Publications by authors named "Brown J"

17,652 Publications

Targeting Bruton's Tyrosine Kinase in CLL.

Front Immunol 2021 23;12:687458. Epub 2021 Jun 23.

Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.

Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of and mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.
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http://dx.doi.org/10.3389/fimmu.2021.687458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261291PMC
June 2021

Healthy food retail availability and cardiovascular mortality in the United States: a cohort study.

BMJ Open 2021 Jul 9;11(7):e048390. Epub 2021 Jul 9.

New York Academy of Medicine, New York, New York, USA.

Objectives: We investigated the association of healthy food retail presence and cardiovascular mortality, controlling for sociodemographic characteristics. This association could inform efforts to preserve or increase local supermarkets or produce market availability.

Design: Cohort study, combining Mortality Disparities in American Communities (individual-level data from 2008 American Community Survey linked to National Death Index records from 2008 to 2015) and retail establishment data.

Setting: Across the continental US area-based sociodemographic and retail characteristics were linked to residential location by ZIP code tabulation area (ZCTA). Sensitivity analyses used census tracts instead, restricted to urbanicity or county-based strata, or accounted for non-independence using frailty models.

Participants: 2 753 000 individuals age 25+ living in households with full kitchen facilities, excluding group quarters.

Primary And Secondary Outcome Measures: Cardiovascular mortality (primary) and all-cause mortality (secondary).

Results: 82% had healthy food retail (supermarket, produce market) within their ZCTA. Density of such retail was correlated with density of unhealthy food sources (eg, fast food, convenience store). Healthy food retail presence was not associated with reduced cardiovascular (HR: 1.03; 95% CI 1.00 to 1.07) or all-cause mortality (HR: 1.05; 95% CI 1.04 to 1.06) in fully adjusted models (with adjustment for gender, age, marital status, nativity, Black race, Hispanic ethnicity, educational attainment, income, median household income, population density, walkable destination density). The null finding for cardiovascular mortality was consistent across adjustment strategies including minimally adjusted models (individual demographics only), sensitivity analyses related to setting, and across gender or household type strata. However, unhealthy food retail presence was associated with elevated all-cause mortality (HR: 1.15; 95% CI 1.11 to 1.20).

Conclusions: In this study using food establishment locations within administrative areas across the USA, the hypothesised association of healthy food retail availability with reduced cardiovascular mortality was not supported; an association of unhealthy food retail presence with higher mortality was not specific to cardiovascular causes.
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http://dx.doi.org/10.1136/bmjopen-2020-048390DOI Listing
July 2021

The use of free versus in situ right internal mammary artery in coronary artery bypass grafting.

J Card Surg 2021 Jul 9. Epub 2021 Jul 9.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Coronary artery bypass grafting (CABG) continues to be the most commonly performed cardiac surgical procedure in the world. The use of multiarterial grafting may confer a long-term survival benefit over the use of vein grafts. However, there is a paucity of data comparing the use of in situ versus free right internal mammary artery (RIMA) in isolated CABG.

Methods: Patients that underwent isolated CABG between 2010 and 2018 where RIMA was used in addition to a left internal mammary artery graft. Patients with prior cardiac surgery or percutaneous coronary intervention were excluded. Propensity matching was used for subanalysis. Mortality and major adverse cardiac and cerebrovascular events (MACCE) were analyzed with Kaplan-Meier survival curves and Cox multivariable regression. Heart failure-specific readmissions were assessed with cumulative incidence curves with Fine and Gray competing risk regression.

Results: A total of 667 patients underwent isolated CABG. Of those, 422 had free RIMA and 245 had in situ RIMA utilized. Mortality was similar between cohorts (p = 0.199) with 5-year mortality rates of 6.6% (free) and 4.1% (in situ). MACCE was similar between cohorts, with 5-year event rates of 33.6% and 33.9% (p = 0.99). RIMA style was not a significant predictor of any outcome.

Conclusion: There was no difference in long-term mortality, complications, MACCE, or heart failure readmissions when comparing a contemporary cohort of patients undergoing isolated CABG utilizing RIMA as a conduit. These data may allow surgeons to consider using RIMA either as an in situ or a free conduit.
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http://dx.doi.org/10.1111/jocs.15797DOI Listing
July 2021

"I Am Okay With It, But I Am Not Going to Do It": The Exogenous Factors Influencing Non-Participation in Medical Assistance in Dying.

