tbuckley/cabot-search huggingface dataset:
Association of Opioid Dose Reduction With Opioid Overdose and Opioid Use Disorder Among Patients Receiving High-Dose, Long-term Opioid Therapy in North Carolina
Authors: Bethany L. DiPrete, Shabbar I. Ranapurwala, Courtney N. Maierhofer, Naoko Fulcher, Paul R. Chelminski, Christopher L. Ringwalt, Timothy J. Ives, Nabarun Dasgupta, Vivian F. Go, Brian W. Pence
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Rapid reduction or discontinuation of long-term opioid therapy may increase risk of opioid overdose or opioid use disorder (OUD). Current guidelines for chronic pain management caution against rapid dose reduction but are based on limited evidence. <h3>Objective</h3> To characterize the association between rapid reduction or abrupt discontinuation of opioid therapy (vs maintained or gradual reduction) and incidence of opioid overdose and OUD among patients prescribed high-dose, long-term opioid therapy (HDLTOT). <h3>Design, Setting, and Participants</h3> This retrospective cohort study was conducted among patients aged 18 to 64 years who were prescribed HDLTOT (≥90 daily morphine milligram equivalents for ≥90% of 90 days) from January 2006 to September 2018, with follow-up up to 4 years after cohort entry. Claims data were drawn from a large private health insurer in North Carolina and analyzed from March 1, 2006, to September 30, 2018. <h3>Exposures</h3> Time-varying exposure of rapid dose reduction or discontinuation (&gt;10% dose reduction/week) vs maintenance, increase, or gradual reduction or discontinuation. <h3>Main Outcomes and Measures</h3> The main outcome was incident opioid overdose (fatal or nonfatal) or diagnosed OUD. Inverse probability-weighted cumulative incidence of outcomes were estimated using the cumulative incidence function and hazard ratios (HRs) using marginal structural Fine-Gray models as a function of rapid dose tapering or discontinuation (vs gradual reduction or discontinuation or maintained or increased), accounting for competing risks. <h3>Results</h3> A total of 19 443 patients (median [IQR] age, 49 [41-55] years; 10 073 [51.8%] men) who received HDLTOT were identified. Rapid reduction or discontinuation was associated with higher risk of fatal and nonfatal overdoses compared with gradual reduction after the first year (year 1: HR, 1.43; 95% CI, 0.94-2.18; years 2-4: HR, 1.95; 95% CI, 1.31-2.90). There was no association between rapid reduction or discontinuation and diagnosed OUD through 2 years of follow-up; however, the hazard of incident OUD among patients exposed to rapid tapering or discontinuation was greater 25 to 48 months after the start of follow-up (HR, 1.28; 95% CI, 1.01-1.63). <h3>Conclusions and Relevance</h3> In this cohort study, rapid dose reduction or discontinuation was associated with increased risk of opioid overdose and OUD during long-term follow-up. These findings reinforce prior concerns about safety of rapid dose reductions for patients receiving HDLTOT and highlight the need for caution when reducing opioid doses.
Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial
Authors: Ju Hee Oh, Dae Won Jun, Hye Young Kim, Seung Min Lee, Eileen L. Yoon, Jungwook Hwang, Jung Hwan Park, Hanbi Lee, Wankyu Kim, Hyunsung Kim
Journal: Clinical and Molecular Hepatology (2022)

We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.
