tbuckley/cabot-search huggingface dataset:
Effect of Reduced-Dose Capecitabine Plus Cetuximab as Maintenance Therapy for <i>RAS</i> Wild-Type Metastatic Colorectal Cancer
Authors: Lu Wang, Ying Liu, Xianli Yin, Weijia Fang, Jianping Xiong, Ben Zhao, Mingsheng Zhang, Yanmei Zou, Hong Qiu, Xianglin Yuan
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Fluorouracil-based chemotherapy combined with anti–epidermal growth factor receptor/vascular endothelial growth factor therapy is the standard first-line treatment for metastatic colorectal cancer followed by low-intensity maintenance therapy to balance the clinical efficacy and adverse effects (AEs). However, there have been concerns about the AEs of capecitabine plus cetuximab as a maintenance therapy in patients with<i>RAS</i>wild-type metastatic colorectal cancer. <h3>Objective</h3> To evaluate the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy for<i>RAS</i>wild-type metastatic colorectal cancer. <h3>Design, Setting, and Participants</h3> This phase 2 prospective clinical trial was conducted from April 29, 2016, to April 29, 2019, at 5 centers in China. Patients diagnosed as having<i>RAS</i>wild-type metastatic colorectal cancer were recruited to receive fluorouracil-based cytotoxic agents combined with cetuximab followed by capecitabine plus cetuximab for maintenance therapy. Forty-seven patients with histologically confirmed metastatic colorectal cancer and genetic test results showing a wild-type<i>RAS</i>were enrolled in maintenance therapy. <h3>Interventions</h3> Induction therapy for patients with<i>RAS</i>wild-type metastatic colorectal cancer was 8 to 12 cycles of fluorouracil-based chemotherapy combined with cetuximab. After stable disease status or better was achieved, reduced-dose capecitabine plus cetuximab was administered for maintenance therapy. <h3>Main Outcomes and Measures</h3> The primary end point was progression-free survival during maintenance therapy. The secondary end points were total progression-free survival, overall survival, quality of life, safety, and toxic effects of treatment. <h3>Results</h3> Forty-seven patients were enrolled in maintenance therapy, with a median age of 52 years (range, 25-81 years) and 32 (68%) of them being men. The median maintenance progression-free survival was 7.2 (95% CI, 5.8-8.6) months. The median progression-free survival was 12.7 (95% CI, 11.8-15.4) months. The median overall survival was 27.4 (95% CI, 21.4-35.5) months. Grade 3 to 4 AEs during induction therapy included neutropenia (4 patients [9%]), diarrhea (4 patients [9%]), nausea or vomiting (3 patients [6%]), rash acneiform (10 patients [21%]), and hand-foot syndrome (8 patients [17%]). Grade 3 to 4 AEs during maintenance therapy included diarrhea (2 patients [4%]), rash acneiform (8 patients [17%]), and hand-foot syndrome (5 patients [11%]). <h3>Conclusions and Relevance</h3> Reduced-dose capecitabine plus cetuximab after initial chemotherapy is a novel maintenance therapy for patients with<i>RAS</i>wild-type metastatic colorectal cancer that achieved good outcomes and tolerable nonserious AEs. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02717923
SAT0086 Cartilage derived serologic markers and radiographic progression of knee osteoarthritis
Authors: M Olejarova, V Vilim, H Hulejova, J Gatterova, S Machacek, K Pavelka
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine relation between serum levels of cartilage derived markers (cartilage oligomeric matrix protein ? COMP, human gp 39 – chondrex, YKL-40) and radiographic progression in knee osteoarthritis (OA) patients. <h3>Methods</h3> A cohort of 202 patients with symptomatic knee OA was introduced into the study and followed-up over the period of 3 years. Serum levels of markers were measured at the baseline and at the end of the study. COMP was measured using monoclonal antibodies, developed in our institute. Chondrex was measured using chondrex-kit (Biometra, USA). Radiographic progression was defined as reduction of joint space width (JSW) &gt; 0.5 mm over the 3 years follow-up. Baseline serum COMP and chondrex levels were compared in patients with and without radiographic progression and correlated with maximal JSW reduction (one knee) and a total of JSW reductions from both knees. <h3>Results</h3> Totally 118 patients completed the 3 years follow-up; 22 of them showed JSW reduction at least in one knee joint. The levels of both markers in progressive and non-progressive groups are summarised in the Table 1. Maximal JSW reduction (one knee) significantly correlated with entry and final COMP levels (ρ = 0.201, p &lt; 0.05,ρ = 0.187, p &lt; 0.05); JSW reduction from both knees correlated with final COMP level (ρ = 0.162, p &lt; 0.05); the correlation with entry COMP level nearly reached the significance level (p = 0.07). Chondrex levels did not correlate with JSW reduction at all. <h3>Conclusion</h3> COMP could represent biochemical predictor of radiographic progression in knee OA. The possible predictive role of chondrex in radiographic progression of knee OA was not proven in this study.
Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice
Authors: Ted J Kaptchuk, Christopher C Hemond, Franklin G Miller
Journal: BMJ (2020)

ABSTRACT Despite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights “predictive coding” and “bayesian brain” as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.
Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China
Authors: Li Zhang, Xiaokai Feng, Danqing Zhang, Chunguo Jiang, Heng Mei, Jing Wang, Cuihong Zhang, Hong Li, Xiaoling Xia, Shuangshuang Kong, Jia Liao, Huijun Jia, Xueqin Pang, Yue Song, Ying Tian, Bin Wang, Chun Wu, Hongliang Yuan, Yongxing Zhang, Yuman Li, Wei Sun, Yanting Zhang, Shuangshuang Zhu, Shuyuan Wang, Yuji Xie, Shuping Ge, Liming Zhang, Yu Hu, Mingxing Xie
Journal: Circulation (2020)

Background: To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center. Methods: We studied a total of 143 patients with COVID-19 from January 29, 2020 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, and comparisons were made between groups with and without DVT. Results: Of the 143 patients hospitalized with COVID-19 (age 63±14 years, 74 [51.7%] men), 66 patients developed lower extremity DVT (46.1%: 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT). Compared with patients who did not have DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis, including an increased proportion of deaths (23 [34.8%] versus 9 [11.7%]; P =0.001) and a decreased proportion of patients discharged (32 [48.5%] versus 60 [77.9%]; P &lt;0.001). Multivariant analysis showed an association only between CURB-65 (confusion status, urea, respiratory rate, and blood pressure) score 3 to 5 (odds ratio, 6.122; P =0.031), Padua prediction score ≥4 (odds ratio, 4.016; P =0.04), D-dimer &gt;1.0 μg/mL (odds ratio, 5.818; P &lt;0.014), and DVT in this cohort, respectively. The combination of a CURB-65 score 3 to 5, a Padua prediction score ≥4, and D-dimer &gt;1.0 μg/mL has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥4 and whose ultrasound scans were performed &gt;72 hours after admission, DVT was present in 18 (34.0%) patients in the subgroup receiving venous thromboembolism prophylaxis versus 35 (66.0%) patients in the nonprophylaxis group ( P =0.010). Conclusions: The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in hospitalized patients.
Family meetings in paediatric palliative care: An integrative review of structure, process and outcomes
Authors: Natalie Bradford, Stuart Ekberg, Geoffrey Mitchell, Theresa Beane, Khali Ferranti, Anthony Herbert
Journal: BMJ (2020)

Objective: Our aim was to synthesise the available evidence surrounding the structure, processes and outcomes of family meetings in the paediatric palliative care literature.   Methods: We undertook an integrative literature review informed by the Preferred Method of Reporting Items for Systematic reviews and Meta-Analyses (PRIMSA) guidelines. The protocol was registered with PROSPERO (CRD42019138938). Electronic databases were systematically search using key words and hand searching of reference articles and grey literature was also completed. Results: Ten empirical studies and five theoretical articles were included in the synthesis. Empirical studies provided more information about meeting structure, whereas theoretical articles more frequently described a desired process for planning and undertaking meetings. No articles identified how the success of a meeting was defined or made recommendations for doing so. Despite reports family meetings are commonly occurring, few articles described outcomes from either the family or clinician perspectives.  Conclusions: Family meetings are essential communication strategies commonly used in paediatric palliative care, yet there is little guidance about how meetings should be organised and conducted, who should participate and when they should occur. The limited data available on the outcomes of family meetings suggest improvements are required to meet the needs of families. We present a framework that synthesises the available evidence. The framework offers an overview of the elements to consider when planning for and undertaking family meetings in paediatric palliative care and may be useful for both clinicians and researchers.