Qual Health Res 2021 Jul 8:10497323211027130. Epub 2021 Jul 8.

University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Medical assistance in dying (MAID) processes are complex, shaped by legislated directives, and influenced by the discourse regarding its emergence as an end-of-life care option. Physicians and nurse practitioners (NPs) are essential in determining the patient's eligibility and conducting MAID provisions. This research explored the exogenous factors influencing physicians' and NPs' non-participation in formal MAID processes. Using an interpretive description methodology, we interviewed 17 physicians and 18 NPs in Saskatchewan, Canada, who identified as non-participators in MAID. The non-participation factors were related to (a) the health care they work within, (b) the where they live, (c) their current context, (d) how their participation choices were to others, (e) the of participation to themselves and others, (f) factors, (g) the impact of participation on the , and (h) relationship, and contextual factors. Practice considerations to support the evolving social contact of care were identified.
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http://dx.doi.org/10.1177/10497323211027130DOI Listing
July 2021

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Neurocrit Care 2021 Jul 8;35(Suppl 1):4-23. Epub 2021 Jul 8.

Department of Neurology, New York Medical College, Valhalla, NY, USA.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.
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http://dx.doi.org/10.1007/s12028-021-01260-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264966PMC
July 2021

Impact of an Urban Sanitation Intervention on Enteric Pathogen Detection in Soils.

Environ Sci Technol 2021 Jul 8;55(14):9989-10000. Epub 2021 Jul 8.

Department of Environmental Sciences and Engineering, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States of America.

Environmental fecal contamination is common in many low-income cities, contributing to a high burden of enteric infections and associated negative sequelae. To evaluate the impact of a shared onsite sanitation intervention in Maputo, Mozambique on enteric pathogens in the domestic environment, we collected 179 soil samples at shared latrine entrances from intervention (n = 49) and control (n = 51) compounds during baseline (preintervention) and after 24 months (postintervention) as part of the Maputo Sanitation Trial. We tested soils for the presence of nucleic acids associated with 18 enteric pathogens using a multiplex reverse transcription qPCR platform. We detected at least one pathogen-associated gene target in 91% (163/179) of soils and a median of 3 (IQR = 1, 5) pathogens. Using a difference-in-difference analysis and adjusting for compound population, visibly wet soil, sun exposure, wealth, temperature, animal presence, and visible feces, we estimate the intervention reduced the probability of detecting ≥1 pathogen gene by 15% (adjusted prevalence ratio, aPR = 0.85; 95% CI: 0.70, 1.0) and the total number of pathogens by 35% (aPR = 0.65; 0.44, 0.95) in soil 24 months following the intervention. These results suggest that the intervention reduced the presence of some fecal contamination in the domestic environment, but pathogen detection remained prevalent 24 months following the introduction of new latrines.
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http://dx.doi.org/10.1021/acs.est.1c02168DOI Listing
July 2021

Datasets exploring putative lncRNA-miRNA-mRNA axes in breast cancer cell lines.

Data Brief 2021 Aug 24;37:107241. Epub 2021 Jun 24.

Department of Pathology, Dalhousie University, Halifax, NS, B3H 4R2, Canada.

Long non-coding RNA (lncRNA)/microRNA (miRNA)/messenger RNA (mRNA) interactions regulate oncogenesis and tumour suppression in breast cancer. Oncogenic lncRNA/miRNA/mRNA axes may offer novel therapeutic targets; therefore, identifying such axes is a clinically relevant undertaking. To explore miRNAs regulated by oncogenic lncRNAs, we queried the NCBI Gene Expression Omnibus (GEO) database to find datasets that profiled gene expression changes upon lncRNA knockdown in breast cancer. We identified four microarray datasets that permitted our interrogation of genes regulated by lncRNAs LincK, LincIN, SPRY4-IT1 and AC009283.1. We specifically analysed changes in miRNA transcripts within these datasets to study miRNAs regulated by each of the four lncRNAs. We subsequently identified the predicted mRNA targets for these miRNAs to uncover possible lncRNA/miRNA/mRNAs axes in breast cancer. These axes may be candidates for future investigation of gene regulation in breast cancer.
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http://dx.doi.org/10.1016/j.dib.2021.107241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250161PMC
August 2021

Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies.

Regul Toxicol Pharmacol 2021 Jul 3;125:104987. Epub 2021 Jul 3.

Johnson & Johnson, 410 George Street, New Brunswick, NJ, 08901, USA; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.

