Miracle-dz/UniFAR-FTUs huggingface dataset:
A likelihood ratio test on temporal trends in age‐period‐cohort models with applications to the disparities of heart disease mortality among US populations and comparison with
 Japan

In this article, we introduce the recently developed intrinsic estimator method in the age‐period‐cohort (APC) models in examining disease incidence and mortality data, further develop a likelihood ratio (L‐R) test for testing differences in temporal trends across populations, and apply the methods to examining temporal trends in the age, period or calendar time, and birth cohort of the US heart disease mortality across racial and sex groups. The temporal trends are estimated with the intrinsic estimator method to address the model identification problem, in which multiple sets of parameter estimates yield the same fitted values for a given dataset, making it difficult to conduct comparison of and hypothesis testing on the temporal trends in the age, period, and cohort across populations. We employ a penalized profile log‐likelihood approach in developing the L‐R test to deal with the issues of multiple estimators and the diverging number of model parameters. The identification problem also induces overparametrization of the APC model, which requires a correction of the degree of freedom of the L‐R test. Monte Carlo simulation studies demonstrate that the L‐R test performs well in the Type I error calculation and is powerful to detect differences in the age or period trends. The L‐R test further reveals disparities of heart disease mortality among the US populations and between the US and Japanese populations.
Filtering for the best policy: An economic evaluation of policy options for kidney replacement coverage in the Philippines

Kidney failure patients in the Philippines have free choice on their kidney replacement therapy (KRT), with a majority choosing haemodialysis (HD) over peritoneal dialysis (PD) and transplantation despite the inadequate coverage of HD. Although national health insurance coverage is limited, KRT remains to be one of the top benefits pay‐outs in the country. The study aims to identify the most cost‐effective policy strategy for financing KRT in the Philippines, in the context of a universal healthcare policy.
An Electrophysiological Study of Aging and Perceptual Letter-Matching

ABSTRACT Background: Previous studies on perceptual letter-matching have found that younger and older adults showed “fast-same” effects for response time and “false-different” effects for errors but the effects were more pronounced for older adults. According to the Noisy Operator Theory, internal noise in visual processing distorts “same” trials into appearing different whereas distortion for “different” trials does not affect performance. Older adults have a “noisier” representation of items within perceptual processing which can impact perceptual matching. However, EEG measures may provide a more direct measure of letter-matching decisions. Methods: We measured the P300 event-related potential (ERP) amplitude, an index of familiarity in stimulus categorization, and behavioral measures (response time and accuracy) to assess letter-matching performance. Results: Individuals responded faster to “same” trials than to “different” trials but were less accurate. Older adults showed similar P300 amplitudes across trial type whereas younger adults produced a larger amplitude for “same” than “different” trials, suggesting that older adults showed less familiarity for “same” trials than did younger adults – a prediction of the Noisy Operator Theory. Conclusions: These ERP results are consistent with the Noisy Operator Theory – suggesting that an age-related increase in internal noise affected letter-matching performance.
Alpine glacier resilience and Neoglacial fluctuations linked to Holocene snowfall trends in the western United States

Alpine lake sediments provide rare 10,000-year glacier record and highlight influence of winter precipitation. Geological evidence indicates that glaciers in the western United States fluctuated in response to Holocene changes in temperature and precipitation. However, because moraine chronologies are characteristically discontinuous, Holocene glacier fluctuations and their climatic drivers remain ambiguous, and future glacier changes are uncertain. Here, we construct a continuous 10-thousand-year (ka) record of glacier activity in the Teton Range, Wyoming, using glacial and environmental indicators in alpine lake sediments. We show that Teton glaciers persisted in some form through early Holocene warmth, likely as small debris-covered glaciers or rock glaciers. Subsequent Neoglacial ice expansion began ~6.3 ka, with two prominent glacier maxima at ~2.8 and 0.1 ka that were separated by a multicentennial phase of ice retreat. Comparison with regional paleoclimate records suggests that glacier activity was dominantly controlled by winter precipitation variability superposed on long-term Holocene temperature trends, offering key insights into western U.S. glacier resilience and vulnerability to future warming.
Early Postoperative Complications From National Surgical Quality Improvement Program

