tbuckley/cabot-search huggingface dataset:
Cardiac resynchronization is pro-arrhythmic in the absence of reverse ventricular remodelling: a systematic review and meta-analysis
Authors: Bishoy Deif, Brennan Ballantyne, Fahad Almehmadi, Michael Mikhail, William F McIntyre, Jaimie Manlucu, Raymond Yee, John L Sapp, Jason D Roberts, Jeff S Healey, Peter Leong-Sit, Anthony S Tang
Journal: Cardiovascular Research (2018)

Cardiac resynchronization therapy (CRT) has been shown to reduce mortality and heart failure (HF) hospitalization but its effects on the rate of ventricular arrhythmias (VAs) appears to be neutral. We hypothesize that CRT with LV epicardial stimulation is inherently pro-arrhythmic and increases VA rates in the absence of reverse ventricular remodelling while conferring an anti-arrhythmic effect in mechanical responders. In this systematic review and meta-analysis, we considered retrospective cohort, prospective cohort, and randomized controlled trials comparing VA rates between cardiac resynchronization therapy-defibrillator (CRT-D) non-responders, CRT-D responders and those with implantable cardioverter-defibrillator (ICD) only. Studies were eligible if they defined CRT-D responders using a discrete left ventricular volumetric value as assessed by any imaging modality. Studies were identified through searching electronic databases from their inception to July 2017. We identified 2579 citations, of which 23 full-text articles were eligible for final analysis. Our results demonstrated that CRT-D responders were less likely to experience VA than CRT-D non-responders, relative risk (RR) 0.49 [95% confidence interval (CI) 0.41–0.58, P < 0.01] and also less than patients with ICD only: RR 0.59 (95% CI 0.50–0.69, P < 0.01). However, CRT-D mechanical non-responders had a greater likelihood of VA compared with ICD only, RR 0.76 (95% CI 0.63–0.92, P = 0.004). CRT-D non-responders experienced more VA than CRT-D responders and also more than those with ICD only, suggesting that CRT with LV epicardial stimulation may be inherently pro-arrhythmic in the absence of reverse remodelling.
MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis
Authors: Diego A. Calvopina, Mark D. Chatfield, Anna Weis, Miranda A. Coleman, Manuel A. Fernandez‐Rojo, Charlton Noble, Louise E. Ramm, Daniel H. Leung, Peter J. Lewindon, Grant A. Ramm
Journal: Hepatology (2018)

Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on nonspecific assessments, whereas liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase (AST) to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical, and imaging assessments as follows: CFLD (n = 44), CF patients with no evidence of liver disease (CFnoLD; n = 40), and healthy controls (n = 40). Serum miRNAs were analyzed using miRNA sequencing (miRNA-Seq). Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p, and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, whereas miR-142-3p and let-7g-5p were down-regulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p, and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an area under the receiver operating characteristics curve (AUROC) = 0.91 (sensitivity = 83%, specificity = 92%; P < 0.0001). Expression levels of serum miR-18a-5p were correlated with increasing hepatic fibrosis (HF) stage in CFLD (rs = 0.56; P < 0.0001), showing good diagnostic accuracy for distinguishing severe (F3-F4) from mild/moderate fibrosis (F0-F2). A unit increase of miR-18a-5p showed a 7-fold increased odds of having severe fibrosis with an AUROC = 0.82 (sensitivity = 93%, specificity = 73%; P = 0.004), indicating its potential to predict fibrosis severity. Conclusion: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF.
Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth
Authors: Lorena Fontán, Qi Qiao, John M. Hatcher, Gabriella Casalena, Ilkay Us, Matt Teater, Matt Durant, Guangyan Du, Min Xia, Natalia Bilchuk, Spandan Chennamadhavuni, Giuseppe Palladino, Giorgio Inghirami, Ulrike Philippar, Hao Wu, David A. Scott, Nathanael S. Gray, Ari Melnick
Journal: Journal of Clinical Investigation (2018)

The paracaspase MALT1 plays an essential role in activated B cell–like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.
Child mental health: dedicated staff will be deployed to schools and colleges from next year
Authors: Ingrid Torjesen
Journal: BMJ (2018)

The government has unveiled plans for an army of new mental health staff to work in and around schools and colleges from next year to support mental health needs in young people.

