tbuckley/cabot-search huggingface dataset:
Modeling comparative cost-effectiveness of SARS-CoV-2 vaccine dose fractionation in India
Authors: Zhanwei Du, Lin Wang, Abhishek Pandey, Wey Wen Lim, Matteo Chinazzi, Ana Pastore y. Piontti, Eric H. Y. Lau, Peng Wu, Anup Malani, Sarah Cobey, Benjamin J. Cowling
Journal: Nature Medicine (2022)

Given global Coronavirus Disease 2019 (COVID-19) vaccine shortages and inequity of vaccine distributions, fractionation of vaccine doses might be an effective strategy for reducing public health and economic burden, notwithstanding the emergence of new variants of concern. In this study, we developed a multi-scale model incorporating population-level transmission and individual-level vaccination to estimate the costs of hospitalization and vaccination and the economic benefits of reducing COVID-19 deaths due to dose-fractionation strategies in India. We used large-scale survey data of the willingness to pay together with data of vaccine and hospital admission costs to build the model. We found that fractional doses of vaccines could be an economically viable vaccination strategy compared to alternatives of either full-dose vaccination or no vaccination. Dose-sparing strategies could save a large number of lives, even with the emergence of new variants with higher transmissibility.
Nintedanib in Patients With Autoimmune Disease–Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the <scp>INBUILD</scp> Trial
Authors: Eric L. Matteson, Clive Kelly, Jörg H. W. Distler, Anna‐Maria Hoffmann‐Vold, James R. Seibold, Shikha Mittoo, Paul F. Dellaripa, Martin Aringer, Janet Pope, Oliver Distler, Alexandra James, Rozsa Schlenker‐Herceg, Susanne Stowasser, Manuel Quaresma, Kevin R. Flaherty
Journal: Arthritis & Rheumatology (2022)

To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype.The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs.Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.
Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group
Authors: Torsten O Nielsen, Samuel C. Y Leung, David L Rimm, Andrew Dodson, Balazs Acs, Sunil Badve, Carsten Denkert, Matthew J Ellis, Susan Fineberg, Margaret Flowers, Hans H Kreipe, Anne-Vibeke Laenkholm, Hongchao Pan, Frédérique M Penault-Llorca, Mei-Yin Polley, Roberto Salgado, Ian E Smith, Tomoharu Sugie, John M. S Bartlett, Lisa M McShane, Mitch Dowsett, Daniel F Hayes
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
Influence of ejection fraction on biomarker expression and response to spironolactone in people at risk of heart failure: findings from the <scp>HOMAGE</scp> trial
Authors: João Pedro Ferreira, Job A.J. Verdonschot, Nicolas Girerd, Erwan Bozec, Pierpaolo Pellicori, Timothy Collier, Beatrice Mariottoni, Franco Cosmi, Mark Hazebroek, Joe Cuthbert, Johannes Petutschnigg, Stephane Heymans, Jan A. Staessen, Burkert Pieske, Frank Edelman, Andrew L. Clark, Javier Díez, Arantxa González, Patrick Rossignol, John G. Cleland, Faiez Zannad
Journal: European Journal of Heart Failure (2022)
Oesophageal disease
Authors: G Stacher, G Moser, Th.-A Abatzi, T Wenzel, U Weber, C Schneider, W Schima, P Pokieser, D Denk, H Bergmann
Journal: Gut (1994)

