tbuckley/cabot-search huggingface dataset:
Prevalence of SARS-CoV-2 in Karnataka, India
Authors: Manoj Mohanan, Anup Malani, Kaushik Krishnan, Anu Acharya
Journal: JAMA (2021)

Prevalence of SARS-CoV-2 in Karnataka, IndiaLow-and middle-income countries contain the majority of confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).India has the second highest number of reported cases, but most seroprevalence estimates come from cities. Cities, with denser population, are more vulnerable to SARS-CoV-2.However, millions of city workers fled to rural India where lockdown was less stringent.We assessed SARS-CoV-2 prevalence among volunteers from population-representative households in urban and rural areas of the state of Karnataka (population, 67.5 million).Methods | This study was approved by the Indian government and institutional review boards at participating institutions.Written informed consent was obtained from all participants (orally if respondents were unable to read or write).The sample was drawn from a population-representative panel survey, the Consumer Pyramids Household Survey 1 (CPHS) (details in the eAppendix in the Supplement).The primary sampling units were towns (urban) or villages (rural); the ultimate sampling units were households.From the CPHS's 9717 Karnataka households, we randomly selected 2912 to represent urban and rural areas of 5 state regions.We surveyed consenting household members aged 12 years or older between June 15 and August 29, 2020 (during partial lockdown).We requested 5 mL of blood and a nasopharyngeal swab from 1 volunteer per household.We compared the sex and age distribution of volunteers with the CPHS and the 2021 projection from the 2011 census.
Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA)
Authors: J. Randolph Hecht, Sara Lonardi, Johanna Bendell, Hao-Wen Sim, Teresa Macarulla, Charles D. Lopez, Eric Van Cutsem, Andres J. Muñoz Martin, Joon Oh Park, Richard Greil, Hong Wang, Rebecca R. Hozak, Ivelina Gueorguieva, Yong Lin, Sujata Rao, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2021)

PURPOSE SEQUOIA compared efficacy and safety of adding pegilodecakin (PEG), a pegylated recombinant human interleukin (IL)-10, with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients following progression on first-line gemcitabine-containing therapy with metastatic pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS SEQUOIA, a randomized, global phase III study, compared FOLFOX with PEG + FOLFOX as second line in gemcitabine-refractory PDAC. Patients were randomly assigned 1:1 (PEG + FOLFOX:FOLFOX) and stratified by prior gemcitabine and region. Eligible patients had only one prior gemcitabine-containing treatment. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), response evaluation per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1, and safety. Exploratory analyses included biomarkers related to immune activation. RESULTS Between March 1, 2017, and September 9, 2019, 567 patients were randomly assigned PEG + FOLFOX (n = 283) or FOLFOX (n = 284). Most (94.7%) patients received prior gemcitabine plus nab paclitaxel. OS was similar comparing PEG + FOLFOX versus FOLFOX (median: 5.8 v 6.3 months; hazard ratio = 1.045; 95% CI, 0.863 to 1.265). Also, PFS (median 2.1 v 2.1 months; hazard ratio = 0.981; 95% CI, 0.808 to 1.190) and objective response rate (4.6% v 5.6%) were similar between the treatment arms. Most common (≥ 35%) treatment-emergent adverse events in PEG + FOLFOX versus FOLFOX were thrombocytopenia (55% v 20%), anemia (40% v 16%), fatigue (61% v 45%), neutropenia (39% v 28%), abdominal pain (37% v 29%), nausea (45% v 41%), neuropathy (37% v 38%), and decreased appetite (35% v 31%). Exploratory analyses revealed increases in total IL-18, interferon (IFN)-γ, and granzyme B and decreases in transforming growth factor (TGF)-β with the addition of PEG. CONCLUSION PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.
Author Correction: High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
Authors: Kobe C. Yuen, Li-Fen Liu, Vinita Gupta, Shravan Madireddi, Shilpa Keerthivasan, Congfen Li, Deepali Rishipathak, Patrick Williams, Edward E. Kadel, Hartmut Koeppen, Ying-Jiun Chen, Zora Modrusan, Jane L. Grogan, Romain Banchereau, Ning Leng, AnnChristine Thastrom, Xiadong Shen, Kenji Hashimoto, Darren Tayama, Michiel S. van der Heijden, Jonathan E. Rosenberg, David F. McDermott, Thomas Powles, Priti S. Hegde, Mahrukh A. Huseni, Sanjeev Mariathasan
Journal: Nature Medicine (2021)
Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement
Authors: Ashley Wu, Matthew A. Scult, Emily D. Barnes, Jessica A. Betancourt, Avital Falk, Faith M. Gunning
Journal: npj Digital Medicine (2021)

