tbuckley/cabot-search huggingface dataset:
Opioid Prescription, Morbidity, and Mortality in United States Dialysis Patients
Authors: Paul L. Kimmel, Chyng-Wen Fwu, Kevin C. Abbott, Anne W. Eggers, Prudence P. Kline, Paul W. Eggers
Journal: Journal of the American Society of Nephrology (2017)

Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006–2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year ( n =671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort ( n =153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, &gt;60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1–89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration.
IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis
Authors: Daniel Engelbertsen, Sara Rattik, Maria Wigren, Jenifer Vallejo, Goran Marinkovic, Alexandru Schiopu, Harry Björkbacka, Jan Nilsson, Eva Bengtsson
Journal: Cardiovascular Research (2017)

The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis.We transferred apoe-/-myd88+/+ or apoe-/-myd88-/- CD4+ T cells to T- and B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88+/+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-γ. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells.We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.
Image Gallery: Leukonychia induced by selenium deficiency related to long‐term parenteral nutrition in a patient with Hirschsprung disease
Authors: J.W. Yun, Y.R. Woo, M. Kim, J.H. Chung, M.H. Jung, H.J. Park
Journal: British Journal of Dermatology (2017)

Funding sources: this work was supported by the Basic Science Research programme through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science and Technology (2015R1C1A2A01055073, 2016M3D1A1021387). Conflicts of interest: none declared. Dear Editor, A 7‐year‐old boy presented with a 6‐month history of leukonychia (a). He had undergone three segmental resections of the small bowel due to Hirschsprung disease and had been on long‐term parenteral nutrition. Acquired leukonychia can be idiopathic or induced by trauma, drugs, infections, various systemic diseases or nutritional defects (including selenium).1,2 Laboratory examination revealed low serum selenium levels. Selenium was supplied enterally for 8 weeks, and the proximal half of the nails became normal (b). All of the nails were totally normal by 12 weeks (c), at which point the serum selenium levels were elevated.
Efficacy of guselkumab in subpopulations of patients with moderate‐to‐severe plaque psoriasis: a pooled analysis of the phase <scp>III VOYAGE</scp> 1 and <scp>VOYAGE</scp> 2 studies
Authors: K.B. Gordon, A. Blauvelt, P. Foley, M. Song, Y. Wasfi, B. Randazzo, Y.K. Shen, Y. You, C.E.M. Griffiths
Journal: British Journal of Dermatology (2017)

Significant advances have been made in the treatment of moderate‐to‐severe plaque psoriasis with biological therapies; however, these agents may not work equally in all populations. To evaluate the efficacy of guselkumab in patient subgroups with moderate‐to‐severe psoriasis from the pooled guselkumab VOYAGE 1 and VOYAGE 2 phase III studies. Using data from the pooled VOYAGE 1 and VOYAGE 2 psoriasis studies, analyses were performed to evaluate the consistency of efficacy [Investigator's Global Assessment (IGA) 0/1 (cleared or minimal psoriasis) and IGA 0 (cleared)] across subpopulations defined by demographics, baseline disease characteristics and previous psoriasis treatment. A total of 1829 patients were randomized. Baseline demographics, disease characteristics and previous psoriasis treatment were comparable across treatment groups in the pooled population. Guselkumab, an anti‐interleukin (IL)‐23 monoclonal antibody that binds to the p19 subunit of IL‐23, provided substantial benefit across almost all subpopulations, with greater proportions of patients achieving IGA 0/1 vs. placebo at week 16, and vs. adalimumab (an antitumour necrosis factor monoclonal antibody) at week 24. Patients treated with guselkumab achieved greater efficacy (IGA 0/1 and IGA 0) compared with adalimumab at week 24 across all weight quartiles, most notably among patients weighing ≥ 100 kg. This analysis demonstrates a high degree of efficacy with guselkumab treatment compared with placebo at week 16 and with adalimumab at week 24 among broad subpopulations of patients with varying baseline demographics, disease characteristics and previous psoriasis treatments.
Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL)
Authors: Nidhi Tandon, Surbhi Sidana, Angela Dispenzieri, Morie A. Gertz, Martha Q. Lacy, David Dingli, Francis K. Buadi, Amie L. Fonder, Suzanne R. Hayman, Yi Lisa Hwa, Miriam A. Hobbs, Prashant Kapoor, Wilson I. Gonsalves, Nelson Leung, Ronald S. Go, John A. Lust, Stephen J. Russell, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2017)

Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10-year period (2006-2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi-organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.
Impact of alectinib on survival after crizotinib failure in ALK-positive NSCLC patients.
Authors: Tatsuya Yoshida, Yuko Oya, Junichi Shimizu, Kosuke Tanaka, Yoshitsugu Horio, Toyoaki Hida, Yasushi Yatabe
Journal: Journal of Clinical Oncology (2015)

e19138 Background: The next generation ALK inhibitor, alectinib, reportedly has potent efficacy after crizotinib failure in ALK-positive NSCLC patients. In the present study, we investigated progression patterns at crizotinib failure and clinical outcome after crizotinib failure, and evaluated the impact of progression patterns and alectinib on survival after crizotinib failure. Methods: Among a total of 76 ALK-positive NSCLC patients who underwent chemotherapy from January 2010 to December 2014 at our institution, 71 were treated with ALK inhibitors, 49 of whom were treated with crizotinib as the initial ALK inhibitor. We retrospectively evaluated these 49 patients for baseline characteristics, initial response to crizotinib, initial progression sites, treatment after crizotinib and post progression survival (PPS) from Response Evaluation Criteria in Solid Tumors- progressive disease (RECIST-PD) on crizotinib. Results: Of the 49 patients treated with crizotinib, 18 (37%) were male, median age was 52 years (range: 31–80), 33 (67%) were stage IV at diagnosis, and 39 (80%) patients received crizotinib as first or second line treatment. The overall response rate (ORR) and median progression free survival (PFS) on crizotinib was 61% and 298 days (range: 26–1421), respectively. Thirty-five (71%) patients had RECIST-PD, as assessed by radiologic findings. In 35 of the patients with RECIST-PD, the initial progression sites were isolated brain metastasis in 9 (26%) patients, and systemic in 26 (74%) patients. Disease progression consisted of solitary lesions in 7 (20%) patients, and multiple lesions in 28 (80%). After crizotinib failure, 11 patients were treated with alectinib, nine of whom (82%) had partial response. The median PPS from RECIST-PD on crizotinib in patients treated with alectinib was significantly longer than those without alectinib (NR vs. 4.5 months, p = 0.0003). Multivariate analysis identified that treatment with alectinib after crizotinib failure was associated with significantly longer PPS (Alectinib: HR 0.118, 95% confidence interval [CI] 0.018-0.427, P< 0.001). Conclusions: Alectinib was significantly associated with longer PPS after crizotinib failure in ALK-positive NSCLC patients.
JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia
Authors: Maria De Grandis, Florence Bardin, Cyril Fauriat, Christophe Zemmour, Abdessamad El-Kaoutari, Arnauld Sergé, Samuel Granjeaud, Laurent Pouyet, Camille Montersino, Anne-Sophie Chretien, Marie-Joelle Mozziconacci, Remy Castellano, Ghislain Bidaut, Jean-Marie Boher, Yves Collette, Stéphane J.C. Mancini, Norbert Vey, Michel Aurrand-Lions
Journal: Cancer Research (2017)

Acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells that acquire somatic mutations, leading to disease and clonogenic evolution. AML is characterized by accumulation of immature myeloid cells in the bone marrow and phenotypic cellular heterogeneity reflective of normal hematopoietic differentiation. Here, we show that JAM-C expression defines a subset of leukemic cells endowed with leukemia-initiating cell activity (LIC). Stratification of de novo AML patients at diagnosis based on JAM-C-expressing cells frequencies in the blood served as an independent prognostic marker for disease outcome. Using publicly available leukemic stem cell (LSC) gene expression profiles and gene expression data generated from JAM-C-expressing leukemic cells, we defined a single cell core gene expression signature correlated to JAM-C expression that reveals LSC heterogeneity. Finally, we demonstrated that JAM-C controls Src family kinase (SFK) activation in LSC and that LIC with exacerbated SFK activation was uniquely found within the JAM-C-expressing LSC compartment. Cancer Res; 77(23); 6627-40. ©2017 AACR.
Abstract 12982: Abnormal P-Wave Axis is Associated With an Increased Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ankit Maheshwari, Faye L Norby, Wesley T O’Neal, Elsayed Z Soliman, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2016)

Introduction: P-wave indices, such as prolonged p-wave duration and abnormal p-wave terminal force in V1, have been associated with incident AF. Hypothesis: We hypothesized that abnormal p-wave axis (aPWA) is associated with AF independent of traditional cardiovascular risk factors and tested our hypothesis in the ARIC study, a community-based prospective cohort study. Methods: We included in 15,319 participants without prevalent AF (age, 54.2 ± 5.7 yrs, 55.2% women, 26.5% blacks) who attended the baseline exam (1987-89). We defined aPWA as any value outside 0-75 degrees using 12-lead ECGs obtained during the baseline exam. Incident AF was identified by hospital discharge records, death certificates, and ECGs obtained during the study examinations. We used Cox proportional hazard models to estimate the hazard ratios and 95% confidence intervals of aPWA for AF. Results: During a mean follow-up of 19.8 years (1987-2012), there were 2377 incident AF cases. aPWA was independently associated with a 1.41-fold (95% CI, 1.22-1.62) increased risk of AF in the multivariable model (Table). Conclusions: aPWA is independently associated with incident AF in the general population. Further research is warranted to evaluate the ability of this readily available ECG measure in improving risk prediction of AF.
Performance study of an amplification-based NGS test on clinical FFPE specimens in China’s first multi-center study.
Authors: Feng Ye, Xiaoyan Zhou, Huaiyin Shi, Haijing Liu, Li Liang, Xiaodong Teng, Zhe Wang, Sanpeng Xu, Guoping Wang, Gang Chen, Yingyong Hou, Huanwen M. Wu, Tingdong Tang, Rui Liu, Bo Zhang, Zhiyong Liang, Hong Bu
Journal: Journal of Clinical Oncology (2017)

e13112 Background: Next Generation Sequencing (NGS) assays provide a comprehensive view of clinically actionable variations in patients. The increasing application of NGS holds new promise towards accurate diagnosis, personalized treatment and precision medicine. Formalin-fixed Paraffin-embedded (FFPE) treatment remains to be the most popular format of tissue preservation. To further standardize the whole process of the application of NGS assays on FFPE tissues, the Chinese Medical Association Pathology Division organized a multi-center performance study of a NGS assay on more than 1,000 clinical FFPE specimens by inviting top pathology departments in the country. Methods: OncoAim Tumor Mutation and PharmGx Detection Kit (Singlera Genomics, Shanghai) was used for this study. Reference samples with known mutations and allele frequencies together with 1045 clinical FFPE specimens from 11 participating hospitals were tested. Among them, 615 Colorectal Cancer (CRC) and 430 Non-Small Cell Lung Cancer (NSCLC) FFPE samples were processed and sequenced on Illumina Miseq platform and Thermo ion torrent PGM platform, respectively. Results: The results on reference materials show 100% (Confidence interval = 100%) analytical sensitivity for mutations with MAF ≥ 10% when median coverage is ≥ 500X.Positive predictive value of &gt; 99% was observed for mutations with MAF at 5% (data not shown). The median depth for CRC and NSCLC samples were 977Xand 828X, respectively. Among all CRC samples, 564 (91.7%) samples were found containing at least 1 clinical hotspot alteration. The top mutated genes were TP53, KRAS, APC, PIK3CA, SMAD4, BRAF, FBXW7, NRAS, PTEN, and ERBB2. For all the NSCLC samples, 304 (70.69%) were detected containing at least 1 clinical hotspot mutation. The top 10 mutated genes were EGFR, TP53, KRAS, PIK3CA PTEN, VHL, ERBB2, SMAD4, NFE2L2 and CTNNB1. Conclusions: In this study, we showed that the amplification-based NGS assay can achieve very high sensitivity and specificity for samples with median depth over 500X. The samples containing at least 1 clinical hotspot mutation were about 83% on average, suggesting NGS could be of great use for further characterization of the tissues.
Clinical results with combination of anti-CD27 agonist antibody, varlilumab, with anti-PD1 antibody nivolumab in advanced cancer patients.
Authors: Rachel E. Sanborn, Michael J. Pishvaian, Harriet M. Kluger, Margaret K. Callahan, Amy M. Weise, Jose Lutzky, Michael Jay Yellin, Tracey Rawls, Laura Vitale, Abdel Halim, Tibor Keler, Tom Davis, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2017)

