Publications by authors named "Jennifer Lin"

259 Publications

PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer.

J Natl Cancer Inst 2021 Jun 7. Epub 2021 Jun 7.

University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA.

Background: In the Phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced/metastatic triple-negative breast cancer (TNBC) patients who were programmed death-ligand 1 (PD-L1) + (tumor-infiltrating immune cells [IC] ≥1%) using the SP142 immunohistochemistry (IHC) assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes.

Methods: Samples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by IHC for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3).

Results: Using SP142, SP263, and 22C3 assays, PD-L1 IC ≥ 1% prevalence was 46.4% (95% confidence interval [CI] = 42.5-50.4%), 74.9% (95% CI = 71.5-78.3%), and 73.1% (95% CI = 69.6-76.6%), respectively; 80.9% were 22C3 at CPS ≥1. At IC ≥ 1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263 + (29.6%) or 22C3 + (29.0%) cases were SP142- (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival [PFS] hazard ratios [HRs] = 0.64-0.68; overall survival [OS] HRs = 0.75-0.79) was driven by double-positive (PFS HRs = 0.60-0.61; OS HRs = 0.71-0.75) rather than single-positive cases (PFS HRs = 0.68-0.81; OS HRs = 0.87-0.95). Concordance for harmonized cutoffs for SP263 (IC ≥ 4%) and 22C3 (CPS ≥10) to SP142 IC ≥ 1% was subpar (approximately 75%).

Conclusions: 22C3 and SP263 assays identified more patients as PD-L1 + (IC ≥ 1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥ 1% subgroup nested within 22C3 and SP263 PD-L1 + (IC ≥ 1%) populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djab108DOI Listing
June 2021

Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

JAMA 2021 05;325(19):1978-1997

Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon.

Importance: Colorectal cancer (CRC) remains a significant cause of morbidity and mortality in the US.

Objective: To systematically review the effectiveness, test accuracy, and harms of screening for CRC to inform the US Preventive Services Task Force.

Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1, 2015, to December 4, 2019; surveillance through March 26, 2021.

Study Selection: English-language studies conducted in asymptomatic populations at general risk of CRC.

Data Extraction And Synthesis: Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted.

Main Outcomes And Measures: Colorectal cancer incidence and mortality, test accuracy in detecting cancers or adenomas, and serious adverse events.

Results: The review included 33 studies (n = 10 776 276) on the effectiveness of screening, 59 (n = 3 491 045) on the test performance of screening tests, and 131 (n = 26 987 366) on the harms of screening. In randomized clinical trials (4 trials, n = 458 002), intention to screen with 1- or 2-time flexible sigmoidoscopy vs no screening was associated with a decrease in CRC-specific mortality (incidence rate ratio, 0.74 [95% CI, 0.68-0.80]). Annual or biennial guaiac fecal occult blood test (gFOBT) vs no screening (5 trials, n = 419 966) was associated with a reduction of CRC-specific mortality after 2 to 9 rounds of screening (relative risk at 19.5 years, 0.91 [95% CI, 0.84-0.98]; relative risk at 30 years, 0.78 [95% CI, 0.65-0.93]). In observational studies, receipt of screening colonoscopy (2 studies, n = 436 927) or fecal immunochemical test (FIT) (1 study, n = 5.4 million) vs no screening was associated with lower risk of CRC incidence or mortality. Nine studies (n = 6497) evaluated the test accuracy of screening computed tomography (CT) colonography, 4 of which also reported the test accuracy of colonoscopy; pooled sensitivity to detect adenomas 6 mm or larger was similar between CT colonography with bowel prep (0.86) and colonoscopy (0.89). In pooled values, commonly evaluated FITs (14 studies, n = 45 403) (sensitivity, 0.74; specificity, 0.94) and stool DNA with FIT (4 studies, n = 12 424) (sensitivity, 0.93; specificity, 0.85) performed better than high-sensitivity gFOBT (2 studies, n = 3503) (sensitivity, 0.50-0.75; specificity, 0.96-0.98) to detect cancers. Serious harms of screening colonoscopy included perforations (3.1/10 000 procedures) and major bleeding (14.6/10 000 procedures). CT colonography may have harms resulting from low-dose ionizing radiation. It is unclear if detection of extracolonic findings on CT colonography is a net benefit or harm.

Conclusions And Relevance: There are several options to screen for colorectal cancer, each with a different level of evidence demonstrating its ability to reduce cancer mortality, its ability to detect cancer or precursor lesions, and its risk of harms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2021.4417DOI Listing
May 2021

Colorectal Cancer Screening: An Updated Modeling Study for the US Preventive Services Task Force.

JAMA 2021 05;325(19):1998-2011

Department of Public Health, Erasmus Medical Center, Rotterdam, the Netherlands.