Effects of Anti–Tumor Necrosis Factor Therapy on Osteoblastic Activity at Sites of Inflammatory and Structural Lesions in Radiographic Axial Spondyloarthritis: A Prospective <scp>Proof‐of‐Concept</scp> Study Using Positron Emission Tomography/Magnetic Resonance Imaging of the Sacroiliac Joints and Spine
Authors: Nils Martin Bruckmann, Christoph Rischpler, Styliani Tsiami, Julian Kirchner, Daniel B. Abrar, Timo Bartel, Jens Theysohn, Lale Umutlu, Ken Herrmann, Wolfgang P. Fendler, Christian Buchbender, Gerald Antoch, Lino M. Sawicki, Athanasios Tsobanelis, Juergen Braun, Xenofon Baraliakos
Journal: Arthritis & Rheumatology (2022)

Proof-of-concept trial to determine the effects of tumor necrosis factor inhibitor (TNFi) therapy on osteoblastic activity at sites of inflammatory and structural lesions in patients with radiographic axial spondyloarthritis (SpA), using fluorine 18-labeled NaF (18 F-NaF) positron emission tomography/magnetic resonance imaging (PET/MRI).Sixteen patients with clinically active radiographic axial SpA were prospectively enrolled to receive TNFi treatment and undergo 18 F-NaF PET/MRI of the sacroiliac (SI) joints and spine at baseline and at a follow-up visit 3-6 months after treatment initiation. Three readers (1 for PET/MRI and 2 for conventional MRI) evaluated all images, blinded to time point. Bone marrow edema, structural lesions (i.e., fat lesions, sclerosis, erosions, and ankylosis), and 18 F-NaF uptake at SI joint quadrants and vertebral corners (VCs) were recorded.Overall, 11 male and 5 female patients (mean age ± SD 38.6 ± 12.0 years) were followed up for a mean duration of 4.6 months (range 3-6). 18 F-NaF PET/MRI was conducted on SI joints for 16 patients and the spine for 10; 128 SI joint quadrants and 920 VCs were analyzed at each time point. At baseline, 18 F-NaF uptake was demonstrated in 96.0% of SI joint quadrants with bone marrow edema, 94.2% with sclerosis, and 88.3% with fat lesions. At follow-up, 65.3% of SI joint quadrants with bone marrow edema (P < 0.001), 33.8% with sclerosis (P = 0.23), and 24.5% with fat lesions (P = 0.01) had less 18 F-NaF uptake, compared with baseline. For VCs, 18 F-NaF uptake at baseline was found in 81.5% of edges with sclerosis, 41.9% with fat lesions, and 33.7% with bone marrow edema. At follow-up, 73.5% of VCs with bone marrow edema (P = 0.01), 53.3% with fat lesions (P = 0.03), and 55.6% with sclerosis (P = 0.16) showed less 18 F-NaF uptake, compared with baseline.Anti-TNF antibody treatment led to a significant decrease in osteoblastic activity within 3-6 months, especially, but not solely, at sites of inflammation. Larger data sets are needed for confirmation of the antiosteoblastic effects of TNFi for the prevention of radiographic progression in axial SpA.
The Importance of Office Blood Pressure Measurement Frequency and Methodology in Evaluating the Prevalence of Hypertension in Children and Adolescents With Type 1 Diabetes: The SWEET International Database
Authors: Andriani Vazeou, Sascha R. Tittel, Niels H. Birkebaek, Olga Kordonouri, Violeta Iotova, Barbara Piccini, Banshi Saboo, Auste Pundziute Lyckå, Sebastian Seget, David M. Maahs, George Stergiou
Journal: Diabetes Care (2022)

The prevalence of hypertension is higher in children and adolescents with type 1 diabetes (T1D) compared with those without. This retrospective analysis of a large cohort of children and adolescents with T1D from the SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) international consortium of pediatric diabetes centers aimed to 1) estimate the prevalence of elevated office blood pressure (BP) and hypertension and 2) investigate the influence of BP measurement methodology on the prevalence of hypertension.A total of 27,120 individuals with T1D, aged 5-18 years, were analyzed. Participants were grouped into those with BP measurements at three or more visits (n = 10,440) and fewer than 3 visits (n = 16,680) per year and stratified by age and sex. A subgroup analysis was performed on 15,742 individuals from centers providing a score indicating BP measurement accuracy.Among participants with BP measurement at three or more visits, the prevalence of hypertension was lower compared with those with fewer than three visits (10.8% vs. 17.5% P < 0.001), whereas elevated BP and normotension were higher (17.5% and 71.7% vs. 15.3% and 67.1%, respectively; both P < 0.001). The prevalence of hypertension and elevated BP was higher in individuals aged ≥13 years than in younger ones (P < 0.001) and in male than female participants (P < 0.001). In linear regression models, systolic and diastolic BP was independently determined by the BP measurement methodology.The estimated prevalence of elevated BP and hypertension in children and adolescents with T1D is ∼30% and depends on the BP measurement methodology. Less frequent BP evaluation may overestimate the prevalence of hypertension.
