bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk
Authors: Olafsdottir Thorhildur , Stacey Simon N. , Sveinbjornsson Gardar , Thorleifsson Gudmar , Norland Kristjan , Sigurgeirsson Bardur , Thorisdottir Kristin , Kristjansson Arni Kjalar , Tryggvadottir Laufey , Sarin Kavita Y. , Benediktsson Rafn , Jonasson Jon G. , Sigurdsson Asgeir , Jonasdottir Aslaug , Kristmundsdottir Snaedis , Jonsson Hakon , Gylfason Arnaldur , Oddsson Asmundur , Fridriksdottir Run , Gudjonsson Sigurjon A. , Zink Florian , Lund Sigrun H. , Rognvaldsson Solvi , Melsted Pall , Steinthorsdottir Valgerdur , Gudmundsson Julius , Mikaelsdottir Evgenia , Olason Pall I. , Stefansdottir Lilja , Eggertsson Hannes P. , Halldorsson Bjarni V. , Thorsteinsdottir Unnur , Agustsson Tomas T. , Olafsson Karl , Olafsson Jon H. , Sulem Patrick , Rafnar Thorunn , Gudbjartsson Daniel F. , Stefansson Kari 
Published: February 2021

Abstract

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10−12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10−4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis.

Significance:
This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.
Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for RAS Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study
Authors: Kagawa Yoshinori , Elez Elena , García-Foncillas Jesús , Bando Hideaki , Taniguchi Hiroya , Vivancos Ana , Akagi Kiwamu , García Ariadna , Denda Tadamichi , Ros Javier , Nishina Tomohiro , Baraibar Iosune , Komatsu Yoshito , Ciardiello Davide , Oki Eiji , Kudo Toshihiro , Kato Takeshi , Yamanaka Takeharu , Tabernero Josep , Yoshino Takayuki 
Published: February 2021

Abstract

Purpose:
OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site.

Experimental Design:
Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden.

Results:
Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10.

Conclusions:
Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.
Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
Authors: Sharma Priyanka , Abramson Vandana G. , O'Dea Anne , Nye Lauren , Mayer Ingrid , Pathak Harsh B. , Hoffmann Marc , Stecklein Shane R. , Elia Manana , Lewis Sharon , Scott Jecinta , De Jong Jilliann A. , Wang Yen Y. , Yoder Rachel , Schwensen Kelsey , Finke Karissa , Heldstab Jaimie , LaFaver Stephanie , Williamson Stephen K. , Phadnis Milind A. , Reed Gregory A. , Kimler Bruce F. , Khan Qamar J. , Godwin Andrew K. 
Published: February 2021

AbstractPurpose:PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and Methods:Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.Results:A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting &gt;12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.Conclusions:The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure
Authors: Shi Huanan , Zhang Bojun , Abo-Hamzy Taylor , Nelson James W. , Ambati Chandra Shekar R. , Petrosino Joseph F. , Bryan Robert M. , Durgan David J. 
Published: February 2021

Rationale:
In recent years, it has been demonstrated that a pathological change in the gut microbiota, termed gut dysbiosis, can be an underlying factor for the development of hypertension. Prevention of this dysbiosis can attenuate or abolish hypertension. Translational mechanisms to prevent gut dysbiosis as well as understanding of the mechanisms linking gut dysbiosis to hypertension are lacking.

Objective:
We first examined the efficacy of intermittent fasting (IF) in altering the gut microbiota and lowering blood pressure (BP). Next, we utilized a multi-omics approach to examine microbial influenced metabolites that may serve as the link between the gut microbiota and host BP regulation.

