tbuckley/cabot-search huggingface dataset:
<i>HAGHL</i> genetic variants increase first fracture risk (FFR) in female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Cindy Im, Nan Li, Wonjong Moon, Lindsay M. Morton, Wendy M. Leisenring, Rebecca M. Howell, Kevin C. Oeffinger, Charles A. Sklar, Carmen Louise Wilson, Yadav Sapkota, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Smita Bhatia, Gregory T. Armstrong, Yutaka Yasui
Journal: Journal of Clinical Oncology (2020)

10554 Background: Recent genome-wide association studies (GWAS) have reported substantial sex differences in the genetic architectures of bone-related phenotypes. We investigated sex-specific genetic determinants of FFR in survivors of childhood cancer. Methods: We performed sex-combined and sex-stratified GWAS for FFR using Cox regression models fitted on follow-up age in 2,453 long-term (≥5 years) survivors in CCSS with ~5.4 million imputed SNPs (minor allele frequency, MAF≥5%), with self-reported FFR defined by first fracture at any site after diagnosis. Replication analyses were conducted in an independent sample of 1,417 SJLIFE survivors with whole-genome sequencing and clinician-assessed FFR. All models were adjusted for relevant genetic (e.g., ancestry) and clinical (e.g., height, weight, treatment) factors. Results: Sex-combined and male-specific analyses yielded no associations with P &lt; 10 −7. Among female CCSS survivors (N = 1,289, 33% ≥1 fractures), we discovered 7 genome-wide significant (P &lt; 5x10 −8 ) SNP-FFR associations with strong evidence of sex effect heterogeneity (P &lt; 7x10 −6 ) across 2 independent loci with no known associations with bone phenotypes. We replicated these associations in SJLIFE (P≤0.05) for 3 coding SNPs in the HAGHL gene (16p13.3), among which rs1406815 showed the strongest association (MAF = 20%, meta-analysis HR = 1.43, P = 8.2x10 −9 ; N = 1,935 women, 35% ≥1 fractures). We observed increased HAGHL SNP effects on FFR that corresponded with increasing head/neck (HN) radiation therapy (RT) dose (Table). Public omics data show replicated SNPs are associated with differential HAGHL expression in sex gland and musculoskeletal tissues (GTEx) and in osteoblasts treated with dexamethasone or prostaglandins (GRASP), suggesting sex-/therapy-specific biological pathways involving HAGHL SNPs for fracture are plausible. Conclusions: Novel associations between HAGHL genetic variants and FFR potentially reveal new sex- and therapy-specific biological mechanisms underlying bone-related health conditions in survivors of childhood cancer. [Table: see text]
循证医学与全科医学教育
Authors: 施勇, 王伟杰
Journal: BMJ (2005)

循证医学(evidence-based medicine,EBM)与全科医学这两门新兴学科有着共同的特点以病人为中心和以证据为基础,是相互促进、相互依赖的关系.两者相互渗透是推进两者共同快速发展的重要途径.现就循证医学与全科医学教育的关系综述如下。
New biomarkers in diagnosis of acute myocardial infarction
Authors: Cong Zhao
Journal: BMJ (2016)

With the development of laboratory medicine, more and more biomarkers have been discovered and applied in the diagnosis and treatment of acute myocardial infarction. For patients with suspected myocardial infarction, early diagnosis and timely treatment can save endangered myocardium and reduce fatality rate to a great extent. The proper use of biomarkers is of important value in preventing cardiovascular events and improving prognosis. This paper reviews the recent literature on new biomarkers in diagnosis of acute myocardial infarction, introduces the characteristics of these markers and their clinical diagnostic value.


Key words: 
Myocardial infarction; Troponin
Etiological classification of virus in adult community-acquired pneumonia in Yantai
Authors: Hongxia Yu, Yongqin Chen, Zenghui Pu
Journal: BMJ (2014)

To employ multiplex polymerase chain reaction (PCR) to classify the types of virus in 128 patients of community-acquired pneumonia and analyze the relationship between type of virus, age and seasons. The positive rate of viral pneumonia was 34.4% (44/128). In 44 virus positive patients, the rates of influenza A virus, rhinovirus, adenovirus, parainfluenza type 1, human metapneumovirus virus, influenza B virus, parainfluenza type 2, parainfluenza type 3 and enterovirus were 22.7%(10/44), 15.9%(7/44), 15.9%(7/44), 9.1%(4/44), 9.1%(4/44)6.8%(3/44), 2.3%(1/44), 2.3%(1/44) and 2.3%(1/44)respectively. And other 6(13.6%) patients were at least infected by one virus. The viral pneumonia had a high positive rate in spring and winter. And the age group of 20 to 29 years had a high positive rate. The major pathogen contributing to adult community-acquired pneumonia in Yantai were influenza A virus, rhinovirus and adenovirus.