Hormonal Signaling Actions on Kv7.1 (KCNQ1) Channels
Authors: Emely Thompson, Jodene Eldstrom, David Fedida
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Kv7 channels (Kv7.1-7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1-5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2-7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2-7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.
Digital Health and Engagement—Looking Behind the Measures and Methods
Authors: John Torous, Erin E. Michalak, Heather L. O’Brien
Journal: JAMA Network Open (2020)

Isabel Chien, MEng; Angel Enrique, PhD; Jorge Palacios, MD, PhD; Tim Regan, PhD; Dessie Keegan, MSc; David Carter, PhD; Sebastian Tschiatschek, PhD; Aditya Nori, PhD; Anja Thieme, PhD; Derek Richards, PhD; Gavin Doherty, DPhil; Danielle Belgrave, PhD
Kidney Disease-Associated APOL1 Variants Have Dose-Dependent, Dominant Toxic Gain-of-Function
Authors: Somenath Datta, Rama Kataria, Jia-Yue Zhang, Savannah Moore, Kaitlyn Petitpas, Adam Mohamed, Nathan Zahler, Martin R. Pollak, Opeyemi A. Olabisi
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement APOL1 alleles G1 and G2 are associated with high incidence and rapid progression of CKD in blacks of West African ancestry. The mechanism of APOL1 cytotoxicity is poorly understood, partly because cell-based models express variable amounts of APOL1 and yield contradictory results. Experiments using a stable human embryonic kidney cell line (HEK293) demonstrate that expression of G1 or G2 at relevant levels causes dose-dependent cytotoxicity, but the wild-type reference allele G0 does not. G0 does not reduce cytotoxicity of G1 or G2 APOL1 . The mutant alleles therefore introduce a dominant toxic gain-of-function. Dose-dependent G1 or G2 cytotoxicity could explain incomplete penetrance of APOL1 nephropathy. Reducing expression of G1 or G2 could represent a therapeutic strategy for APOL1 nephropathy. Background Two coding renal risk variants (RRVs) of the APOL1 gene (G1 and G2) are associated with large increases in CKD rates among populations of recent African descent, but the underlying molecular mechanisms are unknown. Mammalian cell culture models are widely used to study cytotoxicity of RRVs, but results have been contradictory. It remains unclear whether cytotoxicity is RRV-dependent or driven solely by variant-independent overexpression. It is also unknown whether expression of the reference APOL1 allele, the wild-type G0, could prevent cytotoxicity of RRVs. Methods We generated tetracycline-inducible APOL1 expression in human embryonic kidney HEK293 cells and examined the effects of increased expression of APOL1 (G0, G1, G2, G0G0, G0G1, or G0G2) on known cytotoxicity phenotypes, including reduced viability, increased swelling, potassium loss, aberrant protein phosphorylation, and dysregulated energy metabolism. Furthermore, whole-genome transcriptome analysis examined deregulated canonical pathways. Results At moderate expression, RRVs but not G0 caused cytotoxicity in a dose-dependent manner that coexpression of G0 did not reduce. RRVs also have dominant effects on canonical pathways relevant for the cellular stress response. Conclusions In HEK293 cells, RRVs exhibit a dominant toxic gain-of-function phenotype that worsens with increasing expression. These observations suggest that high steady-state levels of RRVs may underlie cellular injury in APOL1 nephropathy, and that interventions that reduce RRV expression in kidney compartments may mitigate APOL1 nephropathy.
