bluuebunny/crossref_metadata_2025_split huggingface dataset:
The FDA Oncology Center of Excellence and precision medicine
Authors: Goldberg Kirsten B , Blumenthal Gideon M , McKee Amy E , Pazdur Richard 
Published: November 2017

In January 2017, the U.S. Food and Drug Administration (FDA) formally established the Oncology Center of Excellence (OCE) to streamline the development of cancer therapies by uniting experts from FDA product centers to conduct expedited review of drugs, biologics, and devices. In May 2017, the FDA approved a cancer treatment based on a biomarker, without regard to the tumor’s site, by granting accelerated approval to pembrolizumab for patients with solid tumors that have the microsatellite instability-high or mismatch repair deficient biomarker. We describe here the OCE’s role in this first site-agnostic approval and OCE programs for further advancement of oncology-related regulatory science and policy. In addition, the FDA’s four expedited review programs that enable transformative therapies to reach patients with life-threatening malignancies earlier in the development process are key to the continued rapid development of safe and effective therapies for patients with few or no other treatment options. These changes at FDA are taking place in the context of recent progress in the understanding of the genetic and immunologic foundations of cancer, resulting in the development of targeted therapies and immunotherapies. The traditional system of phased clinical trials has evolved as early trials of breakthrough therapies use expansion cohorts in a process known as seamless drug development. Increasingly, FDA approvals of targeted therapies are likely to have contemporaneous approvals of companion diagnostics to identify patients whose cancers harbor actionable abnormalities. Impact statement This publication describes the U.S. Food and Drug Administration’s (FDA) first site-agnostic oncology drug approval, a landmark event in the history of cancer drug development. The role of the FDA’s newly established Oncology Center of Excellence (OCE) in this approval is described, as are several OCE programs to advance excellence in regulatory science in the era of precision medicine. Also provided is an overview of FDA’s expedited drug review programs, which are important to the continued acceleration of therapeutics development for patients with life-threatening diseases and few or no other treatment options.
Cortical thickness analysis of the proximal humerus
Authors: Majed Addie , Thangarajah Tanujan , Southgate Dominic , Reilly Peter , Bull Anthony , Emery Roger 
Published: November 2017

Background Structural changes within the proximal humerus influence the mechanical properties of the entire bone and predispose to low-energy fractures with complex patterns. The aim of the present study was to measure the cortical thickness in different regions of the proximal humerus. Methods Thirty-seven proximal humeri were analyzed using novel engineering software to determine cortical thickness in 10 distinct anatomical zones. Results The cortical thickness values ranged from 0.33 mm to 3.5 mm. Fifteen specimens demonstrated a consistent pattern of progressive cortical thinning that increased between the bicipital groove (thickest), the lesser tuberosity and the greater tuberosity (thinnest). Fifteen humeri were characterized by a progressive increase in cortical thickness between the greater tuberosity (thinnest), the bicipital groove and lesser tuberosity (thickest). The diaphysis exhibited the thickest cortical zone in 27 specimens, whereas the articular surface possessed the thinnest cortex in 18 cases. Conclusions In conclusion, this is the first study to comprehensively assess cortical thickness of the humeral head. Our findings suggest that proximal humeral fractures occur along lines of cortical thinning and are displaced by the hard glenoid bone. The identification of specific areas of thick cortices may improve pre-operative planning and optimize fracture fixation.
Thrombotic thrombocytopenic purpura presenting as a severe peripartum cardiogenic shock: Role of myocardial biopsy and assist device for diagnosis and resuscitation
Authors: Champion Sébastien , Belcour Dominique , Gaüzère Bernard Alex 
Published: November 2017

Abstract
We describe the case of a peripartum thrombotic thrombocytopenic purpura with fulminant cardiogenic shock treated with extracorporeal life support. Thrombotic thrombocytopenic purpura should be considered in the case of thrombotic microangiopathy with several or severe organ involvement and needs emergent treatment with plasmapheresis (with or without rituximab). In the case of cardiac involvement, aggressive treatment should be considered given the high mortality and the potential complete recovery.
Female urethral diverticula: An elusive pathology that can cause significant problems
Authors: Abbey Jessica , Hawary Amr 
Published: November 2017