In 2020, the European Commission up-classified pure cobalt metal to a Category 1B hazard, based primarily on data from rodent inhalation carcinogenicity studies of metallic cobalt. The European Commission review did not evaluate cobalt-containing alloys in medical devices, which have very different properties vs. pure cobalt metal and did not include a systematic epidemiologic review. We performed a systematic review and meta-analysis of published, peer-reviewed epidemiologic studies evaluating the association between overall cancer risk and exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings. Study-specific estimates were pooled using random-effects models. Analyses included 20 papers on orthopedic implants and 10 occupational cohort papers (~1 million individuals). The meta-analysis summary estimates (95% confidence intervals) for overall cancer risk were 1.00 (0.96-1.04) overall and 0.97 (0.94-1.00) among high-quality studies. Results were also similar in analyses stratified by type of exposure/data sources (occupational cohort, implant registry or database), comparators (general or implant population), cancer incidence or mortality, follow-up duration (latency period), and study precision. In conclusion, meta-analysis found no association between exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings and overall cancer risk, including an analysis of studies directly comparing metal-on-metal vs. non-metal-on-metal implants.
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http://dx.doi.org/10.1016/j.yrtph.2021.104987DOI Listing
July 2021

Health Care Utilization and Costs Associated With Systemic First-Line Metastatic Melanoma Therapies in the United States.

JCO Oncol Pract 2021 Jul 6:OP2100140. Epub 2021 Jul 6.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL.

Purpose: US Food and Drug Administration approvals of immune checkpoint inhibitors and targeted therapies revolutionized the treatment of metastatic melanoma. Our aim was to assess health care resource utilization and costs for patients with metastatic melanoma treated with systemic therapies in first line between January 2012 and December 2017.

Methods: We conducted a retrospective cohort study of patients with metastatic melanoma using MarketScan data. We included patients diagnosed with melanoma and secondary malignant neoplasm who used pembrolizumab, nivolumab, ipilimumab, ipilimumab plus nivolumab, BRAF-inhibitor (BRAF-i) plus MEK inhibitor (MEK-i), BRAF-i or MEK-i monotherapy, or chemotherapy in first line. We compared health care utilization and costs per patient per month (PPPM) using two-part and generalized linear models.

Results: We identified 1,870 patients, including 185 pembrolizumab, 103 nivolumab, 689 ipilimumab, 185 nivolumab plus ipilimumab, 214 BRAF-i plus MEK-i, 240 BRAF-i or MEK-i monotherapy, and 254 chemotherapy users. Highest PPPM rates of hospitalizations, emergency room visits, and outpatient visits were observed in patients with ipilimumab plus nivolumab therapy (adjusted difference pembrolizumab [aDiff], 0.18, 0.12, and 0.88, respectively; all < .001). Ipilimumab monotherapy users (aDiff, 0.07 and 0.93; all < .001) and chemotherapy users (aDiff, 0.10 and 2.63; all < .001) showed higher PPPM rates of hospitalizations and outpatient visits compared with pembrolizumab users, respectively. Utilization rates in nivolumab, BRAF-i plus MEK-i, and BRAF-i or MEK-i groups were similar to the pembrolizumab group. Highest PPPM total costs and drug-related costs were observed in the ipilimumab group ($80,139 US dollars [USD] and $70,051 USD; all < .001), followed by the ipilimumab plus nivolumab ($71,689 USD and $56,217 USD; all < .001) and the BRAF-i plus MEK-i group ($31,184 USD and $19,648 USD; all < .001). PPPM costs in the nivolumab group were similar to the pembrolizumab group.

Conclusion: Significant differences in health care resource utilization and costs were found across first-line metastatic melanoma regimens. Utilization rates were highest in patients using ipilimumab-containing therapies. High drug costs constituted a major fraction of total PPPM health care costs.
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http://dx.doi.org/10.1200/OP.21.00140DOI Listing
July 2021

Subtalar Distraction Arthrodesis.

J Orthop Trauma 2021 Aug;35(Suppl 2):S54-S55

Department of Orthopaedic Surgery, Baylor Scott and White-Temple, Temple, TX.

Summary: Subtalar distraction arthrodesis is a hindfoot reconstructive procedure designed to treat posttraumatic sequelae of certain calcaneal fractures. This video demonstrates one method of performing this procedure which resulted in dramatic pain improvement and functional restoration.
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http://dx.doi.org/10.1097/BOT.0000000000002172DOI Listing
August 2021

Use of cast immobilisation versus removable brace in adults with an ankle fracture: multicentre randomised controlled trial.