Methods and Results:
We demonstrate that IF significantly altered the makeup of the gut microbiota, cecal and plasma metabolome, and prevented the development of hypertension in the spontaneously hypertensive stroke-prone rat. The beneficial effects of IF were shown to be due to alterations of the gut microbiota through germ-free transplantation studies. Germ-free rats receiving microbiota from IF spontaneously hypertensive stroke-prone rat had significantly lower BP as compared with germ-free rats receiving microbiota from ad libitum fed spontaneously hypertensive stroke-prone rats. Through whole genome shotgun sequence analysis of the microbiota and untargeted metabolomics of cecal content and plasma, we identified bile acid metabolism as a potential mediator in BP regulation. Finally, we show supplementation with cholic acid, or activation of the G protein-coupled bile acid receptor (TGR5), significantly reduced BP of the spontaneously hypertensive stroke-prone rats.

Conclusions:
These studies demonstrate the BP-lowering effects of IF involves manipulation of the gut microbiota and metabolome and implicate disrupted bile acid signaling as novel mechanisms by which gut dysbiosis contributes to hypertension.
SARS‐CoV‐2 Viremia is Associated With Inflammatory, But Not Cardiovascular Biomarkers, in Patients Hospitalized for COVID‐19
Authors: Myhre Peder L. , Prebensen Christian , Jonassen Christine Monceyron , Berdal Jan Erik , Omland Torbjørn 
Published: February 2021

Background
COVID‐19 may present with a variety of cardiovascular manifestations, and elevations of biomarkers reflecting myocardial injury and stress are prevalent. SARS‐CoV‐2 has been found in cardiac tissue, and myocardial dysfunction post‐COVID‐19 may occur. However, the association between SARS‐CoV‐2 RNA in plasma and cardiovascular biomarkers remains unknown.

Methods and Results

COVID MECH (COVID‐19 Mechanisms) was a prospective, observational study enrolling consecutive, hospitalized patients with laboratory‐confirmed infection with SARS‐CoV‐2 and symptoms of COVID‐19. Biobank plasma samples used to measure SARS‐CoV‐2 RNA and cardiovascular and inflammatory biomarkers were collected in 123 patients at baseline, and in 96 patients (78%) at day 3. Patients were aged 60±15 (mean ± SD) years, 71 (58%) were men, 68 (55%) were White, and 31 (25%) received mechanical ventilation during hospitalization. SARS‐CoV‐2 RNA was detected in plasma from 48 (39%) patients at baseline. Patients with viremia were more frequently men, had more diabetes mellitus, and lower oxygen saturation. Patients with viremia had higher concentrations of interleukin‐6, C‐reactive protein, procalcitonin, and ferritin (all <0.001), but comparable levels of cTnT (cardiac troponin T;
P
=0.09), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide;
P
=0.27) and D‐dimer (
P
=0.67) to patients without viremia. SARS‐CoV‐2 RNA was present in plasma at either baseline or day 3 in 50 (52%) patients, and these patients experienced increase from baseline to day 3 in NT‐proBNP and D‐dimer concentrations, while there was no change in cTnT.

Conclusions
SARS‐CoV‐2 viremia was associated with increased concentrations of inflammatory, but not cardiovascular biomarkers. NT‐proBNP and D‐dimer, but not cTnT, increased from baseline to day 3 in patients with viremia.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04314232.
Children’s Rights when Financing Development through Multilateral Development Banks: Mapping the Field and Looking Forward
Authors: Türkelli Gamze Erdem 
Published: February 2021

Abstract
Children and their rights are increasingly recognised as an integral part of the global development agenda as set out by the 2030 Agenda and the accompanying sdg s (Sustainable Development Goals). UN Human Rights Council Resolution 34/16 calls for a child rights-based approach to implementing these goals. Aspirations aside, children’s rights are largely invisible when the debates shift to how development is financed. Consequently, a children’s rights-based inquiry into the governance of institutions that finance development, is largely absent. This article seeks to overcome the relative scarcity of critical academic reflection on how and to what extent children’s rights feature in how development projects are financed by multilateral development banks (mdb s). The article first identifies common strands in norms mdb s use to govern themselves, their clients and borrowers. It then proceeds to situate how children’s rights fit into these administrative governance frameworks and goes on to address future perspectives of engagement to address shortcomings.
Effect of prophylactic laser during small-gauge vitrectomy for epiretinal membranes
Authors: Linton Edward F , Kim Stephen J , Patel Shriji N 
Published: February 2021

