tbuckley/cabot-search huggingface dataset:
Abstract 18054: Improved Myocardial Function After Whole Body Periodic Acceleration (pGz) in Established <i>mdx</i> Cardiomyopathy
Authors: Arkady Uryash, Jos R Lopez, Francis X McGowan, Robert Berg, Vinay Nadkarni, Jose Adams
Journal: Circulation (2015)

Duchenne Muscular Dystrophy (DMD) cardiomyopathy (DMD-C) is progressive leading to heart failure and death. pGz is the sinusoidal motion of the body in a head-foot direction, which activates endothelial nitric oxide synthase (eNOS) to produce small amounts of eNO in heart via pulsatile shear stress. eNO is cardioprotective and important in varied signaling pathway. We recently showed improved muscle function using pGz in a mouse model of mdx Hypothesis: pGz may confer myocardial functional improvement in an established DMD-C. Methods: Male MDX mice were randomized (n=12) at 7-mo of age (an age where DMD-C is already established) to receive daily pGz (ƒ=480 cpm with a displacement Gz ± 3.0 mt/sec 2 ) (MDX-pGz) (1hr/day for 8 weeks or time control (MDX), a separate age matched group of wt (n=6) to serve as non-diseased controls. At 9 mo of age, invasive analysis of the pressure-volume relationship of left ventricle (LV) was carried out with a Millar catheter and a dobutamine stress test performed. In a separate group of mdx mice, pGz was performed and immunoblotting analysis done to determine expression of utrophin (UTR), sarcoglycan β (SARCβ), Dytroglycanβ(DYSβ), eNOS and p-eNOS levels in heart. Results: Compared to wt , mdx mice had reduced LV pressure integral(LVPi) and lower dp/dt max . Treatment with pGz improved LVPi and dp/dt max . Survival to a Dobutamine stress test was: 100% wt , 80% mdx and 90% in mdx -pGz. pGz treatment preserved LVPi relationship and dp/dt max during dobutamine. pGz treatment to mdx mice increased UTR,(56% ), SARCβ (160% ),DYSβ (227%), eNOS(75%) and p-eNOS (37% ) from mdx expression levels (Figure, M±SD) Conclusion: pGz improves myocardial functional phenotype, and preserves myocardial function after dobutamine stress in mdx mice. pGz salutatory effect is associated with an increase in eNOS, p-eNOS UTR, SARCβ, DYSβ expression. This non-invasive and non-pharmacological intervention may constitute a new therapeutic approach to treat DMD cardiomyopathy.
Association Between Persistent Pain and Memory Decline and Dementia in a Longitudinal Cohort of Elders
Authors: Elizabeth L. Whitlock, L. Grisell Diaz-Ramirez, M. Maria Glymour, W. John Boscardin, Kenneth E. Covinsky, Alexander K. Smith
Journal: JAMA Internal Medicine (2017)

Chronic pain is common among the elderly and is associated with cognitive deficits in cross-sectional studies; the population-level association between chronic pain and longitudinal cognition is unknown.To determine the population-level association between persistent pain, which may reflect chronic pain, and subsequent cognitive decline.Cohort study with biennial interviews of 10 065 community-dwelling older adults in the nationally representative Health and Retirement Study who were 62 years or older in 2000 and answered pain and cognition questions in both 1998 and 2000. Data analysis was conducted between June 24 and October 31, 2016."Persistent pain," defined as a participant reporting that he or she was often troubled with moderate or severe pain in both the 1998 and 2000 interviews.Coprimary outcomes were composite memory score and dementia probability, estimated by combining neuropsychological test results and informant and proxy interviews, which were tracked from 2000 through 2012. Linear mixed-effects models, with random slope and intercept for each participant, were used to estimate the association of persistent pain with slope of the subsequent cognitive trajectory, adjusting for demographic characteristics and comorbidities measures in 2000 and applying sampling weights to represent the 2000 US population. We hypothesized that persistent pain would predict accelerated memory decline and increased probability of dementia. To quantify the impact of persistent pain on functional independence, we combined our primary results with information on the association between memory and ability to manage medications and finances independently.Of the 10 065 eligible HRS sample members, 60% were female, and median baseline age was 73 years (interquartile range, 67-78 years). At baseline, persistent pain affected 10.9% of participants and was associated with worse depressive symptoms and more limitations in activities of daily living. After covariate adjustment, persistent pain was associated with 9.2% (95% CI, 2.8%-15.0%) more rapid memory decline compared with those without persistent pain. After 10 years, this accelerated memory decline implied a 15.9% higher relative risk of inability to manage medications and an 11.8% higher relative risk of inability to manage finances independently. Adjusted dementia probability increased 7.7% faster (95% CI, 0.55%-14.2%); after 10 years, this translates to an absolute 2.2% increase in dementia probability for those with persistent pain.Persistent pain was associated with accelerated memory decline and increased probability of dementia.
Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis
Authors: Oscar Alvarez‐Garcia, Tokio Matsuzaki, Merissa Olmer, Lars Plate, Jeffery W. Kelly, Martin K. Lotz
Journal: Arthritis & Rheumatology (2017)