BMJ 2021 07 5;374:n1506. Epub 2021 Jul 5.

Oxford Trauma and Emergency Care, Nuffield Department of Rheumatology, Musculoskeletal and Orthopaedic Sciences, University of Oxford, Oxford, UK.

Objectives: To assess function, quality of life, resource use, and complications in adults treated with plaster cast immobilisation versus a removable brace for ankle fracture.

Design: Multicentre randomised controlled trial.

Setting: 20 trauma units in the UK National Health Service.

Participants: 669 adults aged 18 years and older with an acute ankle fracture suitable for cast immobilisation: 334 were randomised to a plaster cast and 335 to a removable brace.

Interventions: A below the knee cast was applied and ankle range of movement exercises started on cast removal. The removable brace was fitted, and ankle range of movement exercises were started immediately.

Main Outcome Measures: Primary outcome was the Olerud Molander ankle score at 16 weeks, analysed by intention to treat. Secondary outcomes were Manchester-Oxford foot questionnaire, disability rating index, quality of life, and complications at 6, 10, and 16 weeks.

Results: The mean age of participants was 46 years (SD 17 years) and 381 (57%) were women. 502 (75%) participants completed the study. No statistically significant difference was found in the Olerud Molander ankle score between the cast and removable brace groups at 16 weeks (favours brace: 1.8, 95% confidence interval -2.0 to 5.6). No clinically significant differences were found in the Olerud Molander ankle scores at other time points, in the secondary unadjusted, imputed, or per protocol analyses.

Conclusions: Traditional plaster casting was not found to be superior to functional bracing in adults with an ankle fracture. No statistically difference was found in the Olerud Molander ankle score between the trial arms at 16 weeks.

Trial Registration: ISRCTN registry ISRCTN15537280.
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http://dx.doi.org/10.1136/bmj.n1506DOI Listing
July 2021

Hepatic cysteine sulphinic acid decarboxylase depletion and defective taurine metabolism in a rat partial nephrectomy model of chronic kidney disease.

BMC Nephrol 2021 Jul 5;22(1):250. Epub 2021 Jul 5.

Department of Respiratory Sciences, University of Leicester, Leicester, LE1 7RH, UK.

Background: Taurine depletion occurs in patients with end-stage chronic kidney disease (CKD). In contrast, in the absence of CKD, plasma taurine is reported to increase following dietary L-glutamine supplementation. This study tested the hypothesis that taurine biosynthesis decreases in a rat CKD model, but is rectified by L-glutamine supplementation.

Methods: CKD was induced by partial nephrectomy in male Sprague-Dawley rats, followed 2 weeks later by 2 weeks of 12% w/w L-glutamine supplemented diet (designated NxT) or control diet (NxC). Sham-operated control rats (S) received control diet.

Results: Taurine concentration in plasma, liver and skeletal muscle was not depleted, but steady-state urinary taurine excretion (a measure of whole-body taurine biosynthesis) was strongly suppressed (28.3 ± 8.7 in NxC rats versus 78.5 ± 7.6 μmol/24 h in S, P < 0.05), accompanied by reduced taurine clearance (NxC 0.14 ± 0.05 versus 0.70 ± 0.11 ml/min/Kg body weight in S, P < 0.05). Hepatic expression of mRNAs encoding key enzymes of taurine biosynthesis (cysteine sulphinic acid decarboxylase (CSAD) and cysteine dioxygenase (CDO)) showed no statistically significant response to CKD (mean relative expression of CSAD and CDO in NxC versus S was 0.91 ± 0.18 and 0.87 ± 0.14 respectively). Expression of CDO protein was also unaffected. However, CSAD protein decreased strongly in NxC livers (45.0 ± 16.8% of that in S livers, P < 0.005). L-glutamine supplementation failed to rectify taurine biosynthesis or CSAD protein expression, but worsened CKD (proteinuria in NxT 12.5 ± 1.2 versus 6.7 ± 1.5 mg/24 h in NxC, P < 0.05).

Conclusion: In CKD, hepatic CSAD is depleted and taurine biosynthesis impaired. This is important in view of taurine's reported protective effect against cardio-vascular disease - the leading cause of death in human CKD.
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http://dx.doi.org/10.1186/s12882-021-02442-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256558PMC
July 2021

Factors Associated with Same Day Discharge (SDD) after Laparoscopic Surgery in Gynecologic Oncology.