Importance: The US Preventive Services Task Force (USPSTF) is updating its 2016 colorectal cancer screening recommendations.

Objective: To provide updated model-based estimates of the benefits, burden, and harms of colorectal cancer screening strategies and to identify strategies that may provide an efficient balance of life-years gained (LYG) from screening and colonoscopy burden to inform the USPSTF.

Design, Setting, And Participants: Comparative modeling study using 3 microsimulation models of colorectal cancer screening in a hypothetical cohort of 40-year-old US individuals at average risk of colorectal cancer.

Exposures: Screening from ages 45, 50, or 55 years to ages 70, 75, 80, or 85 years with fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy alone or with FIT, computed tomography colonography, or colonoscopy. All persons with an abnormal noncolonoscopy screening test result were assumed to undergo follow-up colonoscopy. Screening intervals varied by test. Full adherence with all procedures was assumed.

Main Outcome And Measures: Estimated LYG relative to no screening (benefit), lifetime number of colonoscopies (burden), number of complications from screening (harms), and balance of incremental burden and benefit (efficiency ratios). Efficient strategies were those estimated to require fewer additional colonoscopies per additional LYG relative to other strategies.

Results: Estimated LYG from screening strategies ranged from 171 to 381 per 1000 40-year-olds. Lifetime colonoscopy burden ranged from 624 to 6817 per 1000 individuals, and screening complications ranged from 5 to 22 per 1000 individuals. Among the 49 strategies that were efficient options with all 3 models, 41 specified screening beginning at age 45. No single age to end screening was predominant among the efficient strategies, although the additional LYG from continuing screening after age 75 were generally small. With the exception of a 5-year interval for computed tomography colonography, no screening interval predominated among the efficient strategies for each modality. Among the strategies highlighted in the 2016 USPSTF recommendation, lowering the age to begin screening from 50 to 45 years was estimated to result in 22 to 27 additional LYG, 161 to 784 additional colonoscopies, and 0.1 to 2 additional complications per 1000 persons (ranges are across screening strategies, based on mean estimates across models). Assuming full adherence, screening outcomes and efficient strategies were similar by sex and race and across 3 scenarios for population risk of colorectal cancer.

Conclusions And Relevance: This microsimulation modeling analysis suggests that screening for colorectal cancer with stool tests, endoscopic tests, or computed tomography colonography starting at age 45 years provides an efficient balance of colonoscopy burden and life-years gained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2021.5746DOI Listing
May 2021

Effectiveness of Liposomal Bupivacaine Compared With Standard- of-Care Measures in Pediatric Cardiothoracic Surgery: A Retrospective Cohort Study.

J Cardiothorac Vasc Anesth 2021 Apr 14. Epub 2021 Apr 14.

Pacira BioSciences, Inc, Parsippany, NJ.

Objective: Effective postsurgical pain management is important for pediatric patients to improve outcomes while reducing resource use and waste. The authors examined opioid consumption and economic outcomes associated with liposomal bupivacaine (LB) or non-LB analgesia use in pediatric patients undergoing cardiothoracic surgery.

Design: The authors retrospectively analyzed Premier Healthcare Database records.

Setting: The data extracted from the database included patient records from hospitals across the United States in both rural and urban locations.

Participants: The records included data from patients aged 12-to-<18 years.

Interventions: The records belonged to patients undergoing video-assisted thoracoscopic procedures (VATS) who received LB or non-LB analgesia after surgery.

Measurements And Main Results: Outcomes included in-hospital postsurgical opioid consumption in morphine milligram equivalents (MMEs), hospital length of stay (LOS), and total hospital costs; the LB and non-LB cohorts were compared using a generalized linear model with inverse probability of treatment weighting to balance the cohorts. For VATS procedures, pediatric patients receiving LB had significant reductions in in-hospital opioid consumption (632 v 991 MMEs; p < 0.0001), shorter LOS (5.1 v 5.6 days; p = 0.0023), and lower total hospital costs ($18,084 v $21,962; p < 0.0001) compared with those receiving non-LB analgesia.

Conclusions: These results support use of LB in multimodal analgesia regimens for managing pain in pediatric patients after cardiothoracic surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jvca.2021.04.003DOI Listing
April 2021

Trends in US emergency department visits and subsequent hospital admission among patients with inflammatory bowel disease presenting with abdominal pain: a real-world study from a national emergency department sample database.

J Mark Access Health Policy 2021 Apr 19;9(1):1912924. Epub 2021 Apr 19.

Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

: This study evaluated emergency department (ED) visit trends, subsequent inpatient admissions for patients with inflammatory bowel disease (IBD) diagnosis and IBD-related abdominal pain (AP), and hospital-level variation in inpatient admission rates in the USA (US). : This population-based, cross-sectional study included data from Nationwide Emergency Department Sample (NEDS, 2006─2013) database. Patients ≥18 years of age with primary ED diagnosis of IBD/IBD-related AP were included. Variables included demographics, insurance information, household income, Quan-Charlson comorbidity score, ED discharge disposition, and length of hospital stay (2006, 2010, and 2013). Variation between hospitals using risk-adjusted admission ratio was estimated. : Annual ED visits for IBD/100,000 US population increased (30 in 2006 vs 42 in 2013, p = 0.09), subsequent admissions remained stable (20 in 2006 vs 23 in 2013, p = 0.52). ED visits for IBD-related AP increased by 71% (7 in 2006 vs 12 in 2013; p = 0.12), subsequent admissions were stable (0.50 in 2006 vs 0.58 in 2013; p = 0.88). Proportion of patients with subsequent hospitalization decreased (IBD: 65.7% to 55.7%; IBD-related AP: 6.9% to 4.9%). Variation in subsequent inpatient admissions was 1.42 (IBD) and 1.96 (IBD-related AP). : An increase in annual ED visits was observed for patients with IBD and IBD-related AP; however, subsequent inpatient admission rate remained stable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20016689.2021.1912924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079064PMC
April 2021

Clinical and Economic Outcomes Associated With Use of Liposomal Bupivacaine Versus Standard of Care for Management of Postsurgical Pain in Pediatric Patients Undergoing Spine Surgery.

J Health Econ Outcomes Res 2021 Apr 14;8(1):29-35. Epub 2021 Apr 14.

Pacira BioSciences, Inc., Parsippany, NJ.

Approximately 60% of hospitalized children undergoing surgery experience at least 1 day of moderate-to-severe pain after surgery. Pain following spine surgery may affect opioid exposure, length of stay (LOS), and costs in hospitalized pediatric patients. This is a retrospective cohort analysis of pediatric patients undergoing inpatient primary spine surgery. To examine the association of opioid-related and economic outcomes with postsurgical liposomal bupivacaine (LB) or non-LB analgesia in pediatric patients who received spine surgery. Premier Healthcare Database records (January 2015-September 2019) for patients aged 1-17 years undergoing inpatient primary spine surgery were retrospectively analyzed. Outcomes included in-hospital postsurgical opioid consumption (morphine milligram equivalents [MMEs]), opioid-related adverse events (ORAEs), LOS (days), and total hospital costs. A generalized linear model adjusting for baseline characteristics was used. Among 10 189 pediatric patients, the LB cohort (n=373) consumed significantly fewer postsurgical opioids than the non-LB cohort (n=9816; adjusted MME ratio, 0.53 [95% confidence interval (CI), 0.45-0.61]; P<0.0001). LOS was significantly shorter in the LB versus non-LB cohort (adjusted rate ratio, 0.86 [95% CI, 0.80-0.94]; P=0.0003). Hospital costs were significantly lower in the LB versus non-LB cohort overall (adjusted rate ratio, 0.92 [95% CI, 0.86-0.99]; P=0.0227) mostly because of decreased LOS and central supply costs. ORAEs were not significantly different between groups (adjusted rate ratio, 0.84 [95% CI, 0.65-1.08]; P=0.1791). LB analgesia was associated with shorter LOS and lower hospital costs compared with non-LB analgesia in pediatric patients undergoing spine surgery. The LB cohort had lower adjusted room and board and central supply costs than the non-LB cohort. These data suggest that treatment with LB might reduce hospital LOS and subsequently health-care costs, and additional cost savings outside the hospital room may factor into overall health-care cost savings. LB may reduce pain and the need for supplemental postsurgical opioids, thus reducing pain and opioid-associated expenses while improving patient satisfaction with postsurgical care. Pediatric patients undergoing spine surgery who received LB had significantly reduced in-hospital postsurgical opioid consumption, LOS, and hospital costs compared with those who did not.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.36469/jheor.2021.21967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049745PMC
April 2021

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids.

Pharmaceuticals (Basel) 2021 Mar 31;14(4). Epub 2021 Mar 31.

Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific -substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph14040304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066833PMC
March 2021

Persistence of symptoms up to 10 months following acute COVID-19 illness.

medRxiv 2021 Mar 8. Epub 2021 Mar 8.

Importance: COVID-19 symptoms are increasingly recognized to persist among a subset of individual following acute infection, but features associated with this persistence are not well-understood.

Objective: We aimed to identify individual features that predicted persistence of symptoms over at least 2 months at the time of survey completion.Design: Non-probability internet survey. Participants were asked to identify features of acute illness as well as persistence of symptoms at time of study completion. We used logistic regression models to examine association between sociodemographic and clinical features and persistence of symptoms at or beyond 2 months.

Setting: Ten waves of a fifty-state survey between June 13, 2020 and January 13, 2021.

Participants: 6,211 individuals who reported symptomatic COVID-19 illness confirmed by positive test or clinician diagnosis.