Publisher Correction: Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
Authors: Elaine T. Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S. Kamumbu, Xiaochang Zhang, Alissa M. D’Gama, Sonia N. Kim, Robert Sean Hill, Arthur P. Goldberg, Christopher Poultney, Nancy J. Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J. Penzol, Angel Carracedo, Alexander Kolevzon, Christina M. Hultman, Lauren A. Weiss, Menachem Fromer, Andreas G. Chiocchetti, Christine M. Freitag, George M. Church, Stephen W. Scherer, Joseph D. Buxbaum, Christopher A. Walsh
Journal: Nature Neuroscience (2020)
AB0088 Pulse cyclophosphamide therapy in a patient of giant cell arteritis with diplopia due to unilateral abducens nerve palsy
Authors: JC Tseng, HH Cheng, RJ Hu, LY Lu
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Patients with giant cell arteritis (GCA) occasionally complain of double vision. The neurologic manifestations of the GCA are protean. All parts of the visual pathway from the cornea to the cortex have been described to be involved. <h3>Objectives</h3> We described a patient of GCA with diplopia due to left abducens nerve palsy which was refractory to corticosteroid therapy initially and recovered with monthly pulse cyclophosphamide therapy five months later. To the best of our knowledge this is the first case described in the medical literature to be treated with monthly pulse intravenous cyclophosphamide and to achieve a successful outcome. <h3>Methods</h3> <h3>Results</h3> <h3>Conclusion</h3> Giant cell arteritis should be considered in the differential diagnois of patients with ocular manifestations. Prompt diagnosis and treatment are reguired if second eye involvement and blindness are to be prevented. <h3>References</h3> Lee AG. Ocular manifestations of giant cell arteritis. Am J Ophthalmol. 1998;126(5):742–4 Glutz von BS, Borruat FX. Neuro-ophthalmic complications of biopsy-proved giant cell arteritis. Eur J Ophthalmol. 1997;7(4):375–82 Johnston JL, Thomson GT, Sharpe JA, Inman RD. Internuclear ophthalmoplegia in giant cell arteritis. J Neurol Neurosurg Psychiatry 1992;55(1):84–5 Goadsby PJ, Mossman S. Giant cell arteritis and ophthalmoplegia. Aust NZ J Med. 1991;21(6):930
Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease
Authors: Laura I. Neumeier, Robert B. Thomson, Martin Reichel, Kai-Uwe Eckardt, Peter S. Aronson, Felix Knauf
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Fecal oxalate excretion is critical in oxalate balance with progression of CKD. However, the identity of the transporter(s) responsible for increased intestinal oxalate secretion in CKD is unknown. Intestinal expression of oxalate transporter Slc26a6 is strongly upregulated in two murine models of CKD. Deletion of Slc26a6 completely abrogates enhanced fecal oxalate excretion in CKD, increasing plasma oxalate concentration. This study demonstrates that Slc26a6 mediates intestinal oxalate secretion and mitigates hyperoxalemia in murine CKD models. The findings suggest that pharmacologic approaches enhancing intestinal Slc26a6 activity may stimulate extrarenal clearance of oxalate and prevent hyperoxalemia in CKD. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance. Background A state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (P ox ) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate via the gut in CKD. Methods Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and Slc26a6 −/− mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal Slc26a6 expression. An oxalate oxidase assay measured fecal and P ox concentrations. Results Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in Slc26a6 −/− mice associated with a significant elevation in plasma oxalate concentration. Slc26a6 mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising P ox without inducing kidney injury did not alter intestinal Slc26a6 expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in P ox . Conclusions Slc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.
Author's reply to Langford, Cowen, Chekroud and Krystal
Authors: D. Healy
Journal: BMJ (2015)

I wrote an almost identical editorial in 1991.1 2 Covering the marketing of serotonin in 1997,3 I cited Jerome Gaub’s 1767 opinion of Leibniz’s views on the relations between mind and body—it is a “fable whose novelty has recommended it, whose recommendation has spread it, whose spread has polished it, refined and adorned it with . . . a pleasing look …
Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial
Authors: Cristina Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Shang-Wen Chen, Sara A. Hurvitz, Sung-Bae Kim, Beverly Moy, Suzette Delaloge, William Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E. Trudeau, Johanna Mattson, Yoon Sim Yap, Ming-Feng Hou, Michelino De Laurentiis, Yu-Min Yeh, Hong-Tai Chang, Thomas Yau, Hans Wildiers, Barbara Haley, Daniele Fagnani, Yen-Shen Lu, John Crown, Johnson Lin, Masato Takahashi, Toshimi Takano, Miki Yamaguchi, Takaaki Fujii, Bin Yao, Judith Bebchuk, Kiana Keyvanjah, Richard Bryce, Adam Brufsky
Journal: Journal of Clinical Oncology (2020)

NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups.N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.