J Minim Invasive Gynecol 2021 Jul 2. Epub 2021 Jul 2.

Levine Cancer Institute, Atrium Health, Charlotte, NC.

Study Objective: To identify factors associated with same day discharge (SDD) after laparoscopic surgery in gynecologic oncology.

Design: Retrospective cohort SETTING: Teaching hospital PATIENTS: A total of 800 patients having minimally invasive surgery (MIS) in the division of gynecologic oncology during a 20-month period.

Intervention: MIS cases were reviewed for determinants of SDD to identify factors that could improve the SDD rate.

Measurement And Main Results: During the study period, 800 minimally invasive procedures were performed with a 43.0% SDD rate.  Patients who had SDD were younger (52.3 years vs. 58.0 years; p < .001), had a lower BMI (31.1 kg/m vs. 33.7 kg/m; p < .001), less likely to have a malignancy (28.2% vs. 55.5%; p < .001), had a lower estimated blood loss (EBL, 36 vs. 72 mL; p < .001), and were more likely to have received an enhanced recovery after surgery (ERAS) protocol (49.8% vs. 39.3%; p < .003). Total surgical time was shorter in women with SDD (156 minutes vs. 208 minutes) as was total narcotic use in morphine equivalents (mg IV MEq, 23.1 mg MEq vs. 28.8 mg MEq). SDD was also associated with earlier start time (p < .001). Laparoscopic cases were most likely to have SDD (51.4%) as compared to robotic assisted surgery (16.1%) or mini-laparotomy (10.5%). There was a wide range of SDD among surgeons ranging from 19.8% to 56.2% (p < .001). In a multivariate analysis, the factors predicting SDD in order of predictive factors were surgical time (p < .001), recovery time (p < 0.001), start time (p < .001), surgeon (p < .001), age (p < .001), EBL (p < .001), type of surgery (p = .005).

Conclusions: Multiple factors affect SDD.  Modifiable factors for SDD include the start time, surgeon preference, and patient expectations for SDD. Given these data, centers should prioritize surgical order by which patients are more likely to go home and surgeons should analyze their own data with respect to achieving higher SDD rates.
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http://dx.doi.org/10.1016/j.jmig.2021.06.026DOI Listing
July 2021

Racial Differences in Clinical Outcomes for Metastatic Renal Cell Carcinoma Patients Treated With Immune-Checkpoint Blockade.

Front Oncol 2021 16;11:701345. Epub 2021 Jun 16.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States.

Background: Immune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs.

Methods: We performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test.

Results: Our cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 25 months, p=0.368) and PFS (3.1 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians.

Conclusions: Our real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.
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http://dx.doi.org/10.3389/fonc.2021.701345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242950PMC
June 2021

Evaluating the Safety of West Nile Virus Immunity During Congenital Zika Virus Infection in Mice.

Front Immunol 2021 18;12:686411. Epub 2021 Jun 18.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Antibody-dependent enhancement (ADE) is a phenomenon that occurs when cross-reactive antibodies generated from a previous flaviviral infection increase the pathogenesis of a related virus. Zika virus (ZIKV) is the most recent flavivirus introduced to the Western Hemisphere and has become a significant public health threat due to the unanticipated impact on the developing fetus. West Nile virus (WNV) is the primary flavivirus that circulates in North America, and we and others have shown that antibodies against WNV are cross-reactive to ZIKV. Thus, there is concern that WNV immunity could increase the risk of severe ZIKV infection, particularly during pregnancy. In this study, we examined the extent to which WNV antibodies could impact ZIKV pathogenesis in a murine pregnancy model. To test this, we passively transferred WNV antibodies into pregnant mice on E6.5 prior to infection with ZIKV. Evaluation of pregnant dams showed weight loss following ZIKV infection; however, no differences in maternal weights or viral loads in the maternal brain, spleen, or spinal cord were observed in the presence of WNV antibodies. Resorption rates, and other fetal parameters, including fetal and placental size, were similarly unaffected. Further, the presence of WNV antibodies did not significantly alter the viral load or the inflammatory response in the placenta or the fetus in response to ZIKV. Our data suggest that pre-existing WNV immunity may not significantly impact the pathogenesis of ZIKV infection during pregnancy. Our findings are promising for the safety of implementing WNV vaccines in the continental US.
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http://dx.doi.org/10.3389/fimmu.2021.686411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250419PMC
June 2021

Oral (-)-Epicatechin Inhibits Progressive Tau Pathology in rTg4510 Mice Independent of Direct Actions at GSK3β.