Exposure: symptomatic COVID-19 illness.

Results: Among 6,211 survey respondents reporting COVID-19 illness, with a mean age of 37.8 (SD 12.2) years and 45.1% female, 73.9% white, 10.0% Black, 9.9% Hispanic, and 3.1% Asian, a total of 4946 (79.6%) had recovered within less than 2 months, while 491 (7.9%) experienced symptoms for 2 months or more. Of the full cohort, 3.4% were symptomatic for 4 months or more and 2.2% for 6 months or more. In univariate analyses, individuals with persistent symptoms on average reported greater initial severity. In logistic regression models, older age was associated with greater risk of persistence (OR 1.10, 95% CI 1.01-1.19 for each decade beyond 40); otherwise, no significant associations with persistence were identified for gender, race/ethnicity, or income. Presence of headache was significantly associated with greater likelihood of persistence (OR 1.44, 95% CI 1.11-1.86), while fever was associated with diminished likelihood of persistence (OR 0.66, 95% CI 0.53-0.83).

Conclusion And Relevance: A subset of individuals experience persistent symptoms from 2 to more than 10 months after acute COVID-19 illness, particularly those who recall headache and absence of fever. In light of this prevalence, strategies for predicting and managing such sequelae are needed.

Trial Registration: NA.

Key Points: Which individuals are at greatest risk for post-acute sequelae of COVID-19? In this non-probability internet survey, among 6,211 individuals with symptomatic COVID-19 illness, 7.9% experienced persistence of symptoms lasting 2 months or longer. Older age, but not other sociodemographic features, was associated with risk for persistence, as was headache. Identifying individuals at greater risk for symptomatic persistence may facilitate development of targeted interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.03.07.21253072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987055PMC
March 2021

Improving the utility of evidence synthesis for decision makers in the face of insufficient evidence.

J Clin Epidemiol 2021 Mar 19. Epub 2021 Mar 19.

RTI-University of North Carolina EPC, Chapel Hill NC, USA.

Objective: To identify and suggest strategies to make insufficient evidence ratings in systematic reviews more actionable.

Study Design And Setting: A workgroup comprising members from the Evidence-Based Practice (EPC) Program of the Agency for Healthcare Research and Quality convened throughout 2020. We conducted iterative discussions considering information from three data sources: a literature review for relevant publications and frameworks, a review of a convenience sample of past systematic reviews conducted by the EPCs, and an audit of methods used in past EPC technical briefs.

Results: We identified five strategies for supplementing systematic review findings when evidence on benefits or harms is expected to be, or found to be, insufficient: 1) reconsider eligible study designs, 2) summarize indirect evidence, 3) summarize contextual and implementation evidence, 4) consider modelling, and 5) incorporate unpublished health system data in the evidence synthesis. While these strategies may not increase the strength of evidence, they may improve the utility of reports for decision makers. Adopting these strategies depends on feasibility, timeline, funding, and expertise of the systematic reviewers.

Conclusion: Throughout the process of evidence synthesis of early scoping, protocol development, review conduct, and review presentation, authors can consider these five strategies to supplement evidence with insufficient rating to make it more actionable for end-users.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jclinepi.2021.02.028DOI Listing
March 2021

Risk of Stroke Outcomes in Atrial Fibrillation Patients Treated with Rivaroxaban and Warfarin.

J Stroke Cerebrovasc Dis 2021 May 17;30(5):105715. Epub 2021 Mar 17.

Hartford HealthCare, Hartford, CT, United States.

Objectives: In a previous real-world study, rivaroxaban reduced the risk of stroke overall and severe stroke compared with warfarin in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study was to assess the reproducibility in a different database of our previously observed results (Alberts M, et al. Stroke. 2020;51:549-555) on the risk of severe stroke among NVAF patients in a different population treated with rivaroxaban or warfarin.

Material And Methods: This retrospective cohort study included patients from the IBM® MarketScan® Commercial and Medicare databases (2011-2019) who initiated rivaroxaban or warfarin after a diagnosis of NVAF, had ≥6 months of continuous health plan enrollment, had a CHADS-VASc score ≥2, and had no history of stroke or anticoagulant use. Patient data were assessed until the earliest occurrence of a primary inpatient diagnosis of stroke, death, end of health plan enrollment, or end of study. Stroke severity was defined by National Institutes of Health Stroke Scale (NIHSS) score, imputed by random forest model. Cox proportional hazard regression was used to compare risk of stroke between cohorts, balanced by inverse probability of treatment weighting.