3007 Background: A phase 1 trial to assess the safety and immunological activity of the combination of varlilumab (V) and nivolumab (N), and recommend a dose of V for the phase 2 study was conducted. Methods: The study was performed using the approved dose of N (3 mg/kg Q2W) and escalating doses of V (0.1, 1, or 10 mg/kg Q2W) in anti-PD-(L)1 naïve patients with advanced cancer. Results: A total of 36 patients (21 CRC, 8 ovarian [OVA], 4 melanoma and 3 SCCHN) were enrolled. Toxicity was consistent with the safety profile of each agent individually; no unexpected toxicities were seen with the combination. No MTD was identified. An OVA cancer patient in the 10 mg/kg cohort had a DLT: hepatitis (G4) and acute kidney injury (G3). A CRC patient in the 10 mg/kg cohort had a drug-related SAE of mixed motor sensory neuropathy (G2) and a CRC patient in the 1 mg/kg cohort had rash (G3). No additional drug related SAEs or DLTs were reported. The majority of tumors were PD-L1 negative (24/27) by IHC at baseline. For patients with post treatment biopsies, PD-L1 expression was observed in 43.5% (10/23) and correlated with increases in CD8 T cell infiltration, consistent with the generation of anti-tumor immunity. Other treatment related biomarker changes included transient increases in serum chemokine levels, and a prominent decrease in circulating Tregs. Biomarker analysis did not clearly differentiate between dose levels, or delineate an optimal V dose. Three patients had objective PR by RECIST [CRC MSI-low (1 mg/kg V), SCCHN (10 mg/kg V) and OVA (10 mg/kg V, uPR)]. The response in the CRC patient is ongoing with a 94% decrease in target lesion diameter and a PFS of 19+ months. There were also 11 patients with SD. Phase 2 cohorts are ongoing in RCC, SCCHN, OVA, CRC and GBM. The Phase 2 portion includes exploration of different dose/regimens of V, including high and low exposure, to better characterize the optimal dosing strategy for V, in combination with a fixed dose of N (240 mg Q2W). Conclusions: The combination of V and N was well tolerated, associated with strong biological signals, and has evidence of clinical activity in subsets of patients with tumor types that are typically resistant to PD-1 inhibitor monotherapy. Clinical trial information: NCT02335918.
Abstract 11814: Pulmonary Hypertension With Altered eNOS and ALK-1 Signaling in the Autoimmuno-disease Mice
Authors: Koichi Sugimoto, Akihiko Sato, Shunsuke Watanabe, Satoshi Suzuki, Takeshi Machida, Shu-ichi Saitoh, Hideharu Sekine, Yasuchika Takeishi
Journal: Circulation (2016)