Purpose: To determine the rate of post-operative retinal detachment after elective pars plana vitrectomy for epiretinal membrane, and to test for the mitigating effect of prophylactic endolaser. Methods: We identified 459 eyes of 411 patients undergoing vitrectomy for epiretinal membrane at Vanderbilt University Medical Center between January 2010 and May 2017. Patients who underwent concurrent endolaser without any identified retinal break were included in the exposure cohort. Patients who underwent no prophylactic retinopexy or ablation were included in the unexposed cohort. Exposure data, demographic data, and outcome data were tabulated for comparison. Results: The final analysis included 343 eyes of 343 patients. Approximately 7% of eyes undergoing ERM surgery were found to have a full-thickness retinal break which was not seen preoperatively. The overall rate of postoperative RD was 2.04%. Postoperative retinal detachment occurred in 0 of the 34 eyes exposed to prophylactic laser, and in 7 of the 309 control eyes. Odds ratio was found to be 0.60 ( p = 0.598 (95%CI 0.0327–10.7), p = 0.72), indicated the results were not statistically significant. Discussion: Looking at patients undergoing routine vitrectomy surgery for epiretinal membrane, no retinal detachments occurred in the group receiving prophylactic treatment, though this association did not reach statistical significance. With modern surgical techniques, post-operative retinal detachment remains relatively rare after vitrectomy for ERM though a thorough intraoperative exam is critical to identify occult retinal breaks.
A critical reflection on the use of improvement science approaches in public health
Authors: Fischbacher Colin M. , Lewsey Jim , Muirie Jill , McCartney Gerry 
Published: February 2021

Objective: ‘Improvement science’ is used to describe specific quality improvement methods (including tests of change and statistical process control). The approach is spreading from clinical settings to population-wide interventions and is being extended from supporting the adoption of proven interventions to making generalisable claims about new interventions. The objective of this narrative review is to evaluate the strengths and risks of current improvement science practice, particularly in relation to how they might be used in population health. Methods: A purposive sampling of published studies to identify how improvement science methods are being used and for what purpose. The setting was Scotland and studies that focused on health and wellbeing outcomes. Results: We have identified a range of improvement science approaches which provide practitioners with accessible tools to assess small-scale changes in policy and practice. The strengths of such approaches are that they facilitate consistent implementation of interventions already known to be effective and motivate and empower staff to make local improvements. However, we also identified a number of potential risks. In particular, their use to assess the effectiveness of new interventions often seems to pay insufficient attention to random variation, measurement bias, confounding and ethical issues. Conclusions: The use of current improvement science methods to generate evidence of effectiveness for population-wide interventions is problematic and risks unjustified claims of effectiveness, inefficient resource use and harm to those not offered alternative effective interventions. Newer methodological approaches offer alternatives and should be more widely considered.
COVID-19 and suicide risk in the construction sector: preparing for a perfect storm
Authors: King Tania L. , Lamontagne Anthony D. 
Published: February 2021

Aims: Worldwide, construction industries are considered to be key economic pillars of the societies they serve, and construction workers constitute a sizeable proportion of the global paid workforce. In many parts of the world, construction workers are at elevated risk of suicide. Here, we examine the extent to which construction workers may be differentially exposed to the economic effects of COVID-19. Methods: A narrative review and synthesis of the literature was conducted. Results: The economic and labour market shock resulting from the COVID-19 pandemic has led to a convergence of factors that may significantly exacerbate suicide risk among construction workers, particularly among those with lower skills. Conclusions: With important insights from previous financial crises, it is vital that governments, industry and workplaces act rapidly to mitigate suicide risk among vulnerable groups such as construction workers. Mental healthcare investment is needed, and must be complemented by prevention and control in the workplace and in the general community. Anticipating, preparing and acting to ameliorate this risk, particularly among low skilled construction workers, will save many livelihoods, as well as lives.
Turning Practicing Surgeons Into Health Technology Innovators: Outcomes From the Stanford Biodesign Faculty Fellowship
Authors: Fuerch Janene H. , Wang Paul , Van Wert Ryan , Denend Lyn 
Published: February 2021