Association of Socioeconomic Status and Infarct Volume With Functional Outcome in Patients With Ischemic Stroke
Authors: Ahmed Ghoneem, Michael T. Osborne, Shady Abohashem, Nicki Naddaf, Tomas Patrich, Tawseef Dar, Amr Abdelbaky, Adeeb Al-Quthami, Jason H. Wasfy, Katrina A. Armstrong, Hakan Ay, Ahmed Tawakol
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Long-term disability after stroke is associated with socioeconomic status (SES). However, the reasons for such disparities in outcomes remain unclear. <h3>Objective</h3> To assess whether lower SES is associated with larger admission infarct volume and whether initial infarct volume accounts for the association between SES and long-term disability. <h3>Design, Setting, and Participants</h3> This cohort study was conducted in a prospective, consecutive population (n = 1256) presenting with acute ischemic stroke who underwent magnetic resonance imaging (MRI) within 24 hours of admission. Patients were recruited in Massachusetts General Hospital, Boston, from May 31, 2009, to December 31, 2011. Data were analyzed from May 1, 2019, until June 30, 2020. <h3>Main Outcomes and Measures</h3> Initial stroke severity (within 24 hours of presentation) was determined using clinical (National Institutes of Health Stroke Scale [NIHSS]) and imaging (infarct volume by diffusion-weighted MRI) measures. Stroke etiologic subtypes were determined using the Causative Classification of Ischemic Stroke algorithm. Long-term stroke disability was measured using the modified Rankin Scale. Socioeconomic status was estimated using zip code–derived median household income and census block group–derived area deprivation index (ADI). Regression and mediation analyses were performed. <h3>Results</h3> A total of 1098 patients had imaging and SES data available (mean [SD] age, 68.1 [15.7] years; 607 men [55.3%]). Income was inversely associated with initial infarct volume (standardized β, −0.074 [95% CI, −0.127 to −0.020];<i>P</i> = .007), initial NIHSS (standardized β, −0.113 [95% CI, −0.171 to −0.054];<i>P</i> &lt; .001), and long-term disability (standardized β, −0.092 [95% CI, −0.149 to −0.035];<i>P</i> = .001), which remained significant after multivariable adjustments. Initial stroke severity accounted for 64% of the association between SES and long-term disability (standardized β, −0.063 [95% CI, −0.095 to −0.029];<i>P</i> &lt; .05). Findings were similar when SES was alternatively assessed using ADI. <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest that lower SES is associated with larger infarct volumes on presentation. These SES-associated differences in initial stroke severity accounted for most of the subsequent disparities in long-term disability in this study. These findings shift the culpability for SES-associated disparities in poststroke disability from poststroke factors to those that precede presentation.
An online breathing and wellbeing programme (ENO Breathe) for people with persistent symptoms following COVID-19: a parallel-group, single-blind, randomised controlled trial
Authors: Keir E J Philip, Harriet Owles, Stephanie McVey, Tanja Pagnuco, Katie Bruce, Harry Brunjes, Winston Banya, Jenny Mollica, Adam Lound, Suzi Zumpe, Amiad M Abrahams, Vijay Padmanaban, Thomas H Hardy, Adam Lewis, Ajit Lalvani, Sarah Elkin, Nicholas S Hopkinson
Journal: The Lancet Respiratory Medicine (2022)

There are few evidence-based interventions for long COVID; however, holistic approaches supporting recovery are advocated. We assessed whether an online breathing and wellbeing programme improves health related quality-of-life (HRQoL) in people with persisting breathlessness following COVID-19.
