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OBJECTIVES Clinical research professionals must be equipped with adequate training in sound scientific methods and appropriate ethics. In this study, we aimed to assess the current clinical research self-efficacy of researchers at Hamad Medical Corporation (HMC). We also evaluated the effects of training courses on researchers’ self-efficacy. METHODS Utilizing a cross-sectional design, we used the shortened Clinical Research Appraisal Inventory (CRAI-12) through an online survey to assess the current clinical research self-efficacy of 600 researchers at HMC, Doha, Qatar. After conducting descriptive analyses, unpaired t test and ANOVA were used to determine significant mean percentages between variables. Pearson correlation coefficients were also calculated to measure the association among the interval variables. All tests were 2-sided, and significance was defined as P 5), reflecting higher self-efficacy for the topics covered in CRAI. Gender differences were significant across all factors, with males reporting higher levels of self-assessed efficacy and in clinical research. Other factors such as higher education degrees and previous (external) clinical research training were also associated with higher self-reported clinical research efficacy. CONCLUSIONS The findings of this study indicate that researchers at HMC possess high clinical research self-efficacy overall, but lower self-efficacy in securing funding. Gender and education level positively influence self-efficacy across CRAI factors. Notably, clinical research training boosts self-efficacy, especially when obtained outside HMC. In conclusion, healthcare providers are strongly encouraged to engage in effective clinical research training courses, both within and outside of their healthcare institutions, to improve their clinical research efficacy and enhance clinical practice.

Introduction: There are scant data on implementation of large-scale direct-acting antiviral treatment for hepatitis C virus in jails in the U.S. New York City Health + Hospitals/Correctional Health Services aimed to scale up hepatitis C virus treatment in the New York City jail system. This study describes the trends in annual hepatitis C virus treatment in New York City jails compared with those in Medicaid-funded treatment in the New York City community from 2014 to 2020. Methods: In this observational study, we extracted annual counts of direct-acting antiviral prescriptions for hepatitis C virus for those (1) in the New York City community who were covered by Medicaid and (2) those detained in New York City jails for 2014–2020. Data sources were New York City Department of Health and Mental Hygiene annual reports and Correctional Health Services treatment records, respectively. We used linear regression analysis to test for significant trends in annual treatment in these 2 cohorts during 2015–2019. Results: From 2015 to 2019, treatments started in New York City jails increased annually (p=0.001), whereas Medicaid-funded prescriptions in the New York City community declined since a peak in 2015 (p

In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.

We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

ABSTRACT Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT‐2i) improve glycemic control and weight, but might be associated with dehydration, hypotension and ketoacidosis, especially in patients with type 2 diabetes mellitus who fast during Ramadan. This meta‐analysis evaluates the effects of Ramadan fasting on patients with type 2 diabetes mellitus treated with SGLT‐2i. Materials and Methods A literature search was carried out in PubMed, Embase and the Cochrane Library. Quality assessment was carried out using the ROBINS‐I and Cochrane tools for risk of bias, and analyses were carried out using RevMan version 5.3. Results A total of five studies were included in this meta‐analysis. During Ramadan, there was a significant reduction in glycated hemoglobin (P

ABSTRACT Introduction Corneal confocal microscopy (CCM) is a rapid non‐invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN). Aim To undertake a systematic review and meta‐analysis assessing the diagnostic utility of CCM for sub‐clinical DPN (DPN−) and established DPN (DPN+). Data sources Databases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020. Study selection Studies were included if they reported on at least one CCM parameter in patients with diabetes. Data extraction Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta‐analysis was undertaken using RevMan V.5.3. Data synthesis Thirty‐eight studies including ~4,000 participants were included in this meta‐analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPN− vs controls (P

Abstract Background Extended-release buprenorphine (XRB) offers a novel approach to sustained monthly treatment for people who use opioids in criminal justice settings (CJS). This study explores the experiences of adults receiving XRB as a jail-to-community treatment. Methods and findings In-depth qualitative interviews were conducted among adult participants with opioid use disorder (OUD; n = 16) who were recently released from NYC jails and maintained on XRB after switching from daily sublingual buprenorphine (SLB). Interviews elaborated on the acceptability and barriers and facilitators of XRB treatment pre- and post-release. Interviews were audio recorded, transcribed, and analyzed for content related to factors influencing XRB treatment uptake and community reentry. Important themes were grouped into systems, medication, and patient-level factors. Key systems-level factors influencing initiation of XRB in jail included an alternative to perceived stigmatization and privacy concerns associated with daily in-jail SLB administration and less concerns with buprenorphine diversion. In-jail peer networks positively influenced participant adoption of XRB. XRB satisfaction was attributed to reduced in-jail clinic and medication administration visits, perceived efficacy and blockade effects upon the use of heroin/fentanyl following release, and averting the risk of criminal activities to fund opioid use. Barriers to retention included post-injection withdrawal symptoms and cravings attributed to perceived suboptimal medication dosing, injection site pain, and lack of in-jail provider information about the medication. Conclusion Participants were generally favorable to XRB initiation in jail and retention post-release. Further studies are needed to address factors influencing access to XRB in criminal justice settings, including stigma, ensuring patient privacy following initiation on XRB, and patient-, provider-, and correctional staff education pertaining to XRB. Trial Registration ClinicalTrials.gov Identified: NCT03604159.

PurposeNivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial.Experimental designNivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Background The phase 3 CheckMate 214 trial demonstrated higher response rates and improved overall survival with nivolumab plus ipilimumab versus sunitinib in first-line therapy for advanced clear-cell renal cell carcinoma (RCC). An unmet need exists to identify patients with RCC who are most likely to benefit from treatment with nivolumab plus ipilimumab.Methods In exploratory analyses, pretreatment levels of programmed death ligand 1 were assessed by immunohistochemistry. Genomic and transcriptomic biomarkers (including tumor mutational burden and gene expression signatures) were also investigated.Results Biomarkers previously associated with benefit from immune checkpoint inhibitor-containing regimens in RCC were not predictive for survival in patients with RCC treated with nivolumab plus ipilimumab. Analysis of gene expression identified an association between an inflammatory response and progression-free survival with nivolumab plus ipilimumab.Conclusions The exploratory analyses reveal relationships between molecular biomarkers and provide supportive data on how the inflammation status of the tumor microenvironment may be important for identifying predictive biomarkers of response and survival with combination immunotherapy in patients with RCC. Further validation may help to provide biomarker-driven precision treatment for patients with RCC.

Background Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its relationship to clinical factors, biomarkers, and outcome.Methods Using a new Single Molecule Array assay, serum sPD-L1 level were determined in RCC (CheckMate 009, n=91) and melanoma (CheckMate 038-Part 1, n=78) prior to, and at two time points on treatment. Gene expression data was obtained from biopsies taken prior to, and at day 28 on treatment. Results were integrated with clinical variables, tumor PD-L1 status from immuno-histochemistry, and genomic mutation status.Results In RCC patients, sPD-L1 levels were higher in patients with progressive disease as their best response. For both RCC and melanoma patients, progressive or stable disease was associated with an increase in sPD-L1 on nivolumab therapy, whereas mean sPD-L1 levels did not change or declined in patients with objective responses. By categorizing RCC patients into transcriptomic molecular subtypes, we identified a subgroup where the associations between sPD-L1 and progressive disease were particularly evident. In baseline biopsies, we identified six biological processes that were associated with sPD-L1 level in both RCC and melanoma: higher sPD-L1 is associated with lower tumor expression of the Hallmark gene sets ‘hypoxia’, ‘fatty acid metabolism’, ‘glycolysis’, ‘MTORC1 signaling’ and ‘androgen response’, and with higher expression of ‘KRAS signaling_Down’.Conclusion Baseline and on-therapy sPD-L1 levels in RCC have the potential to predict progressive disease on PD-1 inhibitor nivolumab. In a hypothesis-generating analysis of tumor gene expression, high baseline sPD-L1 is associated with a tumor metabolic state reflecting potentially targetable processes in both melanoma and RCC. In both trials, we observed associations between change in sPD-L1 on treatment and outcome metrics. sPD-L1 levels may further refine a nivolumab-refractory subtype of RCC within transcriptionally based subtypes of RCC.

Abstract Background Hepatitis C virus (HCV) is a major public health problem in correctional settings. HCV treatment is often not possible in U.S. jails due to short lengths of stay. Linkage to care is crucial in these settings, but competing priorities complicate community healthcare engagement and retention after incarceration. Methods We conducted a single arm clinical trial of a combined transitional care coordination (TCC) and patient navigation intervention and assessed the linkage rate and factors associated with linkage to HCV care after incarceration. Results During the intervention, 84 participants returned to the community after their index incarceration. Most participants were male and Hispanic, with a history of mental illness and a mean age of 45 years. Of those who returned to the community, 26 (31%) linked to HCV care within a median of 20.5 days; 17 (20%) initiated HCV treatment, 15 (18%) completed treatment, 9 (11%) had a follow-up lab drawn to confirm sustained virologic response (SVR), and 7 (8%) had a documented SVR. Among those with follow-up labs the known SVR rate was (7/9) 78%. Expressing a preference to be linked to the participant’s existing health system, being on methadone prior to incarceration, and feeling that family or a loved one were concerned about the participant’s wellbeing were associated with linkage to HCV care. Reporting drinking alcohol to intoxication prior to incarceration was negatively associated with linkage to HCV care. Conclusion We demonstrate that an integrated strategy with combined TCC and patient navigation may be effective in achieving timely linkage to HCV care. Additional multicomponent interventions aimed at treatment of substance use disorders and increasing social support could lead to further improvement. Trial registration Clinicaltrials.gov NCT04036760 July 30th, 2019 (retrospectively registered).