Results: The mean observation period from index date to either stroke, or end of eligibility or end of data was 28 months. Data from 13,599 rivaroxaban and 39,861 warfarin patients were included. Stroke occurred in 272 rivaroxaban-treated patients (0.97/100 person-years [PY]) and 1,303 warfarin-treated patients (1.32/100 PY). Rivaroxaban patients had lower risk for stroke overall (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.88) and for minor (NIHSS 1 to <5; HR, 0.83; 95% CI, 0.74-0.93), moderate (NIHSS 5 to <16; HR, 0.88; 95% CI, 0.78-0.99), and severe stroke (NIHSS 16 to 42; HR, 0.44; 95% CI, 0.22-0.91).

Conclusions: The results of this study in a larger population of NVAF patients align with previous real-world findings and the ROCKET-AF trial by showing improved stroke prevention with rivaroxaban versus warfarin across all stroke severities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105715DOI Listing
May 2021

Healthcare costs before and after stroke in patients with non-valvular atrial fibrillation who initiated treatment with rivaroxaban or warfarin.

J Med Econ 2021 Jan-Dec;24(1):212-217

Hartford HealthCare, Hartford, CT, USA.

Aims: Rivaroxaban reduces stroke compared with warfarin in patients with non-valvular atrial fibrillation (NVAF). This study compared healthcare costs before and after stroke in NVAF patients treated with rivaroxaban or warfarin.

Materials And Methods: Using de-identified IBM MarketScan Commercial and Medicare databases, this retrospective cohort study (from 2011 to 2019) included patients with NVAF who initiated rivaroxaban or warfarin within 30 days after initial NVAF diagnosis. Patients who developed stroke were identified, and stroke severity was determined by the National Institutes of Health Stroke Scale (NIHSS) score, imputed by a random forest method. Total all-cause per-patient per-year (PPPY) costs of care were determined for patients: (1) who developed stroke during the pre- and post-stroke periods and (2) who remained stroke-free during the follow-up period. Treatment groups were balanced using inverse probability of treatment weighting.

Results: A total of 13,599 patients initiated rivaroxaban and 39,861 initiated warfarin, of which 272 (2.0%) and 1,303 (3.3%), respectively, developed stroke during a mean follow-up of 28 months. Among patients who developed stroke, PPPY costs increased from the pre-stroke to post-stroke period, with greater increases in the warfarin cohort relative to the rivaroxaban cohort. Overall, the costs increased by 1.78-fold for rivaroxaban vs 3.07-fold for warfarin; for less severe strokes (NIHSS < 5), costs increased 0.88-fold and 1.05-fold, respectively. Cost increases for more severe strokes (NIHSS ≥ 5) among rivaroxaban patients were half those for warfarin patients (3.19-fold vs 6.37-fold, respectively). Among patients without stroke, costs were similar during the follow-up period between the two treatment groups.

Conclusions: Total all-cause costs of care increased in the post-stroke period, and particularly in the patients treated with warfarin relative to those treated with rivaroxaban. The lower rate of stroke in the rivaroxaban cohort suggests that greater pre- to post-stroke cost increases result from more strokes occurring in the warfarin cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13696998.2021.1879563DOI Listing
January 2021

Behavioral Counseling to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults With Cardiovascular Risk Factors: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

JAMA 2020 11;324(20):2076-2094

Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon.

Importance: Cardiovascular disease is the leading cause of death in the US, and poor diet and lack of physical activity are major factors contributing to cardiovascular morbidity and mortality.

Objective: To review the benefits and harms of behavioral counseling interventions to improve diet and physical activity in adults with cardiovascular risk factors.

Data Sources: MEDLINE, PubMed, PsycINFO, and the Cochrane Central Register of Controlled Trials through September 2019; literature surveillance through July 24, 2020.

Study Selection: English-language randomized clinical trials (RCTs) of behavioral counseling interventions to help people with elevated blood pressure or lipid levels improve their diet and increase physical activity.

Data Extraction And Synthesis: Data were extracted from studies by one reviewer and checked by a second. Random-effects meta-analysis and qualitative synthesis were used.

Main Outcomes And Measures: Cardiovascular events, mortality, subjective well-being, cardiovascular risk factors, diet and physical activity measures (eg, minutes of physical activity, meeting physical activity recommendations), and harms. Interventions were categorized according to estimated contact time as low (≤30 minutes), medium (31-360 minutes), and high (>360 minutes).

Results: Ninety-four RCTs were included (N = 52 174). Behavioral counseling interventions involved a median of 6 contact hours and 12 sessions over the course of 12 months and varied in format and dietary recommendations; only 5% addressed physical activity alone. Interventions were associated with a lower risk of cardiovascular events (pooled relative risk, 0.80 [95% CI, 0.73-0.87]; 9 RCTs [n = 12 551]; I2 = 0%). Event rates were variable; in the largest trial (Prevención con Dieta Mediterránea [PREDIMED]), 3.6% in the intervention groups experienced a cardiovascular event, compared with 4.4% in the control group. Behavioral counseling interventions were associated with small, statistically significant reductions in continuous measures of blood pressure, low-density lipoprotein cholesterol levels, fasting glucose levels, and adiposity at 12 to 24 months' follow-up. Measurement of diet and physical activity was heterogeneous, and evidence suggested small improvements in diet consistent with the intervention recommendation targets but mixed findings and a more limited evidence base for physical activity. Adverse events were rare, with generally no group differences in serious adverse events, any adverse events, hospitalizations, musculoskeletal injuries, or withdrawals due to adverse events.