Female urethral diverticula are a rare pathology, although thought to be under-diagnosed. They can present with a large variety of symptoms, and can be complicated by stones or malignancy. Magnetic resonance imaging is widely accepted to be the best form of imaging for this condition, although voiding cystourethrogram studies are helpful in providing information on bladder function. Symptomatic patients should be treated surgically through urethral diverticulectomy. Level of evidence: Not applicable for this multicentre audit.
The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study
Authors: Son Do Hung , Thuy-Nhien Nguyen , von Seidlein Lorenz , Le Phuc-Nhi Truong , Phu Ngo Thi , Tuyen Nguyen Thi Kim , Tran Nguyen Huyen , Van Dung Nguyen , Van Quan Bui , Day Nicholas P. J. , Dondorp Arjen M. , White Nicholas J. , Thwaites Guy E. , Hien Tran Tinh 
Published: November 2017

Abstract
Background
Prophylaxis for high-risk populations, such as forest workers, could be one component for malaria elimination in the Greater Mekong Sub-region. A study was conducted to assess the malaria incidence in forest rangers and the feasibility of malaria prophylaxis for rangers sleeping in forest camps.

Methods
Forest rangers deployed in the Bu Gia Map National Park, Vietnam were invited to participate in the study. Plasmodium infections were cleared using presumptive treatment, irrespective of malaria status, with a 3-day course dihydroartemisinin/piperaquine (DP) and a 14-day course of primaquine. Before returning to the forest, study participants were randomly allocated to a 3-day course of DP or placebo. Fifteen days after returning from their forest deployment the participants were tested for Plasmodium infections using uPCR.

Results
Prior to treatment, 30 of 150 study participants (20%) were found to be infected with Plasmodium. Seventeen days (median) after enrolment the rangers were randomized to DP or placebo 2 days before returning to forest camps where they stayed between 2 and 20 days (median 9.5 days). One ranger in the DP-prophylaxis arm and one in the placebo arm were found to be infected with Plasmodium falciparum 15 days (median) after returning from the forest. The evaluable P. falciparum isolates had molecular markers indicating resistance to artemisinins (K13-C580Y) and piperaquine (plasmepsin), but none had multiple copies of pfmdr1 associated with mefloquine resistance.

Conclusion
Anti-malarial prophylaxis in forest rangers is feasible. The findings of the study highlight the threat of multidrug-resistant malaria.
Trial registration NCT02788864
Effects of Levothyroxine on Pregnant Women With Subclinical Hypothyroidism, Negative for Thyroid Peroxidase Antibodies
Authors: Nazarpour Sima , Ramezani Tehrani Fahimeh , Simbar Masoumeh , Tohidi Maryam , Minooee Sonia , Rahmati Maryam , Azizi Fereidoun 
Published: November 2017