Background Nivolumab is an immune checkpoint inhibitor targeting the programmed death-1 receptor that improves survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). In contrast to other tumor types that respond to immunotherapy, factors such as programmed death ligand-1 (PD-L1) status and tumor mutational burden show limited predictive utility in ccRCC. To address this gap, we report here the first molecular characterization of nivolumab response using paired index lesions, before and during treatment of metastatic ccRCC.Methods We analyzed gene expression and T-cell receptor (TCR) clonality using lesion-paired biopsies provided in the CheckMate 009 trial and integrated the results with their PD-L1/CD4/CD8 status, genomic mutation status and serum cytokine assays. Statistical tests included linear mixed models, logistic regression models, Fisher’s exact test, and Kruskal-Wallis rank-sum test.Results We identified transcripts related to response, both at baseline and on therapy, including several that are amenable to peripheral bioassays or to therapeutic intervention. At both timepoints, response was positively associated with T-cell infiltration but not associated with TCR clonality, and some non-Responders were highly infiltrated. Lower baseline T-cell infiltration correlated with elevated transcription of Wnt/β-catenin signaling components and hypoxia-regulated genes, including the Treg chemoattractant CCL28. On treatment, analysis of the non-responding patients whose tumors were highly T-cell infiltrated suggests association of the RIG-I-MDA5 pathway in their nivolumab resistance. We also analyzed our data using previous transcriptional classifications of ccRCC and found they concordantly identified a molecular subtype that has enhanced nivolumab response but is sunitinib-resistant.Conclusion Our study describes molecular characteristics of response and resistance to nivolumab in patients with metastatic ccRCC, potentially impacting patient selection and first-line treatment decisions.Trial registration number NCT01358721.

Background: High patient turnover presents challenges and opportunity to provide hepatitis C virus (HCV) care in US jails (remand facilities). This study describes the HCV care cascade in the New York City (NYC) jail system during the direct-acting antiviral (DAA) treatment era. Methods: Patients admitted to the NYC jail system from January 2014 through December 2017 were included in this retrospective cohort analysis. We describe rates of screening, diagnosis, linkage to jail-based care, and treatment among the overall cohort, and among subgroups with long jail stays (≥120 days) or frequent stays (≥10 admissions). The study protocol was approved by a third-party institutional review board (BRANY, Lake Success, NY). Findings: Among the 121,371 patients in our analysis, HCV screening was performed in 40,219 (33%), 4665 (12%) of whom were viremic, 1813 (39%) seen by an HCV clinician in jail, and 248 (5% of viremic patients) started on treatment in jail. Having a long stay (adjusted risk ratio [aRR] 8·11, 95% confidence interval [CI] 6·98, 9·42) or frequent stays (aRR 1·51, 95% CI 1·04, 2·18) were significantly associated with being seen by an HCV clinician. Patients with long stays had a higher rate of treatment (14% of viremic patients). Sustained virologic response at 12 weeks was achieved in 147/164 (90%) of patients with available virologic data. Interpretation: Jail health systems can reach large numbers of HCV-infected individuals. The high burden of HCV argues for universal screening in jail settings. Length of stay was strongly associated with being seen by an HCV clinician in jail. Treatment is feasible among those with longer lengths of stay. Funding: None.

IntroductionWhile U.S. jails are critical sites for engagement in HCV care, short lengths-of-stay often do not permit treatment in jail. Therefore, linkage to HCV care after incarceration is crucial. However, little is known about HCV treatment acceptability among justice-involved individuals in U.S. jails. The goal of this study was to understand knowledge, attitudes, and acceptability of HCV treatment among people living with HCV in the New York City (NYC) jail system.MethodsWe recruited 36 HCV-antibody-positive individuals in the NYC jails using clinical data reports and performed semi-structured interviews to explore participants' attitudes toward HCV treatment in jail and following return to the community. We continued interviews until reaching thematic saturation and analyzed interviews using an inductive, thematic approach.ResultsParticipants were mostly male, Latina/o, with a mean age of 40 years. Nearly all were aware they were HCV antibody-positive. Two thirds of participants had some awareness of the availability of new HCV therapies. Key themes included: 1) variable knowledge of new HCV therapies affecting attitudes toward HCV treatment, 2) the importance of other incarcerated individuals in communicating HCV-related knowledge, 3) vulnerability during incarceration and fear of treatment interruption, 4) concern for relapse to active drug use and HCV reinfection, 5) competing priorities (such as other medical comorbidities, ongoing substance use, and housing), 6) social support and the importance of family.ConclusionsPatient-centered approaches to increase treatment uptake in jail settings should focus on promoting HCV-related knowledge including leveraging peers for knowledge dissemination. In addition, transitional care programs should ensure people living with HCV in jail have tailored discharge plans focused on competing priorities such as housing instability, social support, and treatment of substance use disorders.