Evaluation of Pulmonary Fibrosis Outcomes by Race and Ethnicity in US Adults

Importance: Pulmonary fibrosis (PF) is characterized by progressive scarring of lung tissue and poor survival. Racial and ethnic minority populations face the greatest risk of morbidity and mortality from disparities impacting respiratory health, but the pattern of age at clinically relevant outcomes across diverse racial and ethnic populations with PF is unknown. Objective: To compare the age at PF-related outcomes and the heterogeneity in survival patterns among Hispanic, non-Hispanic Black, and non-Hispanic White participants. Design, setting, and participants: This cohort study included adult patients with a PF diagnosis and used data from prospective clinical registries: the Pulmonary Fibrosis Foundation Registry (PFFR) for the primary cohort and registries from 4 geographically distinct tertiary hospitals in the US for the external multicenter validation (EMV) cohort. Patients were followed between January 2003 and April 2021. Exposures: Race and ethnicity comparisons between Black, Hispanic, and White participants with PF. Main outcomes and measures: Age and sex distribution of participants were measured at the time of study enrollment. All-cause mortality and age at PF diagnosis, hospitalization, lung transplant, and death were assessed in participants over 14 389 person-years. Differences between racial and ethnic groups were compared using Wilcoxon rank sum tests, Bartlett 1-way analysis of variance, and χ2 tests, and crude mortality rates and rate ratios were assessed across racial and ethnic categories using Cox proportional hazards regression models. Results: In total, 4792 participants with PF were assessed (mean [SD] age, 66.1 [11.2] years; 2779 [58.0%] male; 488 [10.2%] Black, 319 [6.7%] Hispanic, and 3985 [83.2%] White); 1904 were in the PFFR and 2888 in the EMV cohort. Black patients with PF were consistently younger than White patients (mean [SD] age at baseline, 57.9 [12.0] vs 68.6 [9.6] years; P Conclusions and relevance: In this cohort study of participants with PF, racial and ethnic disparities, especially among Black patients, were found in PF-related outcomes, including earlier onset of death. Further research is essential to identify and mitigate the underlying responsible factors.</p

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.</p

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

मांस का दरिया एक अध्ययन

कमलेश्वर अमपने समय के महान एवं प्रतिभाशाली कहानी – लेखक के रूप में उभरे हैं , जिंहोने साहित्य के कण-कण को छान कर उपन्यासों में ही नहीं अपितु कहानियों में भी प्रबल प्रतिभा का परिचय दिया हैं । इनकी कहानियों में सम्बन्धों विघटन ,आथिर्क ,विवशता ,ज़िन्दगी का दुहरापन मानवीयता की खोज आदिचित्रित हुए हैं ।भ्रष्टाचार और उससे उत्पन अमानवीयता कमलेश्वर की कहानियों का नियामक तत्व हैं । रचनाकार के रूप में कमलेश्वर को प्रतिष्ठा को शुरुवात कहानियों से होती हैं । इनकी भाषा सपाट हैं ।ये हिंदी – कहानी के एक प्रमुख प्रवक्ता हैं तथा शिल्प भी हैं । कमलेश्वर की कहानियों में वेयवितक को प्रलय मिलता हैं । कमलेश्वर ने अपनी कहानियों के कथ्य अपने आसपास के परिवेश से लिये हैं ।इनकी प्रराम्भिक कहानियाँ कस्बे की हैं । कस्बे की मांसिकता संक्रमणकालिकता मांसिकता होती हैं । कमलेश्वर की कहानियों का तेवर समय की गतिशीलता के साथ बदलता रहा हैं ।जीवन को उन्होंने सदा उन्मुक्त भाव किया हैं ।उन्होंने चरित्र के विविध पक्षों को कहानियों में चित्रित किया हैं । संक्षेप में, हिंदी की (नयी कहानी) के कृतिकारों में कमलेश्वर अपनी विशिष्ट पहचान बनाने में समर्थ हुए हैं और उनका वैशिष्ट्य सामान्य ज़िनदगी से जुड़े रहने की प्रवृतित्व में हैं

