tbuckley/cabot-search huggingface dataset:
Prevalence of Multiplicity and Appropriate Adjustments Among Cardiovascular Randomized Clinical Trials Published in Major Medical Journals
Authors: Muhammad Shahzeb Khan, Maaz Shah Khan, Zunaira Navid Ansari, Tariq Jamal Siddiqi, Safi U. Khan, Irbaz Bin Riaz, Zain Ul Abideen Asad, John Mandrola, James Wason, Haider J. Warraich, Gregg W. Stone, Deepak L. Bhatt, Samir R. Kapadia, Ankur Kalra
Journal: JAMA Network Open (2020)

Multiple analyses in a clinical trial can increase the probability of inaccurately concluding that there is a statistically significant treatment effect. However, to date, it is unknown how many randomized clinical trials (RCTs) perform adjustments for multiple comparisons, the lack of which could lead to erroneous findings.To assess the prevalence of multiplicity and whether appropriate multiplicity adjustments were performed among cardiovascular RCTs published in 6 medical journals with a high impact factor.In this cross-sectional study, cardiovascular RCTs were selected from all over the world, characterized as North America, Western Europe, multiregional, and rest of the world. Data were collected from past issues of 3 cardiovascular journals (Circulation, European Heart Journal, and Journal of the American College of Cardiology) and 3 general medicine journals (JAMA, The Lancet, and The New England Journal of Medicine) with high impact factors published between August 1, 2015, and July 31, 2018. Supplements and trial protocols of each of the included RCTs were also searched for multiplicity. Data were analyzed December 20 to 27, 2018.Data from the selected RCTs were extracted and verified independently by 2 researchers using a structured data instrument. In case of disagreement, a third reviewer helped to achieve consensus. An RCT was considered to have multiple treatment groups if it had more than 2 arms; multiple outcomes were defined as having more than 1 primary outcome, and multiple analyses were defined as analysis of the same outcome variable in multiple ways. Multiplicity was examined only for the analysis of the primary end point.Outcomes of interest were percentages of primary analyses that performed multiplicity adjustment of primary end points.Of 511 cardiovascular RCTs included in this analysis, 300 (58.7%) had some form of multiplicity; of these 300, only 85 (28.3%) adjusted for multiplicity. Intervention type and funding source had no statistically significant association with the reporting of multiplicity risk adjustment. Trials that assessed mortality vs nonmortality outcomes were more likely to contain a multiplicity risk in their primary analysis (66.3% [177 of 267] vs 50.4% [123 of 244]; P < .001), and larger trials vs smaller trials were less likely to make any adjustments for multiplicity (35.6% [52 of 146] vs 21.4% [33 of 154]; P = .001).Findings from this study suggest that cardiovascular RCTs published in medical journals with high impact factors demonstrate infrequent adjustments to correct for multiple comparisons in the primary end point. These parameters may be improved by more standardized reporting.
ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression
Authors: Meng Yuan, Xiaobing Chen, Yitang Sun, Li Jiang, Zhongni Xia, Kaixiong Ye, Hong Jiang, Bo Yang, Meidan Ying, Ji Cao, Qiaojun He
Journal: Acta Pharmaceutica Sinica B (2020)

The membrane protein claudin-3 (CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both in vitro and in vivo. Of interest, CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3. Moreover, the deprivation of S-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins. Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis. Thus, our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.
GDF15: A Hormone Conveying Somatic Distress to the Brain
Authors: Samuel M Lockhart, Vladimir Saudek, Stephen O’Rahilly
Journal: Endocrine Reviews (2020)

