tbuckley/cabot-search huggingface dataset:
Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study
Authors: Kai Xiang Lim, Frühling Rijsdijk, Saskia P. Hagenaars, Adam Socrates, Shing Wan Choi, Jonathan R. I. Coleman, Kylie P. Glanville, Cathryn M. Lewis, Jean-Baptiste Pingault
Journal: PLoS Medicine (2020)

Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm.Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error.In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.
Image-guided core needle biopsy for relapsed and refractory neuroblastoma: A focus on sample adequacy for genetic sequencing.
Authors: Andrew Samoyedny, Lisa States, Emma Alai, Abhay Srinivasan, John M. Maris, Yael P. Mosse, Anne Marie Cahill
Journal: Journal of Clinical Oncology (2020)

e22521 Background: Relapsed and refractory neuroblastoma (NBL) is a prime target for novel therapies targeting specific mutations. The genomic landscape of NBL can change between time of initial diagnosis and relapse, necessitating subsequent biopsy and next generation sequencing (NGS) to detect mutations within the relapsed neoplasm. Tissue of insufficient quality and quantity leads to specimen failure during NGS. Thus the goal of this study is to review core needle biopsy for relapsed and refractory NBL in a pediatric interventional radiology department and explore factors that enhance biopsy adequacy. Methods: Retrospective review of clinical records and images for 66 patients (36M, 30F) with median age 8.7 years (range 0.9 – 49.3 y) who underwent 95 biopsies (55 bone, 40 soft tissue) over a 12-year period. Results: Biopsy yield for neuroblastic tissue from 123I mIBG-avid masses was 89.7% overall, 84.9% in bone, and 91.6% in soft tissue. 87/95 masses were mIBG-avid; 2 non-avid masses were NBL-positive (but also 18F-FDG avid). 48/59 samples sent for NGS were adequate for analysis (81.4%); bone and soft tissue biopsies did not differ in adequacy (77.1% vs 87.5%, p = 0.32). Tumor cell percent (TC%) for adequate samples was 49.9% vs 11.1% for NGS failures (p = 0.0003). Number of needle passes performed in bone and soft tissue lesions was positively correlated with NGS adequacy (Bone: r 2 = 0.68, Soft: r 2 = 0.33). In bone and soft tissue, adequate biopsies tended towards higher mean needle passes than inadequate ones (Bone: 5.1 vs 3.4, p = 0.0582) (Soft: 10.5 vs 4.7, p = 0.0428). Total needle volume passed into a soft tissue mass (calculated as inner needle cylindrical volume * # of passes) was higher in the “adequate” vs “inadequate” group (0.20 cm 3 vs 0.05 cm 3 , p = 0.0004). Lesion mIBG avidity was quantified with a ratio of lesion:liver SUV; this mIBG SUV ratio was positively correlated with TC% (R 2 = 0.55, N = 14). Using a linear regression line, a TC% of 50% (the mean value for samples adequate for NGS) corresponded to an SUV ratio of 2.89. The rate of minor complications (requiring only nominal therapy) was 7/95 (7.4%). The rate of major complications (requiring longer hospital stay) was 1/95 (1.5%). Conclusions: Image-guided core needle biopsy for relapsed and refractory NBL has a moderately high yield for procuring tumor samples adequate for NGS with a low rate of major complications. Adequate bone and soft tissue biopsies averaged &gt;5 and &gt;10 needle passes, respectively. An approximate lesion:liver mIBG SUV ratio of &gt;3 may maximize specimen quality for NGS.
A machine learning-based approach for the inference of immunotherapy biomarker status in lung adenocarcinoma from hematoxylin and eosin (H&amp;E) histopathology images.
Authors: Cory Batenchuk, Huan-Wei Chang, Peter Cimermancic, Eunhee S. Yi, Apaar Sadhwani, Vanessa Velez, Hardik L. Patel, Ali Behrooz, Kamilla Tekiela, Robert Findlater, Debra Hanks, Kimary Kulig
Journal: Journal of Clinical Oncology (2020)