AbstractContextCurrently, there is no consensus on universal thyroid screening and levothyroxine (LT4) treatment of pregnant women with subclinical hypothyroidism (SCH) who are negative for thyroid peroxidase antibody (TPOAb−).ObjectiveWe aimed to evaluate the benefits of LT4 treatment on pregnancy outcomes in SCH-TPOAb− women.DesignThis study was conducted within the framework of the Tehran Thyroid and Pregnancy Study. A single-blind randomized clinical trial was undertaken in pregnant women who were SCH-TPOAb−.SettingPrenatal care centers of the Shahid Beheshti University of Medical Sciences.PatientsUsing the thyrotropin (TSH) cut point of 2.5 mIU/L, 366 SCH-TPOAb− and 1092 euthyroid TPOAb− women were recruited.InterventionSCH-TPOAb− women were randomly assigned to two groups: group A (n = 183) who were treated with LT4 and group B (n = 183) who received no treatment. A total of 1,028 euthyroid TPOAb− women served as the control group (group C).Main Outcome MeasureThe primary outcome was the rate of preterm delivery.ResultsUsing the TSH cutoff of 2.5 mIU/L, no significant difference in preterm delivery was observed between groups A and B [relative risk (RR): 0.86; 95% confidence interval (CI): 0.47 to 1.55; P = 0.61]. However, log-binomial model analysis based on a cut point of 4.0 mIU/L demonstrated a significantly lower rate of preterm delivery in LT4-treated women compared with those who received no treatment (RR: 0.38; 95% CI: 0.15 to 0.98; P = 0.04).ConclusionsDespite no beneficial effect of LT4 therapy in reducing preterm delivery in SCH-TPOAb− women with a TSH cut point of 2.5 to 4 mIU/L, LT4 could precisely decrease this complication using the newly recommended cutoff ≥4.0 mIU/L.
Intraluminal valves: development, function and disease
Authors: Geng Xin , Cha Boksik , Mahamud Md. Riaj , Srinivasan R. Sathish 
Published: November 2017

ABSTRACT
The circulatory system consists of the heart, blood vessels and lymphatic vessels, which function in parallel to provide nutrients and remove waste from the body. Vascular function depends on valves, which regulate unidirectional fluid flow against gravitational and pressure gradients. Severe valve disorders can cause mortality and some are associated with severe morbidity. Although cardiac valve defects can be treated by valve replacement surgery, no treatment is currently available for valve disorders of the veins and lymphatics. Thus, a better understanding of valves, their development and the progression of valve disease is warranted. In the past decade, molecules that are important for vascular function in humans have been identified, with mouse studies also providing new insights into valve formation and function. Intriguing similarities have recently emerged between the different types of valves concerning their molecular identity, architecture and development. Shear stress generated by fluid flow has also been shown to regulate endothelial cell identity in valves. Here, we review our current understanding of valve development with an emphasis on its mechanobiology and significance to human health, and highlight unanswered questions and translational opportunities.
BRCA1 novel mutation V1736D and in silico analysis of SNP Q356R in Sudanese patients with breast cancer
Authors: Aabdein Mohamed Elmogtba Mouaweia Mohamed , Elimam Alsmawal Awad Mohammed , Altayb Hisham N. , Eldeen Mohamed El-Fatih Mohy , Gasemelseed Mosab Mohamed , FadlAlla Afra AbdElhamid , Osman Marwa Mohamed , Osman Soada Ahmed , Saeed Hajir Ali , Ali Mona ShamsAldeen , Siddig Tomador , Osman Reem Abdelrahman , Elhadi Rehab Ahmed , Hamid Muzamil Mahdi Abdel , Salih Mohamed Ahmed 
Published: November 2017

Background: Breast cancer (BC) remains one of the leading causes of death in women worldwide. The BRCA1 deleterious mutation has a significant role in developing BC, and the risk has been estimated to be 46–87%. Many studies emphasize the need for mining BRCA1 gene mutations that might have a role in BC pathogenesis and could affect early disease onset. This study was conducted to screen for possible pathogenic single nucleotide polymorphisms (SNPs) in BRCA1, targeting three regions: two in exon 11 and the third in exon 20. Methods: 45 blood samples were collected from patients diagnosed with BC. DNA was extracted and selected regions were amplified by PCR using three sets of primers - two within exon 11 and one within exon 20 of BRCA1. Subsets of 10 samples were selected for each primer set (30 PCR products) and sequenced. Sequences were analyzed using various bioinformatics tools. Results: Two missense mutations were found, Q356R (rs1799950) in one patient (27 years old) and a novel SNP, V1736D, in three premenopausal patients (≤45 years), which were located within exons 11 and 20, respectively. Both detected variants were heterozygous, a status found in all patients detected with such monoallelic variation. Both missense variants underwent in silico analysis. The well-known mutation, rs1799950, was predicted to alter the protein activity, conferred by a mutant residue (R-Arg), owing to the position with a bigger size and positive charge. The novel SNP, V1736D, was predicted to play a role in the pathogenesis of BC. Conclusion: Both variants require further investigation, firstly to assess their contribution to BC and secondly to determine their potential diagnostic value when assessed in a larger population.
Amending published articles: time to rethink retractions and corrections?
Authors: Barbour Virginia , Bloom Theodora , Lin Jennifer , Moylan Elizabeth 
Published: November 2017