Background: Pulmonary artery hypertension is often associated with connective tissue disease and major determinant of prognosis. MRL/lpr mouse, which has hypergammaglobulinemia and products various autoimmuno antibody, develops vasculitis and nephritis spontaneously and is widely used as the model of lupus nephritis or Sjogren syndrome. In this study, we examined the right ventricular pressure overload, pathological features and the signaling molecules in the lung tissues of MRL/lpr mice. Methods: We used the female MRL/lpr mice at the age of 12 to 18 weeks. We measured right ventricular systolic pressure (RVSP) by a micro-manometer catheter and the ratio of right ventricular weight to left ventricular weight including ventricular septum (RV/LV). Lung sections were stained with α-smooth muscle actin, and the medial smooth muscle area was expressed as a percentage of the external area of the vessel. Levels of endothelial nitric oxide synthase (eNOS), survivin, endothelin-1 (ET-1), and activin receptor-like kinase-1 (ALK-1) were analyzed by Western blotting. Results: RVSP in the MRL/lpr mice was significantly higher (29.8 ± 7.2 vs. 19.2 ± 1.9 mmHg, P &lt; 0.05) than that in WT C57/Bl6 mice. RV/LV was increased in the MRL/lpr mice compared to the WT C57/Bl6 mice (0.33 ± 0.58 vs. 0.20 ± 0.67, P &lt; 0.05). The medial smooth muscle area of MRL/lpr mice were larger than that of WT C57/bl6 (56.3 ± 4.0 vs. 39.5 ± 6.1%, P &lt; 0.05). Western blot analysis revealed the markedly elevated levels of ET-1 and survivin as well as decreased ALK-1 expression and eNOS phosphorylation in the lung tissue of MRL/lpr mice. Conclusion: We demonstrated that MRL/lpr mice were complicated with pulmonary hypertension. The possible mechanisms include the vasoconstriction enhanced by increased ET-1 level and impaired vasodilatation caused by decreased eNOS phosphorylation and ALK-1 expression. In addition, upregulation of survivin promoted the medial wall thickening of pulmonary vessels. MRL/lpr mice appeared to be a useful model in considering the mechanism of pulmonary hypertension associated with connective tissue diseases.
心筋梗塞後の整列したヒト微小血管を含む予備的に血管が新生組織パッチのInosculationと潅流【Powered by NICT】
Authors: B Riemenschneider Sonja, J Mattia Donald, S Wendel Jacqueline, A Schaefer Jeremy, Ye Lei, A Guzman Pilar, T Tranquillo Robert
Journal: Biomaterials (2016)
Is the “burnout epidemic” an academic fiction?
Authors: Renzo Bianchi
Journal: BMJ (2017)

In their editorial, Lemaire and Wallace1 say that burnout has reached epidemic levels among doctors. This “burnout epidemic,” although widely relayed in medical journals, is unsubstantiated.

The prevalence of burnout cannot be estimated because diagnostic criteria do not exist.2 Estimates that have been made rely on categorisation criteria that are clinically and theoretically …
Last ditch effort to repeal Obamacare gathers steam
Authors: Owen Dyer
Journal: BMJ (2017)

The Affordable Care Act, Barack Obama’s signature health reform, faces a real and fast developing threat from a fourth Senate repeal bill.

As September began, Senate Republicans’ efforts to undo Obamacare were given a small chance of success. But the prospect of definitive failure seems to have galvanized the party, and leaders are sounding increasingly confident, with President Donald Trump and the Senate majority leader, Mitch McConnell, asserting that their new version of “Trumpcare” will pass.

The bill, called Cassidy-Graham, is effectively the last chance this Congress will have to repeal Obamacare before the midterm elections in November 2018. Under Senate rules, after 30 September it will require an unattainable 60 vote majority to pass. Until 30 September it may pass as a budget measure with a simple majority. In a 50-50 Senate split the vice president, Mike Pence, would …