3122 Background: The current standard work-up for both diagnosis and predictive biomarker testing in metastatic non-small cell lung cancer (NSCLC), can exhaust an entire tumor specimen. Notably, gene mutation panels or tumor mutation burden (TMB) testing currently requires 10 tissue slides and ranges from 10 days to 3 weeks from sample acquisition to test result. As more companion diagnostic (CDx)-restricted drugs are developed for NSCLC, rapid, tissue-sparing tests are sorely needed. We investigated whether TMB, T-effector (TEFF) gene signatures and PD-L1 status can be inferred from H&amp;E images alone using a machine learning approach. Methods: Algorithm development included two steps: First, a neural network was trained to segment hand-annotated, pathologist-confirmed biological features from H&amp;E images, such as tumor architecture and cell types. Second, these feature maps were fed into a classification model to predict the biomarker status. Ground truth biomarker status of the H&amp;E-associated tumor samples came from whole exome sequencing (WES) for TMB, RNAseq for the TEFF gene signatures or reverse-phase protein array for PD-L1. Digital H&amp;E images of NSCLC adenocarcinoma for model development were obtained from the cancer genome atlas (TCGA) and commercial sources. Results: This approach achieves &gt; 75% accuracy in predicting TMB, TEFF and PD-L1 status, offers a way to interpret the model, and provides biological insights into the tumor-host microenvironment. Conclusions: These findings suggest that biomarker inference from H&amp;E images is feasible, and may be sufficiently accurate to supplement or replace current tissue-based tests in a clinical setting. Our approach utilizes biological features for inference, and is thus robust, interpretable, and readily verifiable by pathologists. Finally, biomarker status inference from a single H&amp;E image may enable testing in patients whose tumor tissue has been exhausted, spare further tissue use, and return test results within hours to enable rapid treatment decision-making to maximize patient benefit.
Lanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks
Authors: Marc A. Riedl, Marcus Maurer, Jonathan A. Bernstein, Aleena Banerji, Hilary J. Longhurst, H. Henry Li, Peng Lu, James Hao, Salomé Juethner, William R. Lumry
Journal: Allergy (2020)

Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.One hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.Protection with lanadelumab started from the first dose and continued throughout the entire study period.
Covid-19: Pandemic is having “severe” impact on non-communicable disease care, WHO survey finds
Authors: Owen Dyer
Journal: BMJ (2020)

<h3>Abstract</h3> Current treatment of triple negative breast cancer patients is hindered by a high incidence of chemoresistance (30-50%). The prevailing theory is that resistance and subsequent recurrence is driven by cancer stem cells. Unfortunately, the functional characterization of cancer stem cells at the molecular level is still incomplete. We show here, that within the canonical breast cancer stem cell population, a subset of cells characterized by high Notch1 expression possesses the tumor-initiating property associated with cancer stem cells. Moreover, the tumor initiating property of these high Notch1-expressing breast cancer stem cells is mediated by a cleavage independent Notch signaling pathway culminating in the repression of SIRT1. Of note, the Notch1-mediated repression of SIRT1 is required not only for tumor initiation, but also for chemoresistance in breast cancer stem cells. Strikingly, inhibition of SIRT1 obviates the requirement for Notch1, marking the first example of conferring cancer stem cell function by inhibiting the activity of a single protein. We also demonstrate that progenitor-like mammary epithelial cells, which possess both luminal and basal properties, are also characterized by high Notch1 expression and repression of SIRT1 via the non-canonical pathway. These findings provide the first functional mechanistic requirements for tumor initiation by breast cancer stem cells and suggest that activation of the non-canonical Notch1 pathway is hardwired into tumor-initiating progenitor cells and thus a prerequisite for tumor initiation. <h3>Statement of Significance</h3> We demonstrate that chemoresistant and tumor-initiating properties of breast cancer stem cells are driven by repression of SIRT1 via non-canonical Notch signaling, suggesting a novel therapeutic strategy for triple negative breast cancer.
Evaluation of reliability and validity of Chinese version of Diabetes, Hypertension and Hyperlipidemia(DHL) Knowledge Instrument in community diabetic patients
Authors: Hua Yang, Shengbing Zhang, Shanzhu Zhu, Zhigang Pan, Yuanzhi Yuan, Shuyu Li, Zhangyan Chen
Journal: BMJ (2017)

Objective
To evaluate the reliability and validity of the Chinese version of the Diabetes, Hypertension and Hyperlipidemia(DHL)Knowledge Instrument in community diabetic patients.