Objective Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA. Methods OA severity was histologically assessed in 4‐month‐old wild‐type and REDD1 −/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild‐type and REDD1 −/− mice. Results REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1 −/− mice and in cultured REDD1 −/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule‐associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1 −/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1‐deficient chondrocytes. REDD1 was required for AMP‐activated protein kinase–induced PGC‐1α in chondrocytes. Conclusion Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury‐induced OA.
Contemporary breast conservation patient outcomes for ductal carcinoma in situ and margins &lt; 2 mm.
Authors: Audree Tadros, Benjamin D. Smith, Yu Shen, Heather Y. Lin, Savitri Krishnamurthy, Anthony Lucci, Carlos Hernando Barcenas, Rosa F. Hwang, Gaiane Rauch, Lumarie Santiago, Eric A Strom, Sarah Marie DeSnyder, Wei Tse Yang, Dalliah MaShon Black, Constance T. Albarracin, Mariana Chavez-Mac Gregor, Kelly Hunt, Henry Mark Kuerer
Journal: Journal of Clinical Oncology (2017)

559 Background: Recent national consensus guidelines regarding optimal margin width for the management of DCIS have been published; however, controversy remains for managing margins &lt;2mm. The relationship between margin width and locoregional recurrence (LRR) was determined in a contemporary cohort of patients. Methods: 1504 patients with DCIS undergoing definitive breast conserving surgery from 1996 to 2010 were analyzed for clinical and pathologic characteristics from a prospectively managed comprehensive academic cancer center database. Cox proportional hazard models were used to examine the relationship between margin width (&lt;2mm or ≥2mm) and LRR by adjuvant radiation therapy (RT). Patients with positive margins (n=11) were excluded. Results: Overall, 3.4% of patients had a LRR at a median follow-up of 8.7 years. Univariate analysis of age, family history, grade, tumor size, comedonecrosis, RT, adjuvant hormonal therapy, ER status, and margin width found younger age (&lt; 40 yr, p=0.02), no RT (n=299, p=0.005), and margin width &lt;2mm(n=138, p=0.005) to be associated with LRR. The association between margin width and LRR differed by adjuvant radiation therapy status (p=0.02 for the interaction). There was no statistical significant difference in LRR for patients with margins &lt;2mm vs ≥2 mm who received RT, (10-year LRR 6.0% vs 3.2%, respectively; HR 1.5, 95% CI 0.5-4.2, p=0.48). For patients who did not receive RT (n=299), those with margins &lt; 2 mm were significantly more likely to develop a LRR than those with margins ≥2mm (10-year LRR 35.7% vs. 4.6%, respectively; HR 7.2, 95%CI 2.6-19.4, p=0.0001). Conclusions: In patients with &lt;2mm margins receiving adjuvant radiation therapy, there is no difference in locoregional recurrence when compared to patients with ≥2mm margins. Additional surgery for wider margins of resection are not routinely justified in this group of patients but should be obtained for patients with &lt;2mm margins who forego radiotherapy.
Likelihood of late relapse assessed by the Breast Cancer Index (BCI) in LN-invasive lobular compared to invasive ductal carcinoma.
Authors: Raquel Nunes, Max Salganik, Junmei Liu, Catherine A. Schnabel, Andrea Lynn Richardson
Journal: Journal of Clinical Oncology (2017)