The globus sensation is often viewed as pointing at the presence of a con- version disorder or other psychogenicity.We studied prospectively 70 female and 22 male patients (age 22-71 years, median 43 years) referred consec- utively to a psychosomatic clinic and presenting with the sensation as primary symptom.To evaluate whether morphological or other abnormalities underlay their sensation, all underwent a thorough history taking as well as otolaryngological, videokinematographic, and manometric examinations of pharynx and oesophagus.When indicated by history or findings, 24-hour pHmetry, scintigraphy of oesophageal bolus transport or gastric emptying, oe- sophagogastroscopy and other examinations were performed.The investiga- tions revealed that 4 patients had a Zenker diverticulum (1 also oesophageal varices), 1 a velopalatinal insufficiency, 1 an only partial opening of the upper oesophageal sphincter, 16 achalasia, 9 "hypochalasia", 1 diffuse oesophageal spasms, 2 nutcracker oesophagus, 30 nonspecific oesophageal motor abnor- malities, 17 abnormal gastrooesophageal reflux activity (thereof 10 also oe- sophagitis), 6 massively delayed gastric emptying, 1 erosive antral gastritis, and 1 dental malocclusion.Of those having nonspecific oesophageal motor abnormalities, 1 patient had also malocclusion, 4 pharyngitis, 1 erosive gas- tritis and 2 delayed gastric emptying.Eleven patients suffering from one of the above motor disorders had also hyperplastic lingual tonsils, 3 had tonsilli- tis and 1 a cervical spondylophyte.The psychometric investigations showed no higher mean scores for depression, state and trait anxiety, hysteria and hypochondriasis than in general medical outpatients.Psychiatric interviews with 57 patients showed that 44 met DSM-111-R criteria for psychiatric disor- ders.However, neither this nor the psychometric findings bore any relation- ship to the presence, intensity or frequency of the globus sensation or the physical disorders detected.The results suggest that the globus sensation has to be viewed as an indicator of disordered oesophageal and possibly I1A: 9 cases; stage 11 B: 14 cases; stage IV: 3 cases.After therapy, when biop- sies were negative, the staging evaluated by ENS was the following: TONO: 14cases; T1 N1: 2cases; T2N 1: 3cases; T3N1: 4cases; T4NO: 1 case; T4N1: 1 case.CT did not show any parietal thickening or lymph node involvement in 3 patients with tumours staged T3N 1 and in 2 patients with tumour staged T2N1 by ENS.When no infiltration was detected by ENS, no tumoral evolution was observed within at least eight months (median 14 months; extr: on July 12, 2023 by guest.
A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma
Authors: Vincent Law, Zhihua Chen, Francesca Vena, Inna Smalley, Robert Macaulay, Brittany R Evernden, Nam Tran, Yolanda Pina, John Puskas, Gisela Caceres, Simon Bayle, Joseph Johnson, James K C Liu, Arnold Etame, Michael Vogelbaum, Paulo Rodriguez, Derek Duckett, Brian Czerniecki, Ann Chen, Keiran S M Smalley, Peter A Forsyth
Journal: Neuro-Oncology (2022)

Abstract Background Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD. Methods CSF-CTCs were collected from melanoma patients with melanoma-derived LMD and cultured ex vivo using human meningeal cell-conditioned media. Using immunoassays and RNA-sequencing analyses of PD-CSF-CTCs, molecular signaling pathways were examined and new therapeutic targets were tested for efficacy in PD-CSF-CTCs preclinical models. Results PD-CSF-CTCs were successfully established both in vitro and in vivo. Global RNA analyses of PD-CSF-CTCs revealed several therapeutically tractable targets. These studies complimented our prior proteomic studies highlighting IGF1 signaling as a potential target in LMD. As a proof of concept, combining treatment of ceritinib and trametinib in vitro and in vivo demonstrated synergistic antitumor activity in PD-CSF-CTCs and BRAF inhibitor-resistant melanoma cells. Conclusions This study demonstrates that CSF-CTCs can be grown in vitro and in vivo from some melanoma patients with LMD and used as preclinical models. These models retained melanoma expression patterns and had signaling pathways that are therapeutically targetable. These novel models/reagents may be useful in developing rationally designed treatments for LMD.
SARS-CoV-2 antigen lateral flow tests for detecting infectious people: linked data analysis
Authors: Jonathan J Deeks, Anika Singanayagam, Hamish Houston, Alice J Sitch, Seran Hakki, Jake Dunning, Ajit Lalvani
Journal: BMJ (2022)