Abstract GDF15 has recently gained scientific and translational prominence with the discovery that its receptor is a GFRAL-RET heterodimer of which GFRAL is expressed solely in the hindbrain. Activation of this receptor results in reduced food intake and loss of body weight and is perceived and recalled by animals as aversive. This information encourages a revised interpretation of the large body of previous research on the protein. GDF15 can be secreted by a wide variety of cell types in response to a broad range of stressors. We propose that central sensing of GDF15 via GFRAL-RET activation results in behaviors that facilitate the reduction of exposure to a noxious stimulus. The human trophoblast appears to have hijacked this signal, producing large amounts of GDF15 from early pregnancy. We speculate that this encourages avoidance of potential teratogens in pregnancy. Circulating GDF15 levels are elevated in a range of human disease states, including various forms of cachexia, and GDF15-GFRAL antagonism is emerging as a therapeutic strategy for anorexia/cachexia syndromes. Metformin elevates circulating GDF15 chronically in humans and the weight loss caused by this drug appears to be dependent on the rise in GDF15. This supports the concept that chronic activation of the GDF15-GFRAL axis has efficacy as an antiobesity agent. In this review, we examine the science of GDF15 since its identification in 1997 with our interpretation of this body of work now being assisted by a clear understanding of its highly selective central site of action.
Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis
Authors: Arash Derakhshan, Robin P Peeters, Peter N Taylor, Sofie Bliddal, David M Carty, Margreet Meems, Bijay Vaidya, Liangmiao Chen, Bridget A Knight, Farkhanda Ghafoor, Polina V Popova, Lorena Mosso, Emily Oken, Eila Suvanto, Aya Hisada, Jun Yoshinaga, Suzanne J Brown, Judit Bassols, Juha Auvinen, Wichor M Bramer, Abel López-Bermejo, Colin M Dayan, Robert French, Laura Boucai, Marina Vafeiadi, Elena N Grineva, Victor J M Pop, Tanja G Vrijkotte, Leda Chatzi, Jordi Sunyer, Ana Jiménez-Zabala, Isolina Riaño, Marisa Rebagliato, Xuemian Lu, Amna Pirzada, Tuija Männistö, Christian Delles, Ulla Feldt-Rasmussen, Erik K Alexander, Scott M Nelson, Layal Chaker, Elizabeth N Pearce, Mònica Guxens, Eric A P Steegers, John P Walsh, Tim I M Korevaar
Journal: The Lancet Diabetes & Endocrinology (2020)
Association of Sexual Health Interventions With Sexual Health Outcomes in Black Adolescents
Authors: Reina Evans, Laura Widman, McKenzie N. Stokes, Hannah Javidi, Elan C. Hope, Julia Brasileiro
Journal: JAMA Pediatrics (2020)