e12025 Background: Women with HR+ breast cancer remain at risk for late distant recurrences (DR) despite optimal adjuvant therapy. Invasive lobular carcinoma (ILC) is the 2nd most common subtype of invasive breast cancer. When compared to invasive ductal carcinoma (IDC), ILC has distinguishing clinical and pathologic characteristics that may result in different response to therapy and long term prognosis. BCI is a validated gene expression-based assay for pts with early stage HR+ breast cancer that provides risk of late (5-10 y) DR and predicts likelihood of benefit of extended endocrine therapy (EET). Here, we compared BCI assay results in pts with HR+, LN- ILC vs IDC. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains &gt;50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N=14,463). Molecular variables include BCI Prognostic score, HoxB13/IL17BR ratio (H/I), and molecular grade index (MGI). Clinicopathologic variables were abstracted from pathology reports (available for a subset of cases). LN- pts with available pathologic data were analyzed. Chi-squared tests were used to compare BCI results between IDC and ILC subgroups. Results: Analyses included 2554 LN- pts with available histologic subtype data (80.7% IDC; 13.7% ILC; 2.6% mixed; 2.9% other). Median age was 59.3y (range 27-89y; 74% ≥ 50y). BCI Prognostic had a broad distribution of individual risk assessment in both IDC and ILC. However, BCI Prognostic had a lower median BCI scores (P&lt;0.0001) in ILC, and classified a smaller proportion of pts with ILC as high risk for late DR compared to IDC (36.5% vs 53.1%; P&lt;0.0001). IDC had a higher median molecular proliferative status (MGI) compared to ILC (P&lt;0.0001). BCI Predictive (H/I) identified a slightly decreased proportion of pts with ILC benefiting from extended endocrine therapy compared to IDC (38.2% vs 41.1%). There was no difference in quantitative ER or PR (by PCR) between groups. Conclusions: BCI identified a smaller proportion of pts with ILC at high risk of late DR compared to IDC. Further studies evaluating outcomes are warranted to further validate BCI in pts with ILC.
The inexorable death of first peoples: an open letter to the WHO
Authors: Philippe Charlier, Saudamini Deo
Journal: The Lancet Planetary Health (2017)

Indigenous communities experience some of the highest rates of suicide globally, especially among young people. This worrying epidemic has already been shown in Inuit communities of North America and Greenland1,2 and the Amazonian groups of Guyana, but recently has been shown to extend to Australian First Nations people (mainly Aboriginal individuals).3 The international scientific community has already been alerted to the obsolescence of WHO's definition of health,4 and the need to adapt patterns of suicide prevention procedures used in high-income areas to indigenous communities.
Network meta-analysis of adjuvant chemotherapy in early breast cancer.
Authors: Preethi John, Raveendhara R Bannuru, Joshua T. Cohen, Rachel J. Buchsbaum, John Kalil Erban
Journal: Journal of Clinical Oncology (2017)