Background. The Stanford Biodesign Faculty Fellows program was established in 2014 to train Stanford Medical and Engineering faculty in a repeatable innovation process for health technology translation while also being compatible with the busy clinical schedules of surgical faculty members. Methods. Since 2014, 62 faculty members have completed the fellowship with 42% (n = 26) coming from 14 surgical subspecialties. This eight-month, needs-based innovation program covers topics from identifying unmet health-related needs, to inventing new technology, developing plans for intellectual property (IP), regulatory, reimbursement, and business models to advance the technologies toward patient care. Results/Conclusion. Intake and exit survey results from three years of program participants (n = 36) indicate that the fellowship is a valuable hands-on educational program capable of improving awareness and experience with skill sets required for health technology innovation and entrepreneurship.
Custom-made Total Joint Replacement After Segmental Resection of Recurrent Follicular Ameloblastoma
Authors: Alba Ismael Vejar , Arias Guadalupe Jacinto , Soto Emmanuel Guerrero , Zenteno Sara Itzel López 
Published: February 2021

Design: Clinical case report. Objective: To present custom-made total joint replacement as a suitable option after resection of extensive odontogenic tumors. Background: Ameloblastoma is the most common odontogenic tumor. Clinical presentation is characteristic as it presents with a slow growth rate, but highly expansive and recurrent. Ample resection with safety margins is imperative to allow for a functional and predictable reconstruction. Methods: We present the case of a 51-year-old male diagnosed with a recurrent follicular ameloblastoma and was treated with segmental resection and subsequent reconstruction with custom-made total joint replacement. Results: Follow-up at 14 months after surgery showed satisfactory quality of life and proper functionality. Conclusions: Total custom joint replacement is an ideal option after extensive resections involving the articular region.
Treatable traits in an English cohort: prevalence and predictors of future decline in lung function and quality of life in COPD
Authors: Sarwar Muhammad Rehan , McDonald Vanessa Marie , Abramson Michael John , Paul Eldho , George Johnson 
Published: February 2021

Background“Treatable traits (TTs)” is a precision medicine approach for facilitating multidimensional assessment of every patient with chronic airway disease, in order to determine the core traits associated with disease outcomes where targeted treatments may be applied.ObjectivesTo determine the prevalence of TTs in chronic obstructive pulmonary disease (COPD) and which traits predict future decline in lung function and quality of life (QoL).MethodsA 4-year longitudinal evaluation was conducted using data from 3726 participants in the English Longitudinal Study of Ageing (ELSA). TTs were identified based on published recommendations. Traits that predicted decline in lung function and QoL were analysed using generalised estimating equations.ResultsOverall, 21 TTs, including pulmonary (n=5), extra-pulmonary (n=13) and behavioural/lifestyle risk-factors (n=3) were identified. In multivariate analyses, the traits of chronic bronchitis (β −0.186, 95% CI −0.290 to −0.082), breathlessness (β −0.093, 95% CI −0.164 to −0.022), underweight (β −0.216, 95% CI −0.373 to −0.058), sarcopenia (β −0.162, 95% CI −0.262 to −0.061) and current smoking (β −0.228, 95% CI −0.304 to −0.153) predicted decline in forced expiratory volume in 1 s (FEV1). Of the seven traits that predicted decline in QoL, depression (β −7.19, 95% CI −8.81 to −5.57) and poor family and social support (β −5.12, 95% CI −6.65 to −3.59) were the strongest.ConclusionThe core TTs of COPD associated with a decline in lung function and QoL were identified. Targeting these impactful traits with individualised treatment using a precision medicine approach may improve outcomes in people with COPD.