Seroprevalence of Infection-Induced SARS-CoV-2 Antibodies — United States, September 2021–February 2022
Authors: Kristie E.N. Clarke, Jefferson M. Jones, Yangyang Deng, Elise Nycz, Adam Lee, Ronaldo Iachan, Adi V. Gundlapalli, Aron J. Hall, Adam MacNeil
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In December 2021, the B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19, became predominant in the United States. Subsequently, national COVID-19 case rates peaked at their highest recorded levels.* Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, the proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19. This report uses data from CDC's national commercial laboratory seroprevalence study and the 2018 American Community Survey to examine U.S. trends in infection-induced SARS-CoV-2 seroprevalence during September 2021-February 2022, by age group.
Low-Dose Dasiglucagon Versus Oral Glucose for Prevention of Insulin-Induced Hypoglycemia in People With Type 1 Diabetes: A Phase 2, Randomized, Three-Arm Crossover Study
Authors: Christian Laugesen, Ajenthen G. Ranjan, Signe Schmidt, Kirsten Nørgaard
Journal: Diabetes Care (2022)

OBJECTIVE To compare the efficacy of low-dose subcutaneous dasiglucagon with oral glucose for prevention of insulin-induced hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS Twenty adults with type 1 diabetes using multiple daily injection or insulin pump therapy completed a phase 2, randomized, three-arm crossover study. On each study visit, an individualized subcutaneous insulin bolus was administered aiming for a plasma glucose (PG) concentration of 3.0 mmol/L (54 mg/dL). When a PG concentration of 4.5 mmol/L (81 mg/dL) was reached, 15 g oral glucose (CHO) from dextrose tablets, 80 µg dasiglucagon (D80), or 120 µg dasiglucagon (D120) was administered. PG was measured frequently for the following 180 min. RESULTS Hypoglycemia (&amp;lt;3.9 mmol/L [70 mg/dL]) occurred in 10 participants after CHO, in 5 after D80, and in 4 after D120 (CHO vs. D80, P = 0.096; CHO vs. D120, P = 0.034). Time spent in hypoglycemia (&amp;lt;3.9 mmol/L [70 mg/dL]) was 14%, 7%, and 6% for CHO, D80, and D120, respectively (P = 0.273). The median time (95% CI) from intervention to first increase in PG of 1.1 mmol/L (20 mg/dL) was 30 (25–50), 15 (15–20), and 15 (15–20) minutes for CHO, D80, and D120, respectively (CHO vs. D80, P = 0.006; CHO vs. D120, P = 0.003). Episodes of nausea were numerically, but not significantly, higher after dasiglucagon administration. No significant differences in visual analog scale-assessed adverse effects were observed between interventions. CONCLUSIONS Low-dose dasiglucagon safely and effectively prevented insulin-induced hypoglycemia with a faster glucose-elevating profile than oral glucose.
SunRISe-1: Phase 2b study of TAR-200 plus cetrelimab, TAR-200 alone, or cetrelimab alone in participants with high-risk nonmuscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin who are ineligible for or decline radical cystectomy.