Conclusions And Relevance: Medium- and high-contact multisession behavioral counseling interventions to improve diet and increase physical activity for people with elevated blood pressure and lipid levels were effective in reducing cardiovascular events, blood pressure, low-density lipoproteins, and adiposity-related outcomes, with little to no risk of serious harm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.17108DOI Listing
November 2020

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.

Cancer Cell 2020 12 5;38(6):803-817.e4. Epub 2020 Nov 5.

Vanderbilt University Medical Center, Nashville, TN, USA.

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.10.011DOI Listing
December 2020

Black and White Differences in Colorectal Cancer Screening and Screening Outcomes: A Narrative Review.

Cancer Epidemiol Biomarkers Prev 2021 Jan 3;30(1):3-12. Epub 2020 Nov 3.

RAND Corporation, Santa Monica, California.

Racial disparities in colorectal cancer incidence are widely documented. There are two potential mechanisms for these disparities: differences in access to screening, including screening follow-up, and differences in underlying risk of colorectal cancer. We reviewed the literature for evidence of these two mechanisms. We show that higher colorectal cancer incidence in blacks relative to whites emerged only after the dissemination of screening and describe evidence of racial disparities in screening rates. In contrast to the strong evidence for differences in colorectal cancer screening utilization, there is limited evidence for racial differences in adenoma prevalence. In general, black and white patients who are screened have similar adenoma prevalence, though there is some evidence that advanced adenomas and adenomas in the proximal colon are somewhat more likely in black than white patients. We conclude that higher rates of colorectal cancer incidence among black patients are primarily driven by lower rates of colorectal cancer screening. Our findings highlight the need to increase black patients' access to quality screening to reduce colorectal cancer incidence and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-1537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855228PMC
January 2021

Real-world analysis of treatment patterns and clinical outcomes in patients with newly diagnosed chronic lymphocytic leukemia from seven Latin American countries.

Hematology 2020 Dec;25(1):366-371

Janssen Cilag Farmaceutica SA, Buenos Aires, Argentina.

Objective: To describe chronic lymphocytic leukemia (CLL) treatment patterns and patient outcomes in Latin America.

Methods: This chart review study (NCT02559583; 2008-2015)evaluated time to progression (TTP) and overall survival (OS) outcomes among patients with CLL who initiate done (= 261) to two ( = 96) lines of therapy (LOT) since diagnosis. Differences in TTP and OS were assessed by Kaplan-Meier analysis, with a log-rank test for statistical significance. Association between therapeutic regimen and risk for disease progression or death was estimated using Cox proportional hazard regression.

Results: The most commonly prescribed therapies in both LOTs were chlorambucil-, followed by fludarabine- and cyclophosphamide (C)/CHOP-based therapies. Chlorambucil- and C/CHOP-based therapies were largely prescribed to elderly patients (≥65 years) while fludarabine-based therapy was predominantly used by younger patients (≤65 years). In LOT1, relative to chlorambucil-administered patients, those prescribed fludarabine-based therapies had lower risk of disease progression (hazard ratio [HR] and 95% confidence interval [CI] 0.32 [0.19-0.54]), whereas C/CHOP-prescribed patients had higher risk (HR 95%CI 1.88 [1.17-3.04]). Similar results were observed in LOT2. There was no difference in OS between treatments in both LOTs.

Discussion: Novel therapies such as kinase inhibitors were rarely prescribed in LOT1 or LOT2in Latin America. The greater TTP observed forfludarabine-based therapies could be attributed to the fact that fludarabine-based therapies are predominantly administered to young and healthy patients.

Conclusion: Chlorambucil-based therapy, which has limited benefits, is frequently prescribed in Latin America. Prescribing novel agents for fludarabine-based therapy-ineligible patients with CLL is the need of the hour. ClinicalTrials.gov identifier: NCT02559583.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/16078454.2020.1833504DOI Listing
December 2020

Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease.

Diabetes 2021 02 16;70(2):589-602. Epub 2020 Oct 16.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-α/NF-κB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-κB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881868PMC
February 2021

Morbidity of marginal mandibular nerve post vascularized submental lymph node flap transplantation.

J Surg Oncol 2020 Dec 31;122(8):1747-1754. Epub 2020 Aug 31.

Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background: This study investigated the morbidity of the marginal mandibular nerve (MMN) post vascularized submental lymph node (VSLN) harvest.