Abstract Meta-analyses have shown that digital mental health apps can be efficacious in reducing symptoms of depression and anxiety. However, real-world usage of apps is typically not sustained over time, and no studies systematically examine which features increase sustained engagement with apps or the relationship between engagement features and clinical efficacy. We conducted a systematic search of the literature to identify empirical studies that (1) investigate standalone apps for depression and/or anxiety in symptomatic participants and (2) report at least one measure of engagement. Features intended to increase engagement were categorized using the persuasive system design (PSD) framework and principles of behavioral economics. Twenty-five studies with 4159 participants were included in the analysis. PSD features were commonly used, whereas behavioral economics techniques were not. Smartphone apps were efficacious in treating symptoms of anxiety and depression in randomized controlled trials, with overall small-to-medium effects ( g = 0.2888, SE = 0.0999, z(15) = 2.89, p = 0.0119, Q(df = 14) = 41.93, p &lt; 0.0001, I 2 = 66.6%), and apps that employed a greater number of engagement features as compared to the control condition had larger effect sizes (β = 0.0450, SE = 0.0164, t(15) = 2.7344, p = 0.0161). We observed an unexpected negative association between PSD features and engagement, as measured by completion rate (β = −0.0293, SE = 0.0121, t(17) = 02.4142, p = 0.0281). Overall, PSD features show promise for augmenting app efficacy, though engagement, as reflected in study completion, may not be the primary factor driving this association. The results suggest that expanding the use of PSD features in mental health apps may increase clinical benefits and that other techniques, such as those informed by behavioral economics, are employed infrequently.
Microfluidic Reconstitution of Tumor Microenvironment for Nanomedical Applications
Authors: Hyun Jeong Oh, Jaehoon Kim, Hyunho Kim, Nakwon Choi, Seok Chung
Journal: Advanced Healthcare Materials (2021)

Nanoparticles have an extensive range of diagnostic and therapeutic applications in cancer treatment. However, their current clinical translation is slow, mainly due to the failure to develop preclinical evaluation techniques that can draw similar conclusions to clinical outcomes by adequately mimicking nanoparticle behavior in complicated tumor microenvironments (TMEs). Microfluidic methods offer significant advantages over conventional in vitro methods to resolve these challenges by recapitulating physiological cues of the TME such as the extracellular matrix, shear stress, interstitial flow, soluble factors, oxygen, and nutrient gradients. The methods are capable of de-coupling microenvironmental features, spatiotemporal controlling of experimental sequences, and high throughput readouts in situ. This progress report highlights the recent achievements of microfluidic models to reconstitute the physiological microenvironment, especially for nanomedical tools for cancer treatment.
A serum-based DNA methylation assay provides accurate detection of glioma
Authors: Thais S Sabedot, Tathiane M Malta, James Snyder, Kevin Nelson, Michael Wells, Ana C deCarvalho, Abir Mukherjee, Dhananjay A Chitale, Maritza S Mosella, Artem Sokolov, Karam P Asmaro, Adam Robin, Mark L Rosenblum, Tom Mikkelsen, Jack Rock, Laila M Poisson, Ian Lee, Tobias Walbert, Steven Kalkanis, Antonio Iavarone, Ana Valeria Castro, Houtan Noushmehr
Journal: Neuro-Oncology (2021)

The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches.Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients.Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment).Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.
Assessment of Spanish Translation of Websites at Top-Ranked US Hospitals
Authors: Christopher Cole Honeycutt, Karina Moreno Bueno, Tamara Tran, Michael Gao, Suresh Balu, Mark Sendak
Journal: JAMA Network Open (2021)

This cross-sectional study examines whether Spanish translation of top US hospital websites is associated with hospitals with public medical schools, children’s hospitals, larger Latinx population, or local Immigration and Customs Enforcement activities.
Abstract PO023: Preliminary data on metformin therapy in <i>DICER1</i>-deleted endometrial cancer
Authors: Xiyin Wang, Robert Emerson, Russell Broaddus, John Lydon, Francesco DeMayo, Shannon M. Hawkins
Journal: Clinical Cancer Research (2021)