Abstract Objectives To investigate the proportion of lateral flow tests (LFTs) that produce negative results in those with a high risk of infectiousness from SARS-CoV-2, to investigate the impact of the stage and severity of disease, and to compare predictions made by influential mathematical models with findings of empirical studies. Design Linked data analysis combining empirical evidence of the accuracy of the Innova LFT, the probability of positive viral culture or transmission to secondary cases, and the distribution of viral loads of SARS-CoV-2 in individuals in different settings. Setting Testing of individuals with symptoms attending NHS Test-and-Trace centres across the UK, residents without symptoms attending municipal mass testing centres in Liverpool, and students without symptoms screened at the University of Birmingham. Participants Evidence for the sensitivity of the Innova LFT, based on 70 individuals with SARS-CoV-2 and LFT results. Infectiousness was based on viral culture rates on 246 samples (176 people with SARS-CoV-2) and secondary cases among 2 474 066 contacts; distributions of cycle threshold (Ct) values from 231 497 index individuals attending NHS Test-and-Trace centres; 70 people with SARS-CoV-2 detected in Liverpool and 62 people with SARS-CoV-2 in Birmingham (54 imputed). Main outcome measures The predicted proportions who were missed by LFT and viral culture positive and missed by LFT and sources of secondary cases, in each of the three settings. Predictions were compared with those made by mathematical models. Results The analysis predicted that of those with a viral culture positive result, Innova would miss 20% attending an NHS Test-and-Trace centre, 29% without symptoms attending municipal mass testing, and 81% attending university screen testing without symptoms, along with 38%, 47%, and 90% of sources of secondary cases. In comparison, two mathematical models underestimated the numbers of missed infectious individuals (8%, 10%, and 32% in the three settings for one model, whereas the assumptions from the second model made it impossible to miss an infectious individual). Owing to the paucity of usable data, the inputs to the analyses are from limited sources. Conclusions The proportion of infectious people with SARS-CoV-2 missed by LFTs is substantial enough to be of clinical importance. The proportion missed varied between settings because of different viral load distributions and is likely to be highest in those without symptoms. Key models have substantially overestimated the sensitivity of LFTs compared with empirical data. An urgent need exists for additional robust well designed and reported empirical studies from intended use settings to inform evidence based policy.
Current Breast Milk PFAS Levels in the United States and Canada: After All This Time, Why Don’t We Know More?
Authors: Judy S. LaKind, Marc-André Verner, Rachel D. Rogers, Helen Goeden, Daniel Q. Naiman, Satori A. Marchitti, Geniece M. Lehmann, Erin P. Hines, Suzanne E. Fenton
Journal: Environmental Health Perspectives (2022)

Background: Despite 20 y of biomonitoring studies of per- and polyfluoroalkyl substances (PFAS) in both serum and urine, we have an extremely limited understanding of PFAS concentrations in breast milk of women from the United States and Canada. The lack of robust information on PFAS concentrations in breast milk and implications for breastfed infants and their families were brought to the forefront by communities impacted by PFAS contamination. Objectives: The objectives of this work are to: a) document published PFAS breast milk concentrations in the United States and Canada; b) estimate breast milk PFAS levels from maternal serum concentrations in national surveys and communities impacted by PFAS; and c) compare measured/estimated milk PFAS concentrations to screening values. Methods: We used three studies reporting breast milk concentrations in the United States and Canada We also estimated breast milk PFAS concentrations by multiplying publicly available serum concentrations by milk:serum partitioning ratios for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). Measured and estimated breast milk concentrations were compared to children's drinking water screening values. Discussion: Geometric means of estimated breast milk concentrations ranged over approximately two orders of magnitude for the different surveys/communities. All geometric mean and mean estimated and measured breast milk PFOA and PFOS concentrations exceeded drinking water screening values for children, sometimes by more than two orders of magnitude. For PFHxS and PFNA, all measured breast milk levels were below the drinking water screening values for children; the geometric mean estimated breast milk concentrations were close to—or exceeded—the children's drinking water screening values for certain communities. Exceeding a children's drinking water screening value does not indicate that adverse health effects will occur and should not be interpreted as a reason to not breastfeed; it indicates that the situation should be further evaluated. It is past time to have a better understanding of environmental chemical transfer to—and concentrations in—an exceptional source of infant nutrition. https://doi.org/10.1289/EHP10359
Asthma management in low and middle income countries: case for change
Authors: Kevin Mortimer, Helen K. Reddel, Paulo M. Pitrez, Eric D. Bateman
Journal: European Respiratory Journal (2022)