e12071 Background: The NCCN recommends several adjuvant regimens for early stage breast cancer (ESBC) that have not been directly compared in randomized clinical trials (RCTs) making the optimal regimen unclear. Regimens of interest include dose dense doxorubicin/cyclophosphamide followed by paclitaxel (DDAC-T), doxorubicin/cyclophosphamide followed by weekly paclitaxel (ACwkT), docetaxel/doxorubicin/cyclophosphamide (TAC), and docetaxel/cyclophosphamide (TC) x 4 cycles. This is the first network meta-analysis (NMA) to compare the effectiveness of these regimens. Methods: A systematic literature review was performed to identify RCTs that included the above regimens. To complete the network, doxorubicin/cyclophosphamide (AC), doxorubicin/cyclophosphamide followed by paclitaxel (AC-T) every 3 wks, and doxorubicin/cyclophosphamide followed by docetaxel (AC-D) every 3 wks were included. Primary outcomes were progression free survival (PFS) and overall survival (OS) estimated as odds ratios (OR). OR &gt; 1 indicates better survival. Bayesian random effects model with non-informative priors was used. Results: 5 RCTs involving 12,579 females with mainly node positive, Her2- ESBC were analyzed. Although there were no statistically significant differences in PFS or OS among these regimens, AC-D, ACwkT, DDAC-T, TAC, and TC demonstrated better survival outcomes compared to AC and AC-T (not shown). Survival outcomes among DDAC-T, ACwkT, TAC, and TC were comparable. DDAC-T survival outcomes were marginally better than the other regimens. Conclusions: DDAC-T, ACwkT, TC, and TAC were similar in efficacy. Final results with at least one additional RCT will be presented. Although NMA is not a substitute for direct comparison RCTs, it allows indirect comparisons to aid in decision making. Future results from ongoing RCTs will refine estimates of anthracycline vs non anthracycline efficacy and toxicity. [Table: see text]
Patient/oncologist decisions about adjuvant chemotherapy in ER+ve, HER2-ve early breast cancer following endopredict testing.
Authors: David J Bloomfield, Amy Arbon, Jane Cox, Berkin Hack, Julia Hall, Catherine Harper-Wynne, Sebastian Hinde, Val Jenkins, James Mackay, Lucy A Matthews, Shirley F May, Adrian Moss, Gargi Surendra Patel, Richard Simcock, Eirini Thanopoulou, Sarah Westwell, Dominika Wlaszly, Lesley Fallowfield
Journal: Journal of Clinical Oncology (2017)

e12002 Background: Endopredict is a multigene test including tumor size and nodal status; it predicts low or high risk of distant recurrence in patients (pts) with ER+ve, HER2–ve breast cancer treated with adjuvant endocrine therapy alone. We compared adj chemotherapy decisions pre and post Endopredict test results, pts’ anxiety, decisional conflict and oncologists’ (oncs) confidence about decisions made. Methods: 14 oncs in 8 UK hospitals saw 149 pts judged by clinical teams to have equivocal indications for chemotherapy. Pts and oncs discussed provisional treatment decisions based on conventional prognostic factors. Initial decisions were reconsidered when Endopredict results were available. Pre and post-test pts completed Spielberger’s State/Trait Anxiety inventory (STAI) and a decision conflict scale (DCS). Oncs answered questionnaires probing:- basic demographic,/clinical details, agreement with, and confidence about treatment decisions (endocrine (E) therapy +/- chemotherapy(C)) Results: 66.7% pts with an initial E alone decision and a high risk result upgraded to E+C. 9.4% pts with initial E+C decisions and high risk results down-graded to E. None of 46 pts initially favouring E alone who were low risk changed decisions. 82.8% who initially wanted E+C and had low risk scores downgraded to E alone. Endopredict results increased oncs’ confidence (8% ‘strongly agreed’ pre-test, 50% post-test). Oncs neither agreeing nor disagreeing with decisions fell (24% to 5%). Anxiety was stable in pts with unchanged decisions. Pts whose therapy was downgraded had significantly lower anxiety scores (p&lt;0.01); those whose treatment was upgraded had increased scores (p&lt;0.001). Likewise overall uncertainty on DCS fell post-test (p&lt;0.023) Conclusions: Endopredict results increased oncs’ and pts’ decision-making confidence, improved matching of risk with therapy decisions and thus a potential for improved outcomes. Clinical trial information: ISRCTN69220108. [Table: see text]
David Oliver: Unproductive activity and NHS consultants
Authors: David Oliver
Journal: BMJ (2017)

With constrained public money, a growing focus arises on doctors’ key role in reducing variation in processes and outcomes and improving value in healthcare, especially how money is spent and what it delivers in outcomes that matter to patients and system efficiencies.