Black adolescents are at increased risk of contracting HIV and other sexually transmitted infections (STIs) and experiencing unplanned pregnancy. Although sexual health interventions aimed at decreasing these risks exist, evidence of the association between sexual health interventions and the sexual behavior of black adolescents has not been synthesized to our knowledge.To examine the associations between sexual health interventions and behavioral, biological, and psychological outcomes.For this systematic review and meta-analysis, a systematic search was conducted of studies published through January 31, 2019, using the PubMed, PsycINFO, and CINAHL databases and relevant review articles. The following key words were used: youth, adolesc* or teen*; sexual health or safe* sex or sexually transmitted disease or sexually transmitted infection or STD or STI or HIV or AIDS or pregnancy or reproductive health or condom* or contracept* or unprotected sex or abstinence; intervention or program or education or prevention or promotion or trial; latino* or latina* or latinx* or minorit* or ethnic* or hispanic or african american* or black* or race or racial or biracial.Studies were included if they included a US-based sample of black adolescents, evaluated a sexual health intervention using experimental or quasi-experimental designs, included a behavioral outcome, and were published in English.Standardized mean differences and 95% CIs were extracted and meta-analyzed using random-effects models.Behavioral outcomes were abstinence, condom use, and number of sex partners. Biological outcomes were pregnancy and STI contraction. Psychological outcomes were sexual health intentions, knowledge, and self-efficacy.Across 29 studies including 11 918 black adolescents (weighted mean age, 12.43 years), there was a significant weighted mean association of sexual health interventions with improvements in abstinence (Cohen d = 0.14; 95% CI, 0.05-0.24) and condom use (Cohen d = 0.25; 95% CI, 0.11-0.39). No significant mean association of these interventions with number of sex partners, pregnancy, or STI contraction was found. Sexual health interventions were significantly associated with improvements in psychological outcomes: sexual health intentions (Cohen d = 0.17; 95% CI, 0.05-0.30), knowledge (Cohen d = 0.46; 95% CI, 0.30-0.63), and self-efficacy (Cohen d = 0.19; 95% CI, 0.09-0.28). Intervention effect sizes were consistent across factors, such as participant sex and age and intervention dose.The findings suggest that sexual health interventions are associated with improvements in sexual well-being among black adolescents. There appears to be a need for wide-scale dissemination of these programs to address racial disparities in sexual health across the US.
Chronic Lymphocytic Leukemia (CLL) Cells Require Microenvironmental Stimuli to Resist Apoptosis through Activation of STAT3 Mediated by VEGF.
Authors: Iris Gehrke, Julian Paesler, Rajesh Kumar Gandhirajan, Regina Razavi, Alexandra Filipovich, Felix Erdfelder, Magdalena Hertweck, Michael Hallek, Karl Anton Kreuzer
Journal: Blood (2008)
Vemurafenib in Advanced Patients with Hairy Cell Leukemia (HCL): Results of the Acsé Phase II Trial
Authors: Xavier Troussard, Laure Montané, Mourad Tiab, Carine Chaleteix, Isabelle Grulois, Clothilde Lindet, Delphine Legoupil, Frederic Kohser, Diane Pannier, Frederic Maloisel, Pierre Bories, Céline Ait Oukhatar, Natalie Hoog Labouret, Jean-Yves Blay
Journal: Blood (2017)
Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases
Authors: Daniyal J. Jafree, David A. Long
Journal: Journal of the American Society of Nephrology (2020)

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.
Public health response to two imported, epidemiologically related cases of Lassa fever in the Netherlands (ex Sierra Leone), November 2019
Authors: Femke Overbosch, Mark de Boer, Karin Ellen Veldkamp, Pauline Ellerbroek, Chantal P Bleeker-Rovers, Bram Goorhuis, Michele van Vugt, Annemiek van der Eijk, Tjalling Leenstra, Martin Khargi, Jeanette Ros, Diederik Brandwagt, Manon Haverkate, Corien Swaan, Chantal Reusken, Aura Timen, Marion Koopmans, Jaap van Dissel
Journal: Eurosurveillance (2020)

On 20 November 2019, Lassa fever was diagnosed in a physician repatriated from Sierra Leone to the Netherlands. A second physician with suspected Lassa fever, repatriated a few days later from the same healthcare facility, was confirmed infected with Lassa virus on 21 November. Comprehensive contact monitoring involving high- and low-risk contacts proved to be feasible and follow-up of the contacts did not reveal any case of secondary transmission in the Netherlands.
Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020
Authors: Craig P Thompson, Nicholas E Grayson, Robert S Paton, Jai S Bolton, José Lourenço, Bridget S Penman, Lian N Lee, Valerie Odon, Juthathip Mongkolsapaya, Senthil Chinnakannan, Wanwisa Dejnirattisai, Matthew Edmans, Alex Fyfe, Carol Imlach, Kreepa Kooblall, Nicholas Lim, Chang Liu, César López-Camacho, Carol McInally, Anna L McNaughton, Narayan Ramamurthy, Jeremy Ratcliff, Piyada Supasa, Oliver Sampson, Beibei Wang, Alexander J Mentzer, Marc Turner, Malcolm G Semple, Kenneth Baillie, Heli Harvala, Gavin R Screaton, Nigel Temperton, Paul Klenerman, Lisa M Jarvis, Sunetra Gupta, Peter Simmonds
Journal: Eurosurveillance (2020)