Key words: 
Community-acquired infections; Noxae
Radiotherapy after esophageal cancer stenting (ROCS): A pragmatic randomized controlled trial evaluating the role of palliative radiotherapy in maintaining swallow.
Authors: Anthony Thomas Byrne, Douglas Adamson, Catharine Porter, Jane M. Blazeby, Gareth Owen Griffiths, Annmarie Nelson, Bernadette Sewell, Mari Jones, Tony Millin, John Staffurth, Thomas Crosby, Chris Hurt
Journal: Journal of Clinical Oncology (2020)

4569 Background: Most patients with oesophageal cancer (OC) present with incurable disease; 80% of new cases, and deaths, occur in low and middle income nations. Median survival for advanced disease is 3-5 months, a majority requiring intervention for dysphagia. Insertion of self expanding metal stents is the commonest way of palliating, but dysphagia may recur within three months owing to tumour progression. Evidence reviews have called for trials of combination treatment for OC dysphagia. The ROCS study (funding - UK NIHR programme) examined effectiveness of palliative radiotherapy, following stent, in maintaining swallow. It also examined impact on quality of life, bleeding events, and survival. Methods: A multicentre RCT with follow up monthly for a year. Patients referred for stent insertion as primary management of dysphagia related to incurable OC were recruited in secondary care, with all planned follow up at home. Patients were randomised 1:1 to stent insertion alone or stent insertion plus palliative radiotherapy at a dose of 20Gy in five fractions or 30Gy in ten fractions. Primary outcome was difference in proportions of participants with recurrent dysphagia at 12 weeks, defined as deterioration of 11 points or more in the dysphagia scale of the EORTC QLQ-OG25 questionnaire. Secondary outcomes included quality of life, bleeding risk, survival. Results: 220 patients were randomised Dec 2013-Aug 2018 at 23 UK sites. Addition of radiotherapy did not reduce the proportion of primary events at 12 weeks: 49% in control arm vs 45% in the intervention, adjusted OR 0.82 (95%CI 0.40-1.68; p = 0.587) and it was less cost effective. Sensitivity analyses did not alter the results. Dysphagia deterioration-free survival was similar in both arms: adjusted HR 0.92 (95%CI 0.68-1.26; p = 0.618). Median survival was 19.7 weeks in control arm and 18.9 weeks in the intervention. Those in the radiotherapy arm had significantly fewer bleeding events (18.6% compared to 10.3%), giving a number needed to treat of 12. Conclusions: Palliative external beam radiotherapy is widely accessible to patients with advanced cancer. ROCS is the largest trial assessing its role in combination with stenting for OC dysphagia, and is the first to prospectively assess impact on bleeding risk. It demonstrates no reduction in risk of dysphagia recurrence at 12 weeks, nor impact on survival. Reductions in bleeding events should be considered in the context of patient described trade offs of fatigue and burdens of attending hospital. Clinical trial information: NCT01915693 .
Composite grading algorithm for National Cancer Institute’s PRO-CTCAE.
Authors: Amylou C. Dueck, Claus C. Becker, Lauren J. Rogak, Deborah Schrag, Bryce Reeve, Patricia Spears, Mary Lou Smith, Mrinal M. Gounder, Michelle R. Mahoney, Gary K. Schwartz, Antonia Vickery Bennett, Tito R. Mendoza, Charles S. Cleeland, Jeff A. Sloan, Deborah Bruner, Gisela Schwab, Thomas Michael Atkinson, Gita Thanarajasingam, Monica M. Bertagnolli, Ethan M. Basch
Journal: Journal of Clinical Oncology (2020)