Methods
A face-to-face interview was conducted among 513 patients with diabetes in the community from January to March 2016 by using the Chinese version of DHL Knowledge Instrument. Forty of them were randomly sampled and reinvestigated 4 weeks later. The analyses on Cronbach's α coefficient, test-retest reliability, content validity, discriminant validity and construct validity were performed to evaluate reliability and validity of the DHL Knowledge Instrument.


Results
The qualified questionnaires were collected from 488 participants, including 232 males and 256 females with a mean age of (66±6)years. The overall scores of the Chinese version of DHL Knowledge Instrument was 67.7±18.0 and the scores of diabetes, hypertension, hyperlipidemia, medications and general issues sub-scales were 82.0±22.5, 65.9±25.2, 38.2±34.3, 75.5±20.8 and 72.1±22.9, respectively. The standardized Cronbach's α coefficient of the total scale was 0.849 and the test-retest reliability of the total scale was 0.706 (P<0.01). In term of content validity, the correlation coefficient was from 0.580 to 0.827 among total scale and sub-scales (P<0.01). In term of discriminant validity, the difference between the high and the low score group on total scale and sub-scales were significant (t value=-13.486 to -35.528, all P<0.01). In term of construct validity, based on exploratory factor analysis, the scale was revised. According to confirmatory factor analysis of revised scale, four factor model containing 20 items was well fitted(χ2=159.689, df=134, P=0.064); the GFI (goodness of fit index) =0.966, AGFI (adjusted goodness of fit index) =0.952, RMSEA (root mean square error of approximation)=0.020.


Conclusion
The Chinese version of DHL Knowledge Instrument possesses good reliability and validity and is suitable to evaluate the knowledge of community diabetic patients, and the modified version may work better than the original one.


Key words: 
Diabetes mellitus, type 2; The diabetes, hypertension and hyperlipidemia knowledge instrument; Reliability; Validity
Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14-188.
Authors: Christopher J. Hoimes, Nabil Adra, Mark T. Fleming, Hristos Z. Kaimakliotis, Joel Picus, Zachary L Smith, Radhika Walling, Edouard John Trabulsi, Jean H. Hoffman-Censits, Michael O. Koch, Clint Cary, Robert Abouassaly, Cheryl Eitman, Pingfu Fu, Gordon Goolamier, Adam C Calaway, Lee Evan Ponsky, William Kevin Kelly
Journal: Journal of Clinical Oncology (2020)

5047 Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, ≤pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H 0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% &gt; cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766 .
ECOG-ACRIN tomosynthesis mammographic imaging screening trial (EA1151).
Authors: Etta Pisano, Constantine Gatsonis, Martin Yaffe, Melissa Troester, Ilana F Gareen, Laura C. Collins, Amarinthia Curtis, Elodia Cole, Ruth Carlos, Kathy Miller, Christopher Comstock
Journal: Journal of Clinical Oncology (2020)

TPS1597 Background: This randomized trial is intended to determine whether tomosynthesis (TM) should replace the current standard for breast cancer (BC) screening, digital mammography (DM). It is hypothesized that the population of women assigned TM screening for 3-5 rounds will have fewer advanced cancers than the population assigned to DM screening. Methods: 164,946 women, ages 45 to 74 years who present for screening mammography and consent to participate will be enrolled across 150 sites in the US, Canada and abroad. Women will be randomized to TM or DM. The frequency and number of screening examinations over a five year period will vary based on menopausal status and whether they have specific risk factors, including - hormone use, family history of BC, deleterious genes, prior benign breast biopsy with diagnosis of LCIS or atypia any kind, or dense breasts. Blood and buccal cells will be collected from as many enrolled women as are willing to provide the samples. All breast biopsies during the trial will undergo gene expression analysis for the PAM50 and other progression pathways (PAM50-plus). All subjects enrolled will be followed long term for at least eight years. The primary endpoint is the proportion of participants who have an advanced breast cancer diagnosed at any time within 4.5 years of randomization in to the trial. Secondary endpoints include measures of diagnostic and predictive performance; rates of recall, biopsy, and interval cancers, prevalence of breast cancer subtypes, and tumor subtype based on PAM50-plus analysis. As of January 17 th 2020, there are 104 sites open and 21,452 women enrolled in the trial. The DSMC last reviewed the trial in June 2019 and suggested that the trial continue as planned. Clinical trial information: NCT03233191.
Examining the real-world utility of immune checkpoint inhibitors in genitourinary oncology: A single-institution retrospective.
Authors: Lydia Glick, Cassra Clark, Timothy M. Han, James Ryan Mark, Leonard G. Gomella, Nathan Handley, William Kevin Kelly, Edouard John Trabulsi, Costas D. Lallas, Thenappan Chandrasekar
Journal: Journal of Clinical Oncology (2020)