Methods: The VSLN with sacrifying or preserving the medial platysma was retrospectively classified as group I or II. Midline deviation and horizontal tilt were subjectively evaluated. Horizontal, vertical, and "area distribution" of the lower lip excursions of the surgical site were objectively compared with the nonsurgical site.

Results: Seventeen patients in group I and 12 patients in group II were included. At a median follow-up of 48.6 ± 16.8 months in group I and 14.8 ± 7.5 months in group II, no MMN palsy was found in both groups. Median midline deviation and horizontal tilt were 4.53 ± 0.52 and 5 ± 0 in group I and 4.67 ± 0.65 and 5 ± 0 in group II, respectively (P = .419 and 1.000). Median horizontal, vertical and area of distribution of lower lip excursions were 97.5 ± 12.3%, 98.8 ± 14.4% and 87.2 ± 14.7% in group I, and 99.3 ± 15.1%, 95.8 ± 8.2% and 84.2 ± 14.2% in group II, respectively (P = .679, .948 and .711).

Conclusion: The VSLN flap was a safe procedure with minimal MMN morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.26191DOI Listing
December 2020

Optimizing Exogenous Surfactant as a Pulmonary Delivery Vehicle for Chicken Cathelicidin-2.

Sci Rep 2020 06 10;10(1):9392. Epub 2020 Jun 10.

Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.

The rising incidence of antibiotic-resistant lung infections has instigated a much-needed search for new therapeutic strategies. One proposed strategy is the use of exogenous surfactants to deliver antimicrobial peptides (AMPs), like CATH-2, to infected regions of the lung. CATH-2 can kill bacteria through a diverse range of antibacterial pathways and exogenous surfactant can improve pulmonary drug distribution. Unfortunately, mixing AMPs with commercially available exogenous surfactants has been shown to negatively impact their antimicrobial function. It was hypothesized that the phosphatidylglycerol component of surfactant was inhibiting AMP function and that an exogenous surfactant, with a reduced phosphatidylglycerol composition would increase peptide mediated killing at a distal site. To better understand how surfactant lipids interacted with CATH-2 and affected its function, isothermal titration calorimetry and solid-state nuclear magnetic resonance spectroscopy as well as bacterial killing curves against Pseudomonas aeruginosa were utilized. Additionally, the wet bridge transfer system was used to evaluate surfactant spreading and peptide transport. Phosphatidylglycerol was the only surfactant lipid to significantly inhibit CATH-2 function, showing a stronger electrostatic interaction with the peptide than other lipids. Although diluting the phosphatidylglycerol content in an existing surfactant, through the addition of other lipids, significantly improved peptide function and distal killing, it also reduced surfactant spreading. A synthetic phosphatidylglycerol-free surfactant however, was shown to further improve CATH-2 delivery and function at a remote site. Based on these in vitro experiments synthetic phosphatidylglycerol-free surfactants seem optimal for delivering AMPs to the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-66448-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287084PMC
June 2020

Smad4-dependent morphogenic signals control the maturation and axonal targeting of basal vomeronasal sensory neurons to the accessory olfactory bulb.

Development 2020 04 27;147(8). Epub 2020 Apr 27.

Department of Biological Sciences; The RNA Institute; University at Albany, State University of New York, Albany, NY 12222, USA

The vomeronasal organ (VNO) contains two main types of vomeronasal sensory neurons (VSNs) that express distinct vomeronasal receptor (VR) genes and localize to specific regions of the neuroepithelium. Morphogenic signals are crucial in defining neuronal identity and network formation; however, if and what signals control maturation and homeostasis of VSNs is largely unexplored. Here, we found transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signal transduction in postnatal mice, with BMP signaling being restricted to basal VSNs and at the marginal zones of the VNO: the site of neurogenesis. Using different Smad4 conditional knockout mouse models, we disrupted canonical TGFβ/BMP signaling in either maturing basal VSNs (bVSNs) or all mature VSNs. Smad4 loss of function in immature bVSNs compromises dendritic knob formation, pheromone induced activation, correct glomeruli formation in the accessory olfactory bulb (AOB) and survival. However, Smad4 loss of function in all mature VSNs only compromises correct glomeruli formation in the posterior AOB. Our results indicate that Smad4-mediated signaling drives the functional maturation and connectivity of basal VSNs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.184036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197725PMC
April 2020

A Narrative Review and Proposed Framework for Using Health System Data with Systematic Reviews to Support Decision-making.

J Gen Intern Med 2020 06 1;35(6):1830-1835. Epub 2020 Apr 1.

Veterans Health Administration Health Services Research Department Evidence Synthesis Program, Portland, OR, USA.