7018 Background: Standard reporting of symptomatic adverse events (AEs) in oncology relies on clinicians to rate patient (pt) experience using CTCAE; each symptom is represented by a single graded item. To capture direct pt experience, NCI developed PRO-CTCAE to supplement CTCAE. In PRO-CTCAE, the pt answers up to 3 questions per AE about a symptom’s frequency, severity and interference with daily activities. To align PRO-CTCAE with CTCAE, we developed an algorithm for mapping sets of questions for an AE to a single composite numerical grade. Methods: We used a 5-step process. (1) All 187 possible PRO-CTCAE score permutations were presented to clinical investigators to subjectively map permutations to single numerical grades (range 0-3). (2) Permutations with &lt; 75% agreement were presented to investigator committees at a National Clinical Trials Network meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating AEs between study arms was measured in 2 phase III clinical trials (Alliance for Clinical Trials in Oncology A091105 and Exelixis COMET-2). Results: (1) 12/187 score permutations had &lt; 75% initial agreement. (2) Majority consensus was reached for all permutations. (3) 5 mappings were adjusted to assure directional consistency. (4) Composite grades for 46/59 (78%) AEs were higher in pts with ECOG performance status 2-4 vs 0-1 (median effect size 0.23 [range -0.49-0.73]; 32/59 effect size ≥0.2; 25/59 p&lt; 0.05), similar to when conducting analysis on individual unmapped items. The test-retest reliability for 24 selected composite grades ranged from 0.57-0.96 (median intraclass correlation coefficient [ICC] 0.77) with 18/24 (75%) grades having ICC ≥0.7. Median (range) standardized response means in pts reporting worsening, no change, and improvement were 0.20 (0.03-0.34), -0.06 (-0.20-0.03) and -0.12 (-0.32-0.06). (5) Pattern, directionality and statistical significance of between-arm differences in both trials were preserved with composite grades as compared to individual unmapped items. Conclusions: A composite grading algorithm for PRO-CTCAE was rigorously developed and validated. PRO-CTCAE composite grades may be useful in analyses to provide a single metric for each pt-reported AE for trial and real-world reporting. Support: UG1CA189823; U01CA233046; HHSN261200800043C; Bayer (A091105); https://acknowledgments.alliancefound.org .
食管癌术后肝性胸水误诊一例分析
Authors: 刘欣, 李辉, 傅毅立, 胡滨
Journal: BMJ (2011)

肝性胸水临床非常少见,尤其是出现在胸外科术后[1].本文报告食管癌术后肝性胸水误诊为乳糜胸1例,并结合病例谈谈我们粗浅的体会. 患者男性,63岁.因进行性吞咽困难1个月于2004年11月3日入首都医科大学附属北京朝阳医院胸外科.既往有甲型病毒性肝炎及肝硬化病史26年,糖尿病12年.体检:一般情况尚可,精神好,略消瘦.体检肝肋下可触及,余无特殊阳性发现。
Pay attention to the problems in urogenital system during male climacteric
Authors: 王和天, 刘殿池, 郭仲良
Journal: BMJ (2004)

男性同女性一样,也存在更年期问题,并日益受到关注. 进入更年期,男性可利用的雄性激素减少,雌性激素水平增高,血管功能衰退,出现相应疾病,从而出现一系列的生理、心理变化.男性更年期以泌尿生殖系统变化为主,以性功能障碍及前列腺增生为进入更年期的信号与标志。
Trends in FDA cancer registration trial design over time, 1969-2020.
Authors: Jeremy Lyle Warner, Tarsheen Kaur Sethi, Donna R Rivera, Neeta K. Venepalli, Travis John Osterman, Ali Raza Khaki, Sam Rubinstein
Journal: Journal of Clinical Oncology (2020)

2060 Background: The FDA has issued hundreds of cancer drug indications, with many new drugs, expanded indications, and biosimilars approved in recent years. While the gold standard for regulatory approval is the randomized controlled trial (RCT), RCT design including selection of control arms can differ considerably. We sought to investigate trends and patterns in RCT trial design used to support FDA approvals in oncology. Methods: We reviewed the available FDA package inserts of oncology drugs (N=258) for RCTs cited to support initial and expanded indication approvals as of January 2020; biosimilars were excluded. RCTs were linked to the HemOnc ontology, which contains trial-level metadata including publication year, endpoints, and trial design. Log-linear regression was performed to evaluate trends in approvals over time by endpoint. Study drugs were categorized as cytotoxic therapy, targeted therapy, or immunotherapy. RCTs were categorized by four designs: escalation (adding a drug or increasing the drug dose in an established regimen), in-class comparison (comparing two drugs in the same therapeutic class), out-of-class switch (comparing drugs in distinct therapeutic classes), and de-escalation (removing a drug or reducing the drug dose in an established regimen). Results: We identified 556 registration trials, 372 (67%) of which were RCTs. Approvals have been increasing exponentially over time (R 2 0.9, p&lt;0.001), both for RCTs reporting overall survival (OS) endpoints (R 2 0.77, p&lt;0.001), and non-OS endpoints (R 2 0.67, p&lt;0.001). Of the three most common trial designs (Table), in-class comparisons were least likely to report OS (28%; escalations 47%; out-of-class switches 43%, p=0.01 by Chi-squared). Class switches were common in immunotherapy trials compared to targeted or cytotoxic therapy. Conclusions: Despite growth in FDA approvals, a minority of registration trials report paradigmatic shifts in therapeutic approach (out-of-class switches), with the relative exception of immunotherapy trials. Escalation is the most common route to FDA approval, even though this design inevitably increases cost and toxicity. This suggests that new oncology drug approvals are not alone a useful metric of practice-changing innovation. [Table: see text]
Saving the best to the last: Can we wait for second-line?
Authors: Renana Barak, Barliz Waissengrin, Ido Wolf
Journal: Journal of Clinical Oncology (2020)

