and critically analyze the available data on ST gait parameters before and after interventions. A full review of literature was conducted and articles were included which examined ST gait parameters before and after intervention (revascularization and exercise). Thirty-three intervention articles were identified based on 154 articles that evaluated ST gait parameters in PAD. Four articles fully assessed ST gait parameters before and after intervention and were included in our analysis. The systematic review of the literature revealed a limited number of studies assessing ST gait parameters. Of those found, results demonstrated the absence of improvement in gait parameters due to either exercise or surgical intervention. Our study demonstrates significant lack of research examining the effectiveness of treatments on ST gait parameters in patients with PAD. Based on the four published articles, ST gait parameters failed to significantly improve in patients with PAD following intervention

Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes

Charcot-Marie-Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome-mediated intercellular communications may place an overwhelming burden on the nervous system and account for CMT1C molecular pathogenesis. © 2013 Zhu et al

Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection

BACKGROUND AND PURPOSE: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, NIHSS, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%), OR [95%CL] of 4.9 [2.3,10.4], p<0.001). Gross recruitment was 0.11 patients/site/month vs. 0.43 patients/site/month, respectively, before and after the amendment. CONCLUSIONS: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714