साठोत्तरी कथा – साहित्य में महिला कथाकारों का योगदान

साठोत्तरी महिला कहानीकारों ने कहानी के क्षेत्र में वस्तु तथा शिल्प के आधार पर नवीन भूमिया तोड़ डाली । इन्होंने कालान्तर में नई कहानी का वस्तु और शिल्प के आधार पर विद्रोह किया । विद्रोह के कारण नई कहानी में भटकाव्य आ गया है और भटकाव के कारण ही नई कहानी में छोटे – छोटे आन्दोलन चलाने का प्रयत्न किया हैं । उन्होंने उपन्यास के क्षेत्र में भी अपनी विशिष्टता का परिचय दिया हैं । इनहोंने उपन्यास की विभिन्न पद्धतियों को उपन्यास हैं और नारी – मनोविज्ञान को अधिकांशतः लिया हैं । महिला कथाकारों ने अपनी कृतियों में मनुष्य की विशेष कर नारी की व्यथा , पीड़ा , वेदना , भय , संत्रास इनहोंने नारी - मन को व्यथा को अधिक, समझ है और उसे आत्मासात भी किया हैं । इन्होंने जीवन के इन्होंने वर्तमान स्थिति के उन घिनौने सत्यों का इसके अतिरिक्त इन्होंने मध्यवर्गिय विवशता और घुटन को उभर कर अपनी कृत्तियों द्वारा उसका सफल चित्रण किया हैं

Evaluation of Pulmonary Fibrosis Outcomes by Race and Ethnicity in US Adults

ImportancePulmonary fibrosis (PF) is characterized by progressive scarring of lung tissue and poor survival. Racial and ethnic minority populations face the greatest risk of morbidity and mortality from disparities impacting respiratory health, but the pattern of age at clinically relevant outcomes across diverse racial and ethnic populations with PF is unknown.ObjectiveTo compare the age at PF-related outcomes and the heterogeneity in survival patterns among Hispanic, non-Hispanic Black, and non-Hispanic White participants.Design, setting, and participantsThis cohort study included adult patients with a PF diagnosis and used data from prospective clinical registries: the Pulmonary Fibrosis Foundation Registry (PFFR) for the primary cohort and registries from 4 geographically distinct tertiary hospitals in the US for the external multicenter validation (EMV) cohort. Patients were followed between January 2003 and April 2021.ExposuresRace and ethnicity comparisons between Black, Hispanic, and White participants with PF.Main outcomes and measuresAge and sex distribution of participants were measured at the time of study enrollment. All-cause mortality and age at PF diagnosis, hospitalization, lung transplant, and death were assessed in participants over 14 389 person-years. Differences between racial and ethnic groups were compared using Wilcoxon rank sum tests, Bartlett 1-way analysis of variance, and χ2 tests, and crude mortality rates and rate ratios were assessed across racial and ethnic categories using Cox proportional hazards regression models.ResultsIn total, 4792 participants with PF were assessed (mean [SD] age, 66.1 [11.2] years; 2779 [58.0%] male; 488 [10.2%] Black, 319 [6.7%] Hispanic, and 3985 [83.2%] White); 1904 were in the PFFR and 2888 in the EMV cohort. Black patients with PF were consistently younger than White patients (mean [SD] age at baseline, 57.9 [12.0] vs 68.6 [9.6] years; P &lt; .001). Hispanic and White patients were predominantly male (Hispanic: PFFR, 73 of 124 [58.9%] and EMV, 109 of 195 [55.9%]; and White: PFFR, 1090 of 1675 [65.1%] and EMV, 1373 of 2310 [59.4%]), while Black patients were less likely to be male (PFFR, 32 of 105 [30.5%] and EMV, 102 of 383 [26.6%]). Compared with White patients, Black patients had a lower crude mortality rate ratio (0.57 [95% CI, 0.31-0.97), but for Hispanic patients, the mortality rate ratio was similar to that of White patients (0.89; 95% CI, 0.57-1.35). Mean (SD) hospitalization events per person were highest among Black patients compared with Hispanic and White patients (Black: 3.6 [5.0]; Hispanic, 1.8 [1.4]; and White, 1.7 [1.3]; P &lt; .001). Black patients were consistently younger than Hispanic and White patients at first hospitalization (mean [SD] age: Black, 59.4 [11.7] years; Hispanic, 67.5 [9.8] years; and White, 70.0 [9.3] years; P &lt; .001), lung transplant (Black, 58.6 [8.6] years; Hispanic, 60.5 [6.1] years; and White, 66.9 [6.7] years; P &lt; .001), and death (Black, 68.7 [8.4] years; Hispanic, 72.9 [7.6] years; and White, 73.5 [8.7] years; P &lt; .001). These findings remained consistent in the replication cohort and in sensitivity analyses within prespecified deciles of age groups.Conclusions and relevanceIn this cohort study of participants with PF, racial and ethnic disparities, especially among Black patients, were found in PF-related outcomes, including earlier onset of death. Further research is essential to identify and mitigate the underlying responsible factors