e17112 Background: Immune Checkpoint Inhibitors (ICI) are increasingly utilized for genitourinary (GU) malignancies. However, data is lacking on the efficacy of these drugs in “real-world” populations - patients who do not fit the strict clinical trial criteria, but may still benefit from therapy. We performed a retrospective analysis of patients receiving ICI at a single tertiary-care institution, with special attention to clinical trial enrollment, adverse events, progression and survival. Methods: Patients receiving ICI for GU malignancies at Thomas Jefferson University Hospital from January 2017 to January 2019 were identified. Descriptive statistics of treatment and pathologies were performed. Progression-free survival (PFS) was calculated from start of ICI to documentation of progression or last follow-up. PFS and overall survival were assessed using Kaplan Meier log-rank test, stratified by trial enrollment. Results: 111 patients were included: 37 on ICI clinical trial, 70 received ICI “off-trial” and 4 received ICI in both settings. 11 patients (10%) underwent multiple courses of ICI throughout treatment. The number of patients initiating ICI increased annually; by 2018, the number of patients initiated on ICI “off-trial” exceeded those initiating ICI “on-trial” (79% vs 21%). Treated pathology included Urothelial Carcinoma (UC; 42%), Renal Cell Carcinoma (RCC; 28%), and Prostate Adenocarcinoma (PCa; 20%). “Off-trial” ICI was more often administered later in the disease course, compared to a more even distribution of “on-trial” ICI administration. Mean PFS and OS for both cohorts can be seen in Table. Conclusions: As seen in our single-institution referral center, the use of immune checkpoint inhibitors has significantly increased – and is now more commonly used off-trial than on-trial. As their use becomes more common, their efficacy in “off-trial” populations must be further investigated. [Table: see text]
治疗肾病中成药的合理使用
Authors: 张晓阳
Journal: BMJ (2011)

肾病是内涵比较复杂的名词,它可以是西医根据患者肾脏结构或功能异常做出的IgA肾病、狼疮性肾炎、糖尿病肾病、肾病综合征、肾盂肾炎等各种肾脏疾病的统称,也可以是中医根据患者临床症状、体征、舌象、脉象等,依据中医理论做出的肾阴虚、肾阳虚、肾虚腰痛、肾虚耳鸣、肾虚眩晕等与肾相关的临床辨证的简称.因此,在临床上听到患者说有肾病或肾有病时,一定要明确其属于上述两种情况的哪一类.中医特色虽然是辨证论治,但由于中西医结合数十年的发展,推动了中药研究的现代化,现代许多中成药不仅能治疗中医的证,而且对西医所诊断的肾脏相关疾病也有明确的疗效。
贫血(一)
Authors: 吴东, 陈嘉林
Journal: BMJ (2012)

一、贫血的三大主要病因是:合成不足、丢失过多和破坏增加血红蛋白(Hb)的正常水平受人种、性别、年龄和地域影响,按照我国的诊断标准,海平面地区男性成人＜120 g/L,女性成人(非妊娠)＜ 110 g/L,孕妇＜100 g/L诊断为贫血[1].贫血是我国的常见病,发病率高,对人民健康威胁较大.贫血的病因多样,诊疗方法各异.很多贫血患者可以在社区完成治疗(例如叶酸缺乏所致营养性贫血),部分则需要初步判断后转诊至上级医院进一步检查(例如老年人因大肠癌慢性失血而贫血),这就要求全科医生对贫血的临床分类、诊断标准及治疗原则有所了解。