Systematic reviews are a necessary, but often insufficient, source of information to address the decision-making needs of health systems. In this paper, we address when and how the use of health system data might make systematic reviews more useful to decision-makers. We describe the different ways in which health system data can be used with systematic reviews, identify scenarios in which the addition of health system data may be most helpful (i.e., to improve the strength of evidence, to improve the applicability of evidence, and to inform the implementation of evidence), and discuss the importance of framing the limitations and considerations when using unpublished health system data in reviews. We developed a framework to guide the use of health system data alongside systematic reviews based on a narrative review of the literature and empirical experience. We also offer recommendations to improve the transparency of reporting when using health system data alongside systematic reviews including providing rationale for employing additional data, details on the data source, critical appraisal to understand study design biases as well as limitations in data and information quality, and how the unpublished data compares to the systematically reviewed data. Future methodological work on how best to handle internal and external validity concerns of health system data in the context of systematically reviewed data and work on developing infrastructure to do this type of work is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11606-020-05783-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280421PMC
June 2020

HIPK4 is essential for murine spermiogenesis.

Elife 2020 03 12;9. Epub 2020 Mar 12.

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.

Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways that coordinate this process are not well understood, and we demonstrate here that homeodomain-interacting protein kinase 4 (HIPK4) is essential for spermiogenesis and male fertility in mice. HIPK4 is predominantly expressed in round and early elongating spermatids, and knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. mutant sperm have reduced oocyte binding and are incompetent for in vitro fertilization, but they can still produce viable offspring via intracytoplasmic sperm injection. Optical and electron microscopy of HIPK4-null male germ cells reveals defects in the filamentous actin (F-actin)-scaffolded acroplaxome during spermatid elongation and abnormal head morphologies in mature spermatozoa. We further observe that HIPK4 overexpression induces branched F-actin structures in cultured fibroblasts and that HIPK4 deficiency alters the subcellular distribution of an F-actin capping protein in the testis, supporting a role for this kinase in cytoskeleton remodeling. Our findings establish HIPK4 as an essential regulator of sperm head shaping and potential target for male contraception.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.50209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067585PMC
March 2020

Emergency Department Visits and Subsequent Hospital Admission Trends for Patients with Chest Pain and a History of Coronary Artery Disease.

Cardiol Ther 2020 Jun 2;9(1):153-165. Epub 2020 Mar 2.

Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Neville House Second Floor, Boston, MA, 02115, USA.

Introduction: Hospitalization is the largest component of health care spending in the United States. Most hospitalized patients first visit the emergency department (ED), where hospitalization decisions are made. Optimal utilization of hospital resources is critical for all stakeholders.

Methods: We performed a population-based, cross-sectional study evaluating ED visits and subsequent inpatient admissions for patients with coronary artery disease (CAD) and chest pain (CP) suggestive of CAD from 2006 to 2013 using the Nationwide Emergency Department Sample database weighted for national estimates. We analyzed trends using a generalized linear regression model with a Poisson distribution and Wald test.

Results: From 2006 to 2013, there was a 15% decrease in ED visits for CAD (p < 0.01), while ED visit rates for CP increased 31% (p < 0.01). Subsequent inpatient admission rates decreased 18% for CAD (p < 0.01) and 33% for CP (p < 0.01). Trends were not modified by patient and hospital strata.

Conclusion: ED visits and subsequent inpatient admissions resulting from CAD decreased from 2006 to 2013. Patients with CP had a substantially higher number of ED visits, with a significant decline in inpatient admissions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40119-020-00168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237631PMC
June 2020

International Microsurgery Club: An Effective Online Collaboration System.

J Reconstr Microsurg 2020 Jul 28;36(6):412-419. Epub 2020 Feb 28.

Department of Plastic and Reconstructive Surgery, Linkou Medical Center, Chang Gung Memorial Hospital, Chang Gung Medical College, Chang Gung University, Taoyuan, Taiwan.

Background:  This study aimed to determine if International Microsurgery Club (IMC) is an effective online resource for microsurgeons worldwide, in providing an avenue for timely group discussions and advice regarding complicated cases, and an avenue for collaboration and information sharing.

Methods:  All posts on the IMC Facebook group from member 1 to 8,000 were analyzed according to inclusion criteria and categorized into three categories-case discussion, question, and information sharing. Posts were retrospectively analyzed for number of responses, time of responses, number of "likes," number of treatment options, time of day, and demographics of authors and responders.

Results:  A retrospective analysis of 531 cases showed an average response rate of 75.7% within 1 hour and as membership grew. The response rate stabilized averaging between 72.5 and 78% across all times of the day. An average of 11.8 microsurgeons was involved per case discussion, and 5.7 treatment options were provided per case.

Conclusion:  IMC is shown to be an effective resource to allow microsurgeons to access timely advice from other microsurgeons without time and distance limitation, and to have interactive group discussions on complicated cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1702158DOI Listing
July 2020