Abstract We created and characterized the first genetically engineered mouse model of poorly-differentiated endometrial adenocarcinoma (dcKO, PgrCre; Ptenflox/flox; Dicer1flox/flox). As an additional novel model system, using CRISPR-Cas9, we created and characterized an isogenic cell line with the deletion of DICER1 (DICER1−/− Ishikawa cells). Transcriptomic profiling across mouse and human models revealed activated pathways, including AMP kinase and insulin signaling. Ingenuity Pathway Analysis revealed metformin as a likely therapeutic target. Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer in women. However, recent clinical trials showed combined treatment of metformin with paclitaxel and carboplatin was not significantly associated with increased progression-free survival or overall survival for advanced or recurrent endometrial cancer. To test the effects of metformin in our mouse model, female mice received ad lib water containing metformin (5 mg/mL) or water beginning at weaning. Survival studies showed worse survival for well-differentiated endometrial adenocarcinoma (Pten cKO, PgrCre; Ptenflox/flox; Dicer1+/+) with treatment with metformin (P=0.007), while there was no difference for dcKO mice treated with metformin. Similarly, in vitro studies showed that the treatment of DICER1−/− Ishikawa cells treated with metformin did not affect cellular proliferation. Our in vivo and in vitro model systems represent important tools to study metformin and other therapeutics for rare yet aggressive endometrial cancers. Citation Format: Xiyin Wang, Robert Emerson, Russell Broaddus, John Lydon, Francesco DeMayo, Shannon M. Hawkins. Preliminary data on metformin therapy in DICER1-deleted endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO023.
A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis
Authors: Stephen A. Harrison, Mustafa R. Bashir, Kyoung-Jin Lee, Jennifer Shim-Lopez, Jonathan Lee, Brandee Wagner, Nicholas D. Smith, Hubert C. Chen, Eric J. Lawitz
Journal: Journal of Hepatology (2021)
Abstract 16670: Outcomes of Patients With St Elevation Myocardial Infarction and History of Prior Coronary Artery Bypass Graft Surgery
Authors: Judit Karacsonyi, Christian W Schmidt, Santiago Garcia, Timothy D Henry, Bavana V Rangan, Ilias Nikolakopoulos, Evangelia Vemmou, Iosif Xenogiannis, Mario Goessl, Paul Sorajja, Ivan Chavez, Michael R Mooney, Anil Poulose, Jay TRAVERSE, Yale Wang, Kenneth Baran, Steven M Bradley, Michael S Megaly, Ross Garberich, Imre Ungi, Nicholas Burke, Emmanouil S Brilakis
Journal: Circulation (2020)

Introduction: The outcomes of ST elevation myocardial infarction (STEMI) patients with prior coronary bypass graft (CABG) surgery have received limited study. Methods: We compared the clinical and procedural characteristics and outcomes of STEMI patients with and without prior CABG surgery in a contemporary STEMI registry of consecutive STEMI patients with STEMI or new left bundle-branch block within 24 hours of symptom onset presenting between March 2003 and April 2020. Morality and major cardiac adverse events (MACE: death, MI or stroke) were the primary outcomes of the study. Survival curves are depicted using the Kaplan-Meier method and compared with log-rank test. Results: Of the 6,311 patients included in the analyses, 6.9% had history of prior CABG. Mean age was 63.4 ± 13.9 years and most of the patients were men (71%), 21% had prior MI and 19% had diabetes mellitus. Prior CABG patients were older (70.4±11.7 vs. 62.9±13.9 years, p&lt;0.001) and more likely to have diabetes (39% vs. 18%, p&lt;0.001), prior MI (68% vs. 18%, p&lt;0.001) and cardiogenic shock at presentation (14% vs. 9%, p=0.001) compared with patients without CABG. Median door to balloon time (69 [52, 88] vs. 55 [41, 79] min, p&lt;0.001) as well as length of hospital stay (3 [2, 5] vs. 3 [2, 4] days, p=0.032) were longer in prior CABG patients. Survival evaluated by the Kaplan Meier method at 30 days, 1 year, and 5 years were significantly lower in patients with prior CABG (p&lt;0.001, Figure). Landmark survival analyses, with landmark time of hospital discharge, were similar at 30 days (p=0.158) but showed lower survival rates at 1 year and 5 years. MACE occurred with similar incidence at 30 days follow up, but were more common at 1 year follow up. Outcomes were similar to saphenous vein graft and native coronary culprits. Conclusions: Patients with STEMI and previous CABG represent a higher risk cohort with worse in-hospital and long-term outcomes compared to those without previous CABG.
Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia
Authors: Niccolò E. Mencacci, Marisa M. Brockmann, Jinye Dai, Sander Pajusalu, Burcu Atasu, Joaquin Campos, Gabriela Pino, Paulina Gonzalez-Latapi, Christopher Patzke, Michael Schwake, Arianna Tucci, Alan Pittman, Javier Simon-Sanchez, Gemma L. Carvill, Bettina Balint, Sarah Wiethoff, Thomas T. Warner, Apostolos Papandreou, Audrey Soo, Reet Rein, Liis Kadastik-Eerme, Sanna Puusepp, Karit Reinson, Tiiu Tomberg, Hasmet Hanagasi, Thomas Gasser, Kailash P. Bhatia, Manju A. Kurian, Ebba Lohmann, Katrin Õunap, Christian Rosenmund, Thomas C. Südhof, Nicholas W. Wood, Dimitri Krainc, Claudio Acuna
Journal: Journal of Clinical Investigation (2021)