Academic publishing is evolving and our current system of correcting research post-publication is failing, both ideologically and practically. It does not encourage researchers to engage in necessary post-publication changes in a consistent way. Worse yet, post-publication ‘updates’ can be misconstrued as punishments or admissions of misconduct. We propose a different model that publishers of research can apply to the content they publish, ensuring that any post-publication amendments are seamless, transparent and propagated to all the countless places online where descriptions of research appear. At the center of our proposal is use of the neutral term “amendment” to describe all forms of post-publication change to an article. We lay out a straightforward and consistent process that applies to each of three types of amendment that differ only in the extent to which the study is amended: minor, major, and complete. This proposed system supports the dynamic nature of the research process itself as researchers continue to refine or extend the work, and removes the emotive climate particularly associated with retractions and corrections to published work. It allows researchers to cite and share the most up-to-date and complete versions of articles with certainty, and gives decision makers access to the most up-to-date information. Crucially, however, we do not underestimate the importance of investigations of potential misconduct. This proposal allows two interrelated processes - amendment of articles and investigation of misconduct - to be uncoupled temporally, allowing a more rapid correction of the literature at a journal while institutional investigations take place, without either having to follow the others’ timeline.
Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial
Authors: Chen Ray Y. , Via Laura E. , Dodd Lori E. , Walzl Gerhard , Malherbe Stephanus T. , Loxton André G. , Dawson Rodney , Wilkinson Robert J. , Thienemann Friedrich , Tameris Michele , Hatherill Mark , Diacon Andreas H. , Liu Xin , Xing Jin , Jin Xiaowei , Ma Zhenya , Pan Shouguo , Zhang Guolong , Gao Qian , Jiang Qi , Zhu Hong , Liang Lili , Duan Hongfei , Song Taeksun , Alland David , Tartakovsky Michael , Rosenthal Alex , Whalen Christopher , Duvenhage Michael , Cai Ying , Goldfeder Lisa C. , Arora Kriti , Smith Bronwyn , Winter Jill , Barry III Clifton E. ,   Predict TB Study Group
Published: November 2017

Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01). We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. Trial Registration: NCT02821832
Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa
Authors: Heffron Renee , Ngure Kenneth , Odoyo Josephine , Bulya Nulu , Tindimwebwa Edna , Hong Ting , Kidoguchi Lara , Donnell Deborah , Mugo Nelly R. , Bukusi Elizabeth A. , Katabira Elly , Asiimwe Stephen , Morton Jennifer , Morrison Susan , Haugen Harald , Mujugira Andrew , Haberer Jessica E. , Ware Norma C. , Wyatt Monique A. , Marzinke Mark A. , Frenkel Lisa M. , Celum Connie , Baeten Jared M. ,   The Partners Demonstration Project Team
Published: November 2017