Background The progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression. Aim Our objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic. Methods A pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019. Results All samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5–6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic. Conclusion Although blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.
Detection and Mechanisms of GPIIb-IIIa Antagonist Induced Thrombocytopenia: Role for Antibody Induced Platelet Activation.
Authors: Matthew D. Linden, Andrew L. Frelinger, Mark I. Furman, Lori A. Krueger, Youfu Li, Marsha L. Fox, Annette Hughes, John Lown, Marc R. Barnard, Karin Przyklenk, Alan D. Michelson
Journal: Blood (2005)
High Levels of Early Donor Chimerism and Treatment-Responsive Disease Predict Improved Progression-Free Survival Following Non-Myeloablative Transplantation for Advanced CLL.
Authors: Jennifer R. Brown, Shuli Li, Haesook Kim, David C. Fisher, Corey Cutler, Vincent Ho, Stephanie J. Lee, Jerome Ritz, Joseph H. Antin, Robert J. Soiffer, John G. Gribben, Edwin P. Alyea
Journal: Blood (2005)
Levonorgestrel implants and intracranial hypertension [letter]
Authors: Alder Jb, Fraunfelder Ft, Edwards R
Journal: New England Journal of Medicine (1995)

A review of 3 major data sets for a possible association between levonorgestrel use and intracranial hypertension yielded 56 cases of intracranial hypertension or disk edema. The patients were female with a mean age of 22 years who had been treated with levonorgestrel for a mean of 206 days before the onset of the syndrome. Visual-field defects were reported in 7 patients and diplopia in 6. Levonorgestrel has been associated with intracranial hypertension in 2 other patients. Levonorgestrel (Norplant) is a subdermally implanted synthetic progestin that has been available in the United States since 1991. Intracranial hypertension developed in 2 women seen at the Oregon Health Sciences University after the insertion of this implant. The patients were a 16-year-old White female and a 19-year-old Hispanic female in whom disk edema occurred 4-5 months after the implantation of levonorgestrel. Both had normal results on magnetic resonance imaging or computed tomography and both had lumbar-puncture opening pressures that exceeded 550 mm of water with normal chemical and cellular analysis. Presenting symptoms consisted of transient visual obscurations severe headaches or emesis. Ocular findings included visual acuity in the range of 20/20 to 20/25 and florid bilateral papilledema with enlarged blind spots. Intracranial hypertension resolved in the 19-year-old patient; she was free of symptoms after 28 months of follow-up. The 16-year-old patient had 3 recurrences over a period of 18 months each of which was controlled with acetazolamide. Headaches are among the most commonly reported nongynecologic side effects of levonorgestrel implants. It remains unclear whether the drug causes intracranial hypertension. The manufacturers recommendation is supported to wit to examine the ocular fundus in selected patients with visual symptoms or changes in the pattern of their headaches and to remove the implant in patients in whom intracranial pressure increases.
Improving mechanical and antibacterial properties of PMMA via polyblend electrospinning with silk fibroin and polyethyleneimine towards dental applications
Authors: Ugur Yunus Karatepe, Tugba Ozdemir
Journal: Bioactive Materials (2020)

Poly(methylmethacrylate) (PMMA) is a widely used material in dental applications, particularly as denture resins. Due to thermally unstable and wet oral cavity, the implanted PMMA based resins occasionally deform and grow bacterial biofilms at the interface between oral cavity and the biomaterial. Several strategies attempted earlier to improve the bacterial resistance and mechanical performance of PMMA. Poly(ethyleneimine) (PEI) is a hyperbranched cationic polymer shown earlier to improve antibacterial activity of resins but do not improve mechanical properties of the resins alone, while silk fibroin (SF) is a natural biopolymer with unique material properties. In this study, we combined SF and PEI towards development of antibacterial and mechanically superior PMMA based materials towards overcoming its drawbacks. Using polyblend electrospinning to combine SF, PEI and PMMA, we successfully developed intrinsically antibacterial and mechanically reinforced nanofiber mats. We propose that the resulting nanofiber mats have the potential to be incorporated into PMMA based denture resin materials to overcome the problems of patients and improve their quality of life.
Covid-19: “Steady the front line! There is no retreat from here”
Authors: Gordon Muir, Jonathan Boff
Journal: BMJ (2020)

As an ex-army surgeon and a military historian, we have previously felt uneasy about healthcare workers being described as “frontline staff.”1 The front line suggests to us a tangible risk of harm or death at work. No longer. NHS staff are dying of covid-19 acquired from patients.