Front Neurosci 2021 16;15:697319. Epub 2021 Jun 16.

Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.

Aggregation of the microtubule-associated protein tau into paired helical filaments (PHFs) and neurofibrillary tangles is a defining characteristic of Alzheimer's Disease. Various plant polyphenols disrupt tau aggregation but display poor bioavailability and low potency, challenging their therapeutic translation. We previously reported that oral administration of the flavonoid (-)-epicatechin (EC) reduced Amyloid-β (Aβ) plaque pathology in APP/PS1 transgenic mice. Here, we investigated whether EC impacts on tau pathology, independent of actions on Aβ, using rTg4510 mice expressing P301L mutant tau. 4 and 6.5 months old rTg4510 mice received EC (∼18 mg/day) or vehicle (ethanol) via drinking water for 21 days and the levels of total and phosphorylated tau were assessed. At 4 months, tau appeared as two bands of ∼55 kDa, phosphorylated at Ser262 and Ser396 and was unaffected by exposure to EC. At 6.5 months an additional higher molecular weight form of tau was detected at ∼64 kDa which was phosphorylated at Ser262, Ser396 and additionally at the AT8 sites, indicative of the presence of PHFs. EC consumption reduced the levels of the ∼64 kDa tau species and inhibited phosphorylation at Ser262 and AT8 phosphoepitopes. Regulation of the key tau kinase glycogen synthase kinase 3β (GSK3β) by phosphorylation at Ser9 was not altered by exposure to EC in mice or primary neurons. Furthermore, EC did not significantly inhibit GSK3β activity at physiologically-relevant concentrations in a cell free assay. Therefore, a 21-day intervention with EC inhibits or reverses the development of tau pathology in rTg4510 mice independently of direct inhibition of GSK3β.
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http://dx.doi.org/10.3389/fnins.2021.697319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244787PMC
June 2021

International perspectives on suboptimal patient-reported outcome trial design and reporting in cancer clinical trials: A qualitative study.

Cancer Med 2021 Jul 5. Epub 2021 Jul 5.

Centre for Patient-Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Purpose: Evidence suggests that the patient-reported outcome (PRO) content of cancer trial protocols is frequently inadequate and non-reporting of PRO findings is widespread. This qualitative study examined the factors influencing suboptimal PRO protocol content, implementation, and reporting, and use of PRO data during clinical interactions.

Methods: Semi-structured interviews were conducted with four stakeholder groups: (1) trialists and chief investigators; (2) people with lived experience of cancer; (3) international experts in PRO cancer trial design; (4) journal editors, funding panelists, and regulatory agencies. Data were analyzed using directed thematic analysis with an iterative coding frame.

Results: Forty-four interviews were undertaken. Several factors were identified that could influenced effective integration of PROs into trials and subsequent findings. Participants described (1) late inclusion of PROs in trial design; (2) PROs being considered a lower priority outcome compared to survival; (3) trialists' reluctance to collect or report PROs due to participant burden, missing data, and perceived reticence of journals to publish; (4) lack of staff training. Strategies to address these included training research personnel and improved communication with site staff and patients regarding the value of PROs. Examples of good practice were identified.

Conclusion: Misconceptions relating to PRO methodology and its use may undermine their planning, collection, and reporting. There is a role for funding, regulatory, methodological, and journalistic institutions to address perceptions around the value of PROs, their position within the trial outcomes hierarchy, that PRO training and guidance is available, signposted, and readily accessible, with accompanying measures to ensure compliance with international best practice guidelines.
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http://dx.doi.org/10.1002/cam4.4111DOI Listing
July 2021

Use of a mobile app to capture supplemental health information during pregnancy: Implications for clinical research.

Pharmacoepidemiol Drug Saf 2021 Jul 3. Epub 2021 Jul 3.

Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

Purpose: Mobile applications ("apps") may be efficient tools for improving the quality of clinical research among pregnant women, but evidence is sparse. We assess the feasibility and generalizability of a mobile app for capturing supplemental data during pregnancy.