Asthma is the most common noncommunicable disease in children, and among the most common in adults. The great majority of people with asthma live in low and middle income countries (LMICs), which have disproportionately high asthma-related morbidity and mortality. Essential inhaled medications, particularly those containing inhaled corticosteroids (ICS), are often unavailable or unaffordable, and this explains much of the global burden of preventable asthma morbidity and mortality. Guidelines developed for LMICs are generally based on the outdated assumption that patients with asthma symptoms <1-3 times per week do not need (or benefit from) ICS. Even when ICS are prescribed, many patients manage their asthma with oral or inhaled short-acting β
Management of recurrent transudative pleural effusions: can we REDUCE unnecessary interventions?
Authors: Christopher R. Gilbert, José M. Porcel
Journal: European Respiratory Journal (2022)

The management of recurrent, non-malignant pleural effusions has found itself in a quagmire. While significant advances in the field of malignant pleural diseases have occurred over the years, due to innovation and research efforts, this has not necessarily been the case in the field of non-malignant pleural diseases, except perhaps for pleural infections. Data suggests that despite having a “benign” problem, patients with recurrent, non-malignant pleural diseases may have one-year mortality rates in the range of 25–50% [1]. This, combined with nominally proven treatment options, leaves treating clinicians without confidence in what is truly the best therapeutic option for management. Indwelling pleural catheters and therapeutic thoracenteses seem to be equivalent therapeutic options for symptom palliation of recurrent symptomatic transudates <https://bit.ly/3BifaaV>
Association of Medical Financial Hardship and Mortality Among Cancer Survivors in the United States
Authors: K Robin Yabroff, Xuesong Han, Weishan Song, Jingxuan Zhao, Leticia Nogueira, Craig E Pollack, Ahmedin Jemal, Zhiyuan Zheng
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Cancer survivors frequently experience medical financial hardship in the United States. Little is known, however, about long-term health consequences. This study examines the associations of financial hardship and mortality in a large nationally representative sample of cancer survivors. Methods We identified cancer survivors aged 18-64 years (n = 14 917) and 65-79 years (n = 10 391) from the 1997-2014 National Health Interview Survey and its linked mortality files with vital status through December 31, 2015. Medical financial hardship was measured as problems affording care or delaying or forgoing any care because of cost in the past 12 months. Risk of mortality was estimated with separate weighted Cox proportional hazards models by age group with age as the timescale, controlling for the effects of sociodemographic characteristics. Health insurance coverage was added sequentially to multivariable models. Results Among cancer survivors aged 18-64 years and 65-79 years, 29.6% and 11.0%, respectively, reported financial hardship in the past 12 months. Survivors with hardship had higher adjusted mortality risk than their counterparts in both age groups: 18-64 years (hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.04 to 1.30) and 65-79 years (HR = 1.14, 95% CI = 1.02 to 1.28). Further adjustment for health insurance reduced the magnitude of association of hardship and mortality among survivors aged 18-64 years (HR = 1.09, 95% CI = 0.97 to 1.24). Adjustment for supplemental Medicare coverage had little effect among survivors aged 65-79 years (HR = 1.15, 95% CI = 1.02 to 1.29). Conclusion Medical financial hardship was associated with mortality risk among cancer survivors in the United States.
Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy
Authors: Timothy F Cloughesy, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jerry Ping, Jaymes Holland, Ron Weitzman, Patrick Y Wen
Journal: Neuro-Oncology (2017)

Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM). Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety. Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions. Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM. NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)