284 Background: A common perception of some oncologists is that the vast majority of their patients with metastatic disease will receive second-line treatment upon progression. Therefore, “saving” good treatment options for the future may be acceptable. We aimed to examine whether this perception correlates with real-life. Methods: Using an oncology electronic database, consisting of &gt;27,000 patients treated at our institution, we selected consecutive patients with metastatic or locally advanced lung, colon, pancreatic, bile duct and gastric cancers who started standard first-line. We then assessed the correlation between proceeding to second-line therapy and demographic and clinical variables, including age, gender, initial performance status, BMI, hemoglobin, WBC, creatinine, glucose, calcium, as well as duration on first line therapy and survival. Results: A total of 492 patients met the inclusion criteria. Their median age was 67 and 285 were men. Their diagnoses were colon (169), lung (102), pancreas (101), bile duct (65) and gastric (55) cancers. Only 52% (255) received second-line treatment for at least 30 days (36% colon, 26% lung, 18% pancreas, 9% bile duct and 11% gastric). Receipt of second-line therapy was associated with disease site (P=0.001) as well as with age, with patients who received second-line being 5 years younger compared to those who did not (64 vs. 69 years, P=0.004). Patients who reached second-line had better performance status and higher hemoglobin level at presentation, additionally their median duration on first-line chemotherapy was substantially longer (P&lt;0.007 for all comparisons). Survival of patients not starting second-line was significantly shorter across all tumor types (19.8 vs 6.5 months P=0.001). General deterioration and toxicity were the major reasons for avoiding second-line therapy at progression, 43% and 30% respectively. Conclusions: These real-life data indicate that only half of the patients starting standard doublet or triplet treatment for advanced cancers will commence second-line therapy; and this can be hardly predicted in advance using standard clinical and laboratory characteristics. Our data challenge the practice of saving good treatment options for subsequent lines, and call for the development of tools enabling prediction of response and tolerance to treatment, pursuing for better patient selection and patient-tailored therapy.
Prevalence and risk factor of atherosclerotic renal artery stenosis in patients with ischemic stroke
Authors: Kai Wang, Guomin Jiang, Shaoqin Li, Feng Tian, Zhongzhi Jia
Journal: BMJ (2014)

Objective
To investigate the prevalence and risk factors of atherosclerotic renal artery stenosis (ARAS) in patients with ischemic stroke (IS).


Methods
A total of 596 consecutive patients with ischemic stroke underwent cerebrovascular and renal angiography at our hospital from January 2008 to March 2013.Renal artery stenosis was defined as at least one of renal artery narrowing≥50% of luminal diameter.Multivariate logistic regression analysis was performed to investigate the association of the clinical variables with ARAS.


Results
Intracranial arterial stenosis (ICAS) was identified in 203 patients (34.1%), including 108 cases (18.5%) with arteriostenosis≥50%.Extracranial arterial stenosis (ECAS) was identified in 250 patients (41.9%), including 149 cases (25.0%) with arteriostenosis ≥50%.The prevalence of ECAS was higher than that of ICAS(χ2=7.86, P<0.05). ARAS was identified in 77 patients (12.9%), and the prevalence of ARAS in patients with ECAS ≥50% was higher than that in with ICAS ≥50% (30.2 % vs. 18.5%, χ2=4.52, P<0.05). Multivariate analysis showed that the age≥60 y (OR: 2.48, P<0.05) and ECAS≥50% (OR: 5.37, P<0.05) were independent risk factors for prevalence of ARAS.