Background Despite the recent surge in rates of immediate breast reconstruction, there is a paucity of large multicenter studies to compare differences in morbidity after immediate versus delayed breast reconstruction. This study used the National Surgical Quality Improvement Program (NSQIP) to study the association between timing of breast reconstruction and complication rates, stratified by reconstructive modality. Study Design The NSQIP database was used to identify breast reconstructions from 2005 to 2012. Rates of major complications were compared by timing within each reconstructive modality (implant vs autologous). Cohort differences in baseline characteristics and variables associated with increased complication rates were identified in bivariate analyses. A multivariable model was created to compare the association between the timing of reconstruction and major complications. Results Of 24,506 postmastectomy reconstructions, 85.8% were immediate, 14.2% were delayed, 84% were implant, and 16% were autologous reconstructions. Overall, 10.0% of patients suffered a major complication. After stratification, only implant reconstructions showed a statistically higher complication rate with immediate (8.8%) reconstruction compared with delayed (5.3%) (odds ratio, 1.7, P < 0.01). There was no significant difference in complication rates between autologous immediate (18.4%) or delayed (19.0%) reconstructions. After controlling for baseline cohort differences and other risk factors, immediate reconstruction remained as an independent significant predictor of major complications in implant reconstructions (odds ratio, 1.8, P < 0.01). Conclusions Immediate rather than delayed breast reconstruction is associated with a significantly higher rate of major complications in implant reconstruction but not in autologous reconstruction. It is important to include these findings in the routine preoperative surgeon-patient discussion of reconstructive options.
Molecular Profiling of Exceptional Responders to Cancer Therapy.

BACKGROUND The vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments. MATERIALS AND METHODS We analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response and/or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type. RESULTS Twenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response. CONCLUSIONS The genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied. IMPLICATIONS FOR PRACTICE With recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment response and outcomes, thereby allowing precision oncology. In this study, we hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. We found that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in exceptional responders analyzed in this single-center retrospective study. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.
Chemical composition and antifungal efficacy of five essential oils against Calonectria pseudonaviculata, the causal agent of boxwood blight: an in vitro study

Abstract Recent epidemics of box (boxwood) blight caused by the fungus Calonectria pseudonaviculata in Hyrcanian forests led to the search for eco-friendly fungicides. Essential oils (EOs) of medicinal plants undoubtedly have been highlighted as a new therapeutic approach. In this study, EOs from Cuminum cyminum, Lavandula angustifolia, Thymus daenensis, Trachyspermum copticum and Hyssopus officinalis were evaluated for their inhibitory activities against C. pseudonaviculata Cy-08 in vitro. Quantitative and qualitative composition variations of the EOs were also analysed by GC–MS. Based on the high inhibitory efficacy and low related EC50, MFC and MIC values, T. copticum, L. angustifolia and Th. daenensis EOs can be mentioned as those providing extraordinary efficacy against Cy-08, respectively. Major chemical components of T. copticum, L. angustifolia and Th. daenensis EOs were thymol, linalyl acetate and thymol, respectively. Thymol and linalyl acetate may be the most effective compounds against C. pseudonaviculata.
Comprehensive Gene Mutation Profiling of Circulating Tumor DNA in Ovarian Cancer: Its Pathological and Prognostic Impact

Simple Summary Recent advances in cancer genomic medicine enabled gene-profiling of individual tumors using tumor tissue DNA. However, surgical tumor biopsy is invasive and sometimes difficult to perform in advanced/recurrent cancers. Liquid biopsy using circulating tumor DNA (ctDNA), which can analyze in real time and repeatedly, has attracted attention as a non-invasive technique, although it has been rarely used in ovarian cancer. The aim of the present study was to demonstrate the comprehensive gene mutation profiles of ctDNA in ovarian cancer patients with different histological subtypes and its association with clinicopathological and prognostic outcomes. Of 51 patients, 48 showed one or more non-synonymous somatic mutations, including TP53, APC, KRAS, EGFR, MET, and PIK3CA. Patients with higher ctDNA concentration or with any pathogenic mutations showed worse progression-free survival (PFS). These results suggest that ctDNA-based gene profiling may serve as a prognostic indicator and might help in establishing personalized therapeutic strategies for ovarian cancer. Abstract Liquid biopsies from circulating tumor DNA (ctDNA) have been employed recently as a non-invasive diagnostic tool for detecting cancer-specific gene mutations. Here, we show the comprehensive gene mutation profiles of ctDNA in 51 patients with different histological subtypes of stage I–IV ovarian cancer, and their association with clinical outcomes. The ctDNA extracted from pre-treatment patients’ plasma were analyzed using Cancer Personalized Profiling by Deep Sequencing targeting 197 genes. Of 51 patients, 48 (94%) showed one or more non-synonymous somatic mutations, including TP53 (37.3%), APC (17.6%), KRAS (15.7%), EGFR (13.7%), MET (11.8%), PIK3CA (11.8%), NPAP1 (11.8%), and ALK (9.8%). The most frequently mutated genes were as follows: TP53 in high-grade serous carcinoma (66.7%), APC in clear cell carcinoma (30.8%), PIK3CA in endometrioid carcinoma (40%), and KRAS in mucinous carcinoma (66.7%). Higher cell-free (cf)DNA concentration significantly correlated with worse progression-free survival (PFS) in all patients as well as stage III–IV patients (p = 0.01 and 0.005, respectively). Further, patients with any pathogenic mutations showed significantly worse PFS (p = 0.048). Blood tumor mutational burden detected from ctDNA did not significantly correlate with the histological subtypes or survival. Collectively, clinico-genomic profiles of individual ovarian cancer patients could be identified using ctDNA and may serve as a useful prognostic indicator. These findings suggest that ctDNA-based gene profiling might help in establishing personalized therapeutic strategies.
Prevalence and Distribution of Avian Influenza Viruses in Domestic Ducks at the Waterfowl-Chicken Interface in Wetlands