Introduction: Pre-exposure prophylaxis (PrEP) can provide high protection against HIV infection and is a recommended intervention for HIV-negative persons with substantial HIV risk, such as individuals with a partner living with HIV. Demonstration projects of PrEP have been conducted in diverse settings worldwide to illustrate practical examples of how PrEP can be delivered. Methods: We evaluated delivery of PrEP for HIV-negative partners within heterosexual HIV serodiscordant couples in an open-label demonstration project in East Africa. The delivery model integrated PrEP into HIV treatment services, prioritizing PrEP for HIV-negative partners within serodiscordant couples prior to and during the first 6 months after the partner living with HIV initiated antiretroviral therapy (ART). We measured adherence to PrEP through medication event monitoring system (MEMS) bottle caps and quantification of tenofovir in plasma among a random sample of participants. We estimated HIV infections prevented using a counterfactual cohort simulated from the placebo arm of a previous PrEP clinical trial. Results: We enrolled 1,010 HIV serodiscordant couples that were naïve to ART and PrEP. Ninety-seven percent (97%) of HIV-negative partners initiated PrEP, and when PrEP was dispensed, objective measures suggest high adherence: 71% of HIV-negative participants took ≥80% of expected doses, as recorded via MEMS, and 81% of plasma samples had tenofovir detected. A total of 4 incident HIV infections were observed (incidence rate=0.24 per 100 person-years), a 95% reduction (95% CI 86-98%, p<0.0001) in HIV incidence, relative to estimated HIV incidence for the population in the absence of PrEP integrated into HIV treatment services. Conclusions: PrEP uptake and adherence were high and incident HIV was rare in this PrEP demonstration project for African HIV-negative individuals whose partners were known to be living with HIV. Delivery of PrEP to HIV-negative partners within HIV serodiscordant couples was feasible and should be prioritized for wide-scale implementation.
Evaluating integrated development: are we asking the right questions? A systematic review
Authors: Ahner-McHaffie Tessa W , Guest Greg , Petruney Tricia , Eterno Alexandra , Dooley Brian 
Published: November 2017

Background: Emerging global transformations - including a new Sustainable Development Agenda - are revealing increasingly interrelated goals and challenges, poised to be addressed by similarly integrated, multi-faceted solutions. Research to date has focused on determining the effectiveness of these approaches, yet a key question remains: are synergistic effects produced by integrating two or more sectors? We systematically reviewed impact evaluations on integrated development interventions to assess whether synergistic, amplified impacts are being measured and evaluated. Methods: The International Initiative for Impact Evaluation’s (3ie) Impact Evaluation Repository comprised our sampling frame (n = 4,339). Following PRISMA guidelines, we employed a three-stage screening and review process. Results: We identified 601 journal articles that evaluated integrated interventions. Seventy percent used a randomized design to assess impact with regard to whether the intervention achieved its desired outcomes. Only 26 of these evaluations, however, used a full factorial design, the only design capable of statistically detecting synergistic effects produced by integrating sectors. Of those, seven showed synergistic effects. Conclusions: To date, evaluations of integrated development approaches have demonstrated positive impacts in numerous contexts, but gaps remain with regard to documenting whether integrated programming produces synergistic, amplified outcomes. Research on these program models needs to extend beyond impact only, and more explicitly examine and measure the synergies and efficiencies associated with linking two or more sectors. Doing so will be critical for identifying effective integrated development strategies that will help achieve the multi-sector SDG agenda.
Preparatory planning framework for Created Out of Mind: Shaping perceptions of dementia through art and science
Authors: Brotherhood Emilie , Ball Philip , Camic Paul M , Evans Caroline , Fox Nick , Murphy Charlie , Walsh Fergus , West Julian , Windle Gill , Billiald Sarah , Firth Nicholas , Harding Emma , Harrison Charles , Holloway Catherine , Howard Susanna , McKee-Jackson Roberta , Jones Esther , Junghaus Janette , Martin Harriet , Nolan Kailey , Rollins Bridie , Shapiro Lillian , Shapiro Lionel , Twigg Jane , van Leeuwen Janneke , Walton Jill , Warren Jason , Wray Selina , Yong Keir , Zeilig Hannah , Crutch Sebastian J. 
Published: November 2017

Created Out of Mind is an interdisciplinary project, comprised of individuals from arts, social sciences, music, biomedical sciences, humanities and operational disciplines. Collaboratively we are working to shape perceptions of dementias through the arts and sciences, from a position within the Wellcome Collection. The Collection is a public building, above objects and archives, with a porous relationship between research, museum artefacts, and the public. This pre-planning framework will act as an introduction to Created Out of Mind. The framework explains the rationale and aims of the project, outlines our focus for the project, and explores a number of challenges we have encountered by virtue of working in this way.