Methods: In 2017, we conducted a pilot study of the FDA MyStudies mobile app within a pregnant population identified through Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system. We ascertained health conditions, medications, and substance use through app-based questionnaires. In a post-hoc analysis, we utilized electronic health records (EHR) to summarize sociodemographic and health characteristics of pilot participants and, for comparison, a pregnant population identified using similar methods.

Results: Six percent (64/1070) of contacted women enrolled in the pilot study. Nearly half (23/53) reported taking medication for headaches and one-fourth for constipation (13/53) and nausea (12/53) each. Few instances (2/92) of over-the-counter medication use were identified in electronic dispensing records. One-quarter to one-third of participants with depression and anxiety/panic, respectively, reported recently discontinuing medications for these conditions. Eighty-eight percent of pilot participants reported White race (95%CI: 81-95%), versus 67% of the comparison population (N = 2065). More pilot participants filled ≥1 prescription for antianxiety medication (22% [95%CI: 13-35%]) and antidepressants (19% [95%CI 10-31%]) pre-pregnancy than the comparison population (10 and 9%, respectively).

Conclusions: Mobile apps may be a feasible tool for capturing health data not routinely available in EHR. Pregnant women willing to use a mobile app for research may differ from the general pregnant population, but confirmation is needed.
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http://dx.doi.org/10.1002/pds.5320DOI Listing
July 2021

Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and neuroinflammation after hypoxic stress.

J Neurochem 2021 Jul 3. Epub 2021 Jul 3.

Department of Cellular Biology & Anatomy.

Protein arginine methyltransferases (PRMTs) are a family of enzymes involved in gene regulation and protein/histone modifications. PRMT8 is primarily expressed in the central nervous system, specifically within the cellular membrane and synaptic vesicles. Recently, PRMT8 has been described to play key roles in neuronal signaling such as a regulator of dendritic arborization, synaptic function and maturation, and neuronal differentiation and plasticity. Here, we examined the role of PRMT8 in response to hypoxia-induced stress in brain metabolism. Our results from liquid chromatography mass spectrometry, mitochondrial oxygen consumption rate (OCR), and protein analyses indicate that PRMT8(-/-) knockout mice presented with altered membrane phospholipid composition, decreased mitochondrial stress capacity, and increased neuroinflammatory markers, such as TNF-α and ionized calcium binding adaptor molecule 1 (Iba1, a specific marker for microglia/macrophage activation) after hypoxic stress. Furthermore, adenovirus-based overexpression of PRMT8 reversed the changes in membrane phospholipid composition, mitochondrial stress capacity, and neuroinflammatory markers. Together, our findings establish PRMT8 as an important regulatory component of membrane phospholipid composition, short-term memory function, mitochondrial function, and neuroinflammation in response to hypoxic stress.
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http://dx.doi.org/10.1111/jnc.15462DOI Listing
July 2021

Novel use of social media to assess and improve coastal flood forecasts and hazard alerts.

Sci Rep 2021 Jul 2;11(1):13727. Epub 2021 Jul 2.

Sefton Council, Trinity Road, Bootle, Liverpool, L20 3NJ, UK.

Coastal communities and infrastructure need protection from flooding and wave overtopping events. Assessment of hazard prediction methods, used in sea defence design, defence performance inspections and forecasting services, requires observations at the land-sea interface but these are rarely collected. Here we show how a database of hindcast overtopping events, and the conditions that cause them, can be built using qualitative overtopping information obtained from social media. We develop a database for a case study site at Crosby in the Northwest of England, use it to test the standard methods applied in operational flood forecasting services and new defence design, and suggest improvements to these methods. This novel approach will become increasingly important to deliver long-term, cost-effective coastal management solutions as sea-levels rise and coastal populations grow. At sites with limited, or no, monitoring or forecasting services, this approach, especially if combined with citizen science initiatives, could underpin the development of simplified early warning systems.
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http://dx.doi.org/10.1038/s41598-021-93077-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253846PMC
July 2021

Identification of essential genes for Escherichia coli aryl polyene biosynthesis and function in biofilm formation.

NPJ Biofilms Microbiomes 2021 Jul 2;7(1):56. Epub 2021 Jul 2.