Many UK health workers have said that they lack protection. Some have died: whether inadequate personal protective equipment (PPE) was linked, we do not yet know. But overseas data indicate that good PPE might reduce …
Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2–Mediated Blood Pressure Reduction Independent of Cystogenesis
Authors: Jayalakshmi Lakshmipathi, Yang Gao, Chunyan Hu, Deborah Stuart, Jonathan Genzen, Nirupama Ramkumar, Donald E. Kohan
Journal: Journal of the American Society of Nephrology (2020)

Hypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the Pkd1 gene product polycystin-1-the predominant causal factor in ADPKD-itself contributes to ADPKD hypertension independent of cystogenesis.We induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4-5 months of age.Kidneys from the Pkd1 knockout mice showed no apparent renal cysts, tubule dilation, or increased cell proliferation. Compared with control mice, Pkd1 knockout mice exhibited reduced arterial pressure during high salt intake; this associated with an increased natriuretic, diuretic, and kaliuretic response during the first 2-3 days of salt loading. The lower arterial pressure and enhanced natriuresis during high salt loading in Pkd1 knockout mice were associated with lower urinary nitrite/nitrate excretion and markedly increased urinary PGE2 excretion, whereas GFR, plasma renin concentration, and urinary endothelin-1 excretion were similar between knockout and control mice. Kidney cyclooxygenase-2 protein levels were increased in Pkd1 knockout mice during high salt intake; administration of NS-398, a selective cyclooxygenase-2 inhibitor, abolished the arterial pressure difference between the knockout and control mice during high salt intake. Total kidney Na+/K+/2Cl- cotransporter isoform 2 (NKCC2) levels were greatly reduced in Pkd1 knockout mice fed a high salt diet compared with controls.These studies suggest that nephron polycystin-1 deficiency does not itself contribute to ADPKD hypertension and that it may, in fact, exert a relative salt-wasting effect. The work seems to comprise the first in vivo studies to describe a potential physiologic role for nephron polycystin-1 in the absence of cysts, tubule dilation, or enhanced cell proliferation.
Donald William Ebrahim
Authors: Shah Ebrahim
Journal: BMJ (2020)

Donald William Ebrahim (“Don” or “Don Willy”) was born in Cape Town, South Africa. He was one of six children of Florrie, a “Cape Coloured,” and Mohamed Cassim Ebrahim, an Indian businessman, who had migrated from India in 1899. Florrie was a devout Christian, who brought her six children up in this faith. Don became a deeply religious boy, but he decided on medicine rather than the priesthood, enrolling in University of Cape Town medical school in 1948, the year apartheid started. The family decided that he should go to the UK to complete his training, and to return as the first Cape Coloured doctor to provide services to District 6, an inner city area of Cape Town.

After qualifying from Sheffield University Medical School in 1952, he married Marjorie Evans, a nurse, and they had their first child—Shah, followed in rapid succession by Rustum, …
Hematopoietic Stem Cells “Stemness” Genes Contain Many Genes Mutated or Abnormally Expressed in Hematopoietic Malignancies.
Authors: Amos Toren, Bella Bielorai, Jasmine Jacob-Hirsch, Tamar Fisher, Sharon Zelikovsky, David Givol, Eitan Domany, Joseph Itskovitz-Eldor, Iris Kventsel, Ester Rosenthal, Ninette Amariglio, Gideon Rechavi
Journal: Blood (2004)