Earlier this year John Appleby published an analysis in The BMJ comparing current and historical productivity of NHS consultants.1 The headline figures suggest that today’s consultants are less productive than their predecessors in crude terms of “volume of output versus unit of input,” with consultant expansion unmatched by the more slowly rising volume of …
The genomic road to invasion—examining the similarities and differences in the genomes of associated oral pre-cancer and cancer samples
Authors: Henry M. Wood, Catherine Daly, Rebecca Chalkley, Burcu Senguven, Lisa Ross, Philip Egan, Preetha Chengot, Jennifer Graham, Neeraj Sethi, Thian K. Ong, Kenneth MacLennan, Pamela Rabbitts, Caroline Conway
Journal: Genome Medicine (2017)

It is frequently assumed that pre-invasive lesions are simpler precursors of cancer and will contain a limited subset of the genomic changes seen in their associated invasive disease. Driver mutations are thought to occur early, but it is not known how many of these are present in pre-invasive lesions. These assumptions need to be tested with the increasing focus on both personalised cancer treatments and early detection methodologies. We examined genomic copy number changes in 256 pre-invasive and invasive samples from 69 oral cancer patients. Forty-eight samples from 16 patients were further examined using exome sequencing. Evidence of a shared ancestor of both dysplasia and carcinoma was seen in all but one patient. One-third of dysplasias showed independent copy number events. The remainder had a copy number pattern that was similar to or simpler than that of the carcinoma. All dysplasias examined contained somatic mutations absent in the related carcinoma. Previously observed copy number changes and TP53 mutations were very frequently observed, and almost always shared between dysplasia and carcinoma. Other gene changes were more sporadic. Pathway analysis confirmed that each patient's disease developed in a different way. Examining the numbers of shared mutations and the rate of accumulation of mutations showed evidence that all samples contain a population of sub-clones, with little evidence of selective advantage of a subset of these. These findings suggest that most of the genomic changes driving oral cancer occur in the pre-cancerous state by way of gradual random accumulation rather than a dramatic single event.
Stereo vision-based tracking of soft tissue motion with application to online ablation control in laser microsurgery
Authors: Andreas Schoob, Dennis Kundrat, Lüder A. Kahrs, Tobias Ortmaier
Journal: Medical Image Analysis (2017)

Recent research has revealed that image-based methods can enhance accuracy and safety in laser microsurgery. In this study, non-rigid tracking using surgical stereo imaging and its application to laser ablation is discussed. A recently developed motion estimation framework based on piecewise affine deformation modeling is extended by a mesh refinement step and considering texture information. This compensates for tracking inaccuracies potentially caused by inconsistent feature matches or drift. To facilitate online application of the method, computational load is reduced by concurrent processing and affine-invariant fusion of tracking and refinement results. The residual latency-dependent tracking error is further minimized by Kalman filter-based upsampling, considering a motion model in disparity space. Accuracy is assessed in laparoscopic, beating heart, and laryngeal sequences with challenging conditions, such as partial occlusions and significant deformation. Performance is compared with that of state-of-the-art methods. In addition, the online capability of the method is evaluated by tracking two motion patterns performed by a high-precision parallel-kinematic platform. Related experiments are discussed for tissue substitute and porcine soft tissue in order to compare performances in an ideal scenario and in a setup mimicking clinical conditions. Regarding the soft tissue trial, the tracking error can be significantly reduced from 0.72 mm to below 0.05 mm with mesh refinement. To demonstrate online laser path adaptation during ablation, the non-rigid tracking framework is integrated into a setup consisting of a surgical Er:YAG laser, a three-axis scanning unit, and a low-noise stereo camera. Regardless of the error source, such as laser-to-camera registration, camera calibration, image-based tracking, and scanning latency, the ablation root mean square error is kept below 0.21 mm when the sample moves according to the aforementioned patterns. Final experiments regarding motion-compensated laser ablation of structurally deforming tissue highlight the potential of the method for vision-guided laser surgery.