Ducks are a natural reservoir of influenza A viruses (IAVs) and can act as a reassortment vessel. Wetlands, such as Hakaluki and Tanguar haor in Bangladesh, have unique ecosystems including domestic duck (Anas platyrhynchos domesticus) rearing, especially household and free-range ducks. A cross-sectional study was, therefore, conducted to explore avian influenza status and its distribution and risk factors in the wetland areas. During the three consecutive winters of 2015–2017, specifically in December of these years, we collected a total of 947 samples including blood, oropharyngeal and cloacal swabs from domestic ducks (such as free-range ducks (n = 312 samples) and household ducks (n = 635 samples) in wetlands. We screened serum samples using a nucleoprotein competitive enzyme-linked immunosorbent assay (c-ELISA) to estimate seroprevalence of IAV antibodies and swab samples by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) to detect IA viral M gene. Eleven M gene positive samples were subjected to sequencing and phylogenetic analysis. Serological and viral prevalence rates of IAVs were 63.8% (95% CI: 60.6–66.8) and 10.7% (8.8–12.8), respectively. Serological and viral RNA prevalence rates were 51.8% (95% CI: 47.2–56.4) and 10.2% (7.6–13.3) in Hakaluki haor, 75.6% (71.5–79.4) and 11.1% (8.5–14.3) in Tanguar haor, 66.3% (62.5–69.9) and 11.2% (8.8–13.9) in household ducks and 58.7% (52.9–64.2) and 9.6% (6.5–13.4) in free-range ducks, respectively. The risk factors identified for higher odds of AI seropositive ducks were location (OR = 2.9, 95% CI: 2.2–3.8, p < 0.001; Tanguar haor vs. Hakaluki haor), duck-rearing system (OR = 1.4, 1.1–1.8, household vs. free-range), farmer’s education status (OR = 1.5, 1.2–2.0, p < 0.05 illiterate vs. literate) and contact type (OR = 3.0, 2.1–4.3, p < 0.001; contact with chicken vs. no contact with chicken). The risk factors identified for higher odds of AI viral RNA positive ducks were farmer’s education status (OR = 1.5, 1.0–2.3, p < 0.05 for illiterate vs literate), contact type (OR = 2.7, 1.7–4.2, p < 0.001; ducks having contact with chicken vs. ducks having contact with waterfowl). The phylogenetic analysis of 11 partial M gene sequences suggested that the M gene sequences detected in free-range duck were very similar to each other and were closely related to the M gene sequences of previously reported highly pathogenic avian influenza (HPAI) and low pathogenic avian influenza (LPAI) subtypes in waterfowl in Bangladesh and Southeast Asian countries. Results of the current study will help provide significant information for future surveillance programs and model IAV infection to predict the spread of the viruses among migratory waterfowl, free-range ducks and domestic poultry in Bangladesh.
Are older adults insufficiently included in clinical trials?—An umbrella review

Treatment guidelines are primarily based on randomized clinical trials (RCTs). RCTs tend to some extent to exclude older adults despite the fact that physicians need guidance when treating this patient group. By summarizing existing literature, we aimed to (a) quantify the proportion of RCTs and other clinical studies (CTs) that did not adequately include older adults; (b) identify the main barriers for this non‐inclusion; and (c) identify suggested solution for inclusion of older adults in RCTs and other CTs. In this umbrella review, Embase and PubMed were searched for relevant papers, and 2701 papers were identified. The subsequent screening resulted in 22 papers. The Critical Appraisal Skills Program was used as quality assessment tool to evaluate these 22 papers. We found that: (a) The most frequent outcome designating missing inclusion of older adults was the use of age limit as exclusion criterion in studies—the proportion of this was 10%‐60%; (b) barriers for inclusion were mainly exclusion criteria, logistic challenges and financial constraints; and (c) more extensive inclusion would require more explicit inclusion criteria, merely application of exclusion criteria when absolutely needed, change of researchers’ attitude, further inclusion of supporting relatives to overcome the logistical challenges and more financial funding.
Targeting USP13‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer

In non‐small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug‐tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high‐throughput siRNA screen to identify proteins that abrogate the response of EGFR‐mutant NSCLC to EGFR‐targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase‐independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR‐specific cotarget that could improve the treatment efficacy of EGFR‐targeted therapies.
Estimated salt intake and risk of atrial fibrillation in a prospective community‐based cohort

Hypertension predisposes to atrial fibrillation (AF) – a major risk factor for ischaemic stroke. Since a high dietary salt consumption is associated with hypertension, we investigated the association between urinary sodium excretion as a marker for dietary sodium intake and risk of new‐onset AF in community‐dwelling adults.
Left ventricular segmental strain and the prediction of cancer therapy-related cardiac dysfunction.

AIMS We aimed to determine the early changes and predictive value of left ventricular (LV) segmental strain measures in women with breast cancer receiving doxorubicin. METHODS AND RESULTS In a cohort of 237 women with breast cancer receiving doxorubicin with or without trastuzumab, 1151 echocardiograms were prospectively acquired over a median (Q1-Q3) of 7 (2-24) months. LV ejection fraction (LVEF) and 36 segmental strain measures were core lab quantified. A supervised machine learning (ML) model was then developed using random forest regression to identify segmental strain measures predictive of nadir LVEF post-doxorubicin completion. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥10% absolute LVEF decline pre-treatment to a value <50%. Median (Q1-Q3) baseline age was 48 (41-57) years. Thirty-five women developed CTRCD, and eight of these developed symptomatic heart failure. From pre-treatment to doxorubicin completion, longitudinal strain worsened across the basal and mid-LV segments but not in the apical segments; circumferential strain worsened primarily in the septum; radial strain worsened uniformly and transverse strain remained unchanged across all LV segments. In the ML model, anterolateral and inferoseptal circumferential strain were the most predictive features; longitudinal and transverse strain in the basal inferoseptal, anterior, basal anterolateral, and apical lateral segments were also top predictive features. The addition of predictive segmental strain measures to a model including age, cancer therapy regimen, hypertension, and LVEF increased the area under the curve (AUC) from 0.70 (95% confidence interval (CI) 0.60-0.80) to 0.87 (95% CI 0.81-0.92), ΔAUC = 0.18 (95% CI 0.08-0.27) for the prediction of CTRCD. CONCLUSION Our findings suggest that segmental strain measures can enhance cardiotoxicity risk prediction in women with breast cancer receiving doxorubicin.
Unstimulated Pleural Fluid Interferon Gamma for Diagnosis of Tuberculous Pleural Effusion: a Systematic Review and Meta-analysis

Unstimulated interferon gamma may be a useful pleural fluid biomarker in the diagnosis of tuberculous pleural effusion (TPE). However, the exact threshold of pleural fluid interferon gamma and its accuracy during routine clinical decision-making is not clear. ABSTRACT Unstimulated interferon gamma may be a useful pleural fluid biomarker in the diagnosis of tuberculous pleural effusion (TPE). However, the exact threshold of pleural fluid interferon gamma and its accuracy during routine clinical decision-making is not clear. We assessed the performance of pleural fluid interferon gamma in diagnosing TPE and tried to identify a useful assay threshold. We queried the PubMed and Embase databases for publications indexed until May 2020 that provided both sensitivity and specificity data on unstimulated pleural fluid interferon gamma for diagnosis of TPE. A bivariate random effects model was employed to compute summary estimates for diagnostic accuracy parameters, both overall as well as at threshold ranges of <2, 2 to 5, and >5 IU/ml. We retrieved 2,048 citations, of which 67 publications (7,153 patients) were assessed in our review. The summary estimates for sensitivity, specificity, and diagnostic odds ratio were 0.93 (95% confidence interval [CI], 0.91 to 0.95), 0.96 (95% CI, 0.94 to 0.97), and 310.72 (95% CI, 185.24 to 521.18), respectively. Increasing interferon gamma thresholds did not translate into any substantial change in diagnostic performance; however, eight studies using thresholds of >5 IU/ml showed poorer diagnostic accuracy estimates than other studies with lower thresholds. None of the prespecified subgroup variables significantly influenced relative diagnostic odds ratios in a multivariate meta-regression model. All publications demonstrated a high risk of bias. Unstimulated pleural fluid interferon gamma level provides excellent accuracy for diagnosing TPE and has the potential of becoming a first-line test for this purpose.