Conclusion
ARAS is a relatively common finding among patients with ischemic stroke, suggesting that renal angiography should be performed in elderly IS patients, especially for those combined with severe ECAS.


Key words: 
Atherosclerotic renal artery stenosis; Ischemic stroke; Prevalence; Risk factor
Can body size explain the excess cancer risk in men?
Authors: Cecilia Radkiewicz, Arvid Sjölander, Emelie Benyi, Mats Lambe, Paul Dickman, Lars Sävendahl, Gustaf Edgren
Journal: Journal of Clinical Oncology (2020)

e13593 Background: Men are at increased risk of a majority of malignancies affecting both sexes. Since tall stature is associated with elevated cancer risk and since men are taller than women, we decided to investigate to what extent body stature, as a proxy for stem cell number within tissue, can explain the excess cancer risk in men. Methods: We performed a population-based cohort study investigating the association between male sex and cancer, accounting for body height. The analyses included all Swedish men and women with an adult height registration in either the Swedish Passport Register, the Conscription Register, and/or the Medical Birth Register (n = 6,156,659). Height data was linked to the Swedish Cancer Register where we observed 285,778 non-sex-specific cancer cases, diagnosed in 1960-2012. We applied contemporary causal mediation analysis methodology to assess the relative effect of male sex on lifetime cancer risk mediated by body height. Results: A vast majority of the investigated cancer sites were significantly associated with male sex (33 of 39) and height (27 of 39). The proportion of the excess cancer risk in men explained by sex differences in body height ranged from 0.5% (laryngeal) to 100% (salivary glands, colon, melanoma, and AML). The effect of body height and the mediated effect through height on cancer risk was most consistent and pronounced in malignancies with weak, few, or no known risk factors. Conclusions: A large proportion of the excess cancer risk in men is explainable by height. There is no known, height-associated cancer risk factor strong enough to provide an alternative pathway. Our findings supports the notion that a substantial proportion of cancer cases arise stochastically rather than are caused by underlying hereditary and/or environmental factors.
Association between leukoaraiosis and early neurological deterioration in patients with acute ischemic stroke
Authors: Wenting Fu, Changjuan Shao, Qing Li
Journal: BMJ (2017)

Objective
To investigate the association between leukoaraiosis (LA) and early neurological deterioration (END) in patients with acute ischemic stroke.


Methods
Clinical data of 328 patients with acute ischemic stroke admitted in the hospital from January 2013 to January 2016 were retrospectively reviewed. According to the changes of National Institute of Health Stroke Scale (NIHSS) scores within 72 h after admission, 88 patients (26.8%) were identified as END. Clinical manifestations, laboratory tests and radiographic findings were compared between END group and non-END group.


Results
Univariate analysis indicated that age [ (74.6±11.0) vs. (70.7±11.8) years, t=2.67, P=0.01], female sex [51.1% (45/ 88) vs. 38.8%(93/240), χ2= 4.05, P=0.04], initial NIHSS [M(Q1, Q3) 6(3, 9) vs. 3 (2, 6), χ2=-4.38, P=0.00], systolic blood pressure [(155±28) vs. (149±20) mmHg(1 mmHg=0.133 kPa), t=2.04, P=0.04], responsible artery occlusion [18.2% (16/88) vs. 8.3%(20/240) , χ2=6.39, P=0.01], white cell count [(7.8±2.7) 109vs. (7.1±2.2) 109 , t=2.32, P=0.02], fasting blood glucose [ (7.2±2.6) vs. (6.6±2.4) mmol/L, t=2.00, P<0.05] and C-reactive protein level [(24.5±27.1) vs. (14.6±23.2) g/L, t=3.25, P=0.00] were significantly different between END group and non-END group. After adjustment of confounding factors, LA in periventricular with Fazekas grade 2 (OR=2.309, 95%CI: 1.070-4.984, P=0.03) and Fazekas grade 3 (OR=2.861, 95%CI: 1.214-6.742, P=0.02) and LA in centrum semiovale with Fazekas grade 3 (OR=3.047, 95%CI: 1.244-7.461, P=0.02) were independently associated with END.


Conclusion
Leukoaraiosis in periventricular group and centrum semiovale are associated with early neurological deterioration in patients with acute ischemic stroke.


Key words: 
Ischemic stroke; Leukoaraiosis; Early neurological deterioration; Arteriosclerosis