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.
Noninvasive prenatal testing of α-thalassemia and β-thalassemia through population-based parental haplotyping
Authors: Chao Chen, Ru Li, Jun Sun, Yaping Zhu, Lu Jiang, Jian Li, Fang Fu, Junhui Wan, Fengyu Guo, Xiaoying An, Yaoshen Wang, Linlin Fan, Yan Sun, Xiaosen Guo, Sumin Zhao, Wanyang Wang, Fanwei Zeng, Yun Yang, Peixiang Ni, Yi Ding, Bixia Xiang, Zhiyu Peng, Can Liao
Journal: Genome Medicine (2021)

Abstract Background Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes. Methods First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm. Results With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1–100%). Conclusions These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.
Association of Firearm Access, Use, and Victimization During Adolescence With Firearm Perpetration During Adulthood in a 16-Year Longitudinal Study of Youth Involved in the Juvenile Justice System
Authors: Linda A. Teplin, Nicholas S. Meyerson, Jessica A. Jakubowski, David A. Aaby, Nanzi Zheng, Karen M. Abram, Leah J. Welty
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Preventing firearm violence requires understanding its antecedents. Yet no comprehensive longitudinal study has examined how involvement with firearms during adolescence—use, access, and victimization (defined as threatened with a weapon or gunshot injury)—is associated with the perpetration of firearm violence in adulthood. <h3>Objective</h3> To examine the association between firearm involvement during adolescence and subsequent firearm perpetration and ownership in adulthood among youth involved in the juvenile justice system. <h3>Design, Setting, and Participants</h3> This cohort study analyzed interview responses of 1829 randomly selected participants as part of the Northwestern Juvenile Project, a longitudinal study of health needs and outcomes of youth sampled from a temporary juvenile detention center in a large US city. Youth aged 10 to 18 years were interviewed in detention from November 1995 through June 1998. Participants were reinterviewed up to 13 times over 16 years through February 2015, for a total of 17 776 interviews. The sample was stratified by sex, race/ethnicity, age, and legal status (juvenile or adult court). Data were analyzed from April 2017, when data preparation began, through November 2020. <h3>Exposures</h3> Firearm involvement during adolescence: use (ie, threaten, shoot), access (ownership, ease of access, firearm in household, membership in gang that carries firearms), and victimization (gunshot injury, threatened with a weapon). <h3>Main Outcomes and Measures</h3> Firearm involvement during adulthood: perpetration of firearm violence (ie, threatening with or using a firearm) and firearm ownership. <h3>Results</h3> Among the 1829 participants, 1388 had a 16-year follow-up interview: 860 males, 528 females; 809 were African American, 203 were non-Hispanic White; 374 were Hispanic; and 2 were other race/ethnicity; median (interquartile range) age of 32 (30-32) years. Eighty-five percent of males and 63.2% of females were involved with firearms as adolescents. Compared with females, males had significantly higher odds of every type of involvement except having a firearm in the home. In adulthood, 41.3% of males and 10.5% of females perpetrated firearm violence. Adolescents who had been threatened with a weapon or injured by firearms had 3.1 (95% CI, 2.0-4.9) and 2.4 (95% CI, 1.2-4.9) times the odds of perpetrating violence during adulthood. Similar associations were found for firearm ownership. <h3>Conclusions and Relevance</h3> Involvement with firearms during adolescence—including victimization—is a significant risk factor for firearm perpetration and ownership during adulthood.
A clinical perspective on plasma cell leukemia; current status and future directions
Authors: Sherilyn A. Tuazon, Leona A. Holmberg, Omar Nadeem, Paul G. Richardson
Journal: Blood Cancer Journal (2021)

Abstract Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.