Authors: Michiel Simon Van Der Heijden, Christopher Cutie, Shalaka Hampras, Charu Indoria, Rachel Stewart, Milin Acharya, Katherine Stromberg, Xiang Li, Neil Beeharry, John Maffeo, Joseph M Jacob
Journal: Journal of Clinical Oncology (2022)

TPS593 Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) unresponsive to intravesical bacillus Calmette–Guérin (BCG). TAR-200 is an intravesical drug delivery system for local continuous release of gemcitabine within the bladder. The current study will assess the rate of complete response (CR) upon treatment with TAR-200 + systemic cetrelimab (CET [anti–PD-1 antibody]), TAR-200, and CET in BCG-unresponsive participants with HR-NMIBC who are ineligible for or decline radical cystectomy (RC). Methods: SunRISe-1 (NCT04640623) is an open-label, parallel-group, multicenter phase 2b study designed to assess the efficacy and safety of TAR-200 + CET, TAR-200 alone, and CET alone in participants with BCG-unresponsive HR-NMIBC. Eligible participants are aged ≥ 18 years with ECOG PS 0, 1, or 2 and recurrent or persistent histologically confirmed HR-NMIBC (carcinoma in situ) with or without papillary disease (T1, high-grade Ta), who have been diagnosed within 12 months of last BCG treatment and are ineligible for or declined RC. Participants (N≈200) are randomized 2:1:1 to receive TAR-200 + CET (Cohort 1, n≈100), TAR-200 (Cohort 2, n≈50), or CET (Cohort 3, n≈50). In Cohorts 1 and 2, participants receive intravesical TAR-200 every 3 weeks through Week 24, and every 12 weeks thereafter until Week 96. In Cohorts 1 and 3, participants receive CET until Week 78. Primary disease assessments (cystoscopy, urine cytology, transurethral resection of bladder tumor [TURBT], and magnetic resonance imaging/computed tomography) are made at baseline; subsequent cystoscopy and centrally read urine cytology are performed every 12 weeks through Year 2, every 24 weeks until end of Year 3, and in Year 4 and Year 5 in accordance with institutional standards of care. TURBT is conducted at 24 and 48 weeks. The primary end point for the 3 cohorts is overall CR rate at any time point. Secondary end points include duration of response (ie, from time of first CR achieved to first evidence of recurrence, progression, or death [whichever is earlier] for participants who achieve a CR), overall survival, PK immunogenicity of cetrelimab, safety and tolerability, and patient-reported outcomes. Exploratory end points include incidence and time to cystectomy (measured from randomization to date of cystectomy), biomarkers, and health care resource utilization. This study opened in January 2021 and is enrolling participants at ≈165 study sites worldwide. Currently, the study is active in 13 countries with 12 participants enrolled as of September 12, 2021. Clinical trial information: NCT04640623.
The intrinsic and microenvironmental features of diffuse midline glioma: Implications for the development of effective immunotherapeutic treatment strategies
Authors: Mika L Persson, Alicia M Douglas, Frank Alvaro, Pouya Faridi, Martin R Larsen, Marta M Alonso, Nicholas A Vitanza, Matthew D Dun
Journal: Neuro-Oncology (2022)

Diffuse midline glioma (DMG), including those of the brainstem (diffuse intrinsic pontine glioma), are pediatric tumors of the central nervous system (CNS). Recognized as the most lethal of all childhood cancers, palliative radiotherapy remains the only proven treatment option, however, even for those that respond, survival is only temporarily extended. DMG harbor an immunologically "cold" tumor microenvironment (TME) with few infiltrating immune cells. The mechanisms underpinning the cold TME are not well understood. Low expression levels of immune checkpoint proteins, including PD-1, PD-L1, and CTLA-4, are recurring features of DMG and likely contribute to the lack of response to immune checkpoint inhibitors (ICIs). The unique epigenetic signatures (including stem cell-like methylation patterns), a low tumor mutational burden, and recurring somatic mutations (H3K27M, TP53, ACVR1, MYC, and PIK3CA), possibly play a role in the reduced efficacy of traditional immunotherapies. Therefore, to circumvent the lack of efficacy thus far seen for the use of ICIs, adoptive cell transfer (including chimeric antigen receptor T cells) and the use of oncolytic viruses, are currently being evaluated for the treatment of DMG. It remains an absolute imperative that we improve our understanding of DMG's intrinsic and TME features if patients are to realize the potential benefits offered by these sophisticated treatments. Herein, we summarize the limitations of immunotherapeutic approaches, highlight the emerging safety and clinical efficacy shown for sophisticated cell-based therapies, as well as the evolving knowledge underpinning the DMG-immune axis, to guide the development of immunotherapies that we hope will improve outcomes.
Concerns Remain Regarding the Association of Sitting Time and Physical Activity With Cancer Survivorship—Reply
Authors: Chao Cao, Christine M. Friedenreich, Lin Yang
Journal: JAMA Oncology (2022)

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