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Aryl polyenes (APEs) are specialized polyunsaturated carboxylic acids that were identified in silico as the product of the most widespread family of bacterial biosynthetic gene clusters (BGCs). They are present in several Gram-negative host-associated bacteria, including multidrug-resistant human pathogens. Here, we characterize a biological function of APEs, focusing on the BGC from a uropathogenic Escherichia coli (UPEC) strain. We first perform a genetic deletion analysis to identify the essential genes required for APE biosynthesis. Next, we show that APEs function as fitness factors that increase protection from oxidative stress and contribute to biofilm formation. Together, our study highlights key steps in the APE biosynthesis pathway that can be explored as potential drug targets for complementary strategies to reduce fitness and prevent biofilm formation of multi-drug resistant pathogens.
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http://dx.doi.org/10.1038/s41522-021-00226-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253772PMC
July 2021

Neurophysiology of epidurally evoked spinal cord reflexes in clinically motor-complete posttraumatic spinal cord injury.

Exp Brain Res 2021 Jul 2. Epub 2021 Jul 2.

Department of Rehabilitation and Physical Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.

Increased use of epidural Spinal Cord Stimulation (eSCS) for the rehabilitation of spinal cord injury (SCI) has highlighted the need for a greater understanding of the properties of reflex circuits in the isolated spinal cord, particularly in response to repetitive stimulation. Here, we investigate the frequency-dependence of modulation of short- and long-latency EMG responses of lower limb muscles in patients with SCI at rest. Single stimuli could evoke short-latency responses as well as long-latency (likely polysynaptic) responses. The short-latency component was enhanced at low frequencies and declined at higher rates. In all muscles, the effects of eSCS were more complex if polysynaptic activity was elicited, making the motor output become an active process expressed either as suppression, tonic or rhythmical activity. The polysynaptic activity threshold is not constant and might vary with different stimulation frequencies, which speaks for its temporal dependency. Polysynaptic components can be observed as direct responses, neuromodulation of monosynaptic responses or driving the muscle activity by themselves, depending on the frequency level. We suggest that the presence of polysynaptic activity could be a potential predictor for appropriate stimulation conditions. This work studies the complex behaviour of spinal circuits deprived of voluntary motor control from the brain and in the absence of any other inputs. This is done by describing the monosynaptic responses, polysynaptic activity, and its interaction through its input-output interaction with sustain stimulation that, unlike single stimuli used to study the reflex pathway, can strongly influence the interneuron circuitry and reveal a broader spectrum of connectivity.
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http://dx.doi.org/10.1007/s00221-021-06153-1DOI Listing
July 2021

Primary care teams' experiences of delivering mental health care during the COVID-19 pandemic: a qualitative study.

BMC Fam Pract 2021 07 1;22(1):143. Epub 2021 Jul 1.

Department of Family Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Background: Integrated primary care teams are ideally positioned to support the mental health care needs arising during the COVID-19 pandemic. Understanding how COVID-19 has affected mental health care delivery within primary care settings will be critical to inform future policy and practice decisions during the later phases of the pandemic and beyond. The objective of our study was to describe the impact of the COVID-19 pandemic on primary care teams' delivery of mental health care.

Methods: A qualitative study using focus groups conducted with primary care teams in Ontario, Canada. Focus group data was analysed using thematic analysis.

Results: We conducted 11 focus groups with 10 primary care teams and a total of 48 participants. With respect to the impact of the COVID-19 pandemic on mental health care in primary care teams, we identified three key themes: i) the high demand for mental health care, ii) the rapid transformation to virtual care, and iii) the impact on providers.

Conclusions: From the outset of the COVID-19 pandemic, primary care quickly responded to the rising mental health care demands of their patients. Despite the numerous challenges they faced with the rapid transition to virtual care, primary care teams have persevered. It is essential that policy and decision-makers take note of the toll that these demands have placed on providers. There is an immediate need to enhance primary care's capacity for mental health care for the duration of the pandemic and beyond.
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http://dx.doi.org/10.1186/s12875-021-01496-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248293PMC
July 2021

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

J Pers Med 2021 Jun 11;11(6). Epub 2021 Jun 11.

Geisinger Genomic Medicine Institute, 100 N. Academy Ave, Danville, PA 17822, USA.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.
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http://dx.doi.org/10.3390/jpm11060543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230764PMC
June 2021

IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3Kδ inhibitor idelalisib.

Haematologica 2021 Jul 1. Epub 2021 Jul 1.

Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.278644DOI Listing
July 2021

High-grade heart block associated with ibrutinib therapy.

HeartRhythm Case Rep 2021 Jun 19;7(6):391-394. Epub 2021 Mar 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.hrcr.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226304PMC
June 2021