However, the Royal College of Paediatrics and Child Health expressed disappointment with the plans, published on 25 July by the Department of Health and Social Care in its response to the consultation on the green paper for young people’s mental health.1

Max Davie, officer for health promotion at the college, said that the initiative alone was an inadequate response …
Abstract 17446: Patient and Infarct Related Factors Predict the Need for Mechanical Ventilation in STEMI Patients
Authors: Thomas Metkus, Aiham Albaeni, Nisha Chandra-Strobos, Shaker Eid
Journal: Circulation (2016)

Introduction:  Respiratory failure complicating acute coronary syndromes is common in clinical practice; however, predictors of the need for mechanical ventilation in STEMI patients have not been described.   Hypothesis:  Patient co-morbidities and infarct-related clinical features predict need for mechanical ventilation (MV) in STEMI   Methods:  We used the National Inpatient Sample to characterize the use of MV in adult patients with STEMI over a 12-year period. STEMI and MV were identified using ICD-9-CM codes. Patients transferred from another hospital were excluded. Logistic regression was performed to identify patient, hospital, and clinical characteristics associated with requiring MV within 24-hours of hospitalization. Multivariate models were adjusted for factors of  a priori  clinical interest including age, gender, race, Charlson comorbidity index, chronic lung disease, smoking, obesity, weekend admission, cardiac arrest, and cardiogenic shock.   Results:  Of 1,867,114 STEMI patients included from 2002 to 2013, 72,220 were treated with mechanical ventilation (3.9%). Compared to STEMI patients requiring no respiratory support, patients who required MV were older (mean age 68 vs. 64 years), more likely to be female (40% vs. 34%), with more chronic lung disease (21% vs. 15%) and chronic kidney disease (13% vs. 7%) [p   Older age (OR adj  1.04 [95% CI 1.02-1.06] per 10 years), female gender (OR adj  1.08 [95% CI 1.04-1.12]), increasing co-morbidity index, chronic lung disease (OR adj  1.11 [95% CI 1.05-1.17]), weekend admission (OR adj  1.11 [95% CI 1.07-1.16]), presence of cardiogenic shock (OR adj  9.2 [95% CI 8.8-9.7]) and in-hospital arrest (OR adj  20.4 [95% CI 18.9-22.0]) were all independently associated with requiring MV in a multivariate model.   Conclusions:  Patient and infarct related factors predict the need for mechanical ventilation in STEMI patients; given the lower rates of revascularization in this population, targeted strategies to improve treatment for STEMI patients with respiratory failure are warranted.
Concussion management in combat sports: consensus statement from the Association of Ringside Physicians
Authors: John Neidecker, Nitin K Sethi, Randolph Taylor, Raymond Monsell, Don Muzzi, Bruce Spizler, Larry Lovelace, Edmund Ayoub, Rick Weinstein, Joseph Estwanik, Patricio Reyes, Robert C Cantu, Barry Jordan, Margaret Goodman, John W Stiller, Jonathan Gelber, Robert Boltuch, Domenic Coletta, Angela Gagliardi, Stephen Gelfman, Patrick Golden, Nicholas Rizzo, Paul Wallace, Allan Fields, Calvin Inalsingh
Journal: British Journal of Sports Medicine (2018)

Various organisations and experts have published numerous statements and recommendations regarding different aspects of sports-related concussion including definition, presentation, treatment, management and return to play guidelines. 1-7 To date, there have been no written consensus statements specific for combat sports regarding management of combatants who have suffered a concussion or for return to competition after a concussion. In combat sports, head contact is an objective of the sport itself. Accordingly, management and treatment of concussion in combat sports should, and must, be more stringent than for non-combat sports counterparts.The Association of Ringside Physicians (an international, non-profit organisation dedicated to the health and safety of the combat sports athlete) sets forth this consensus statement to establish management guidelines that ringside physicians, fighters, referees, trainers, promoters, sanctioning bodies and other healthcare professionals can use in the ringside setting. We also provide guidelines for the return of a combat sports athlete to competition after sustaining a concussion. This consensus statement does not address the management of moderate to severe forms of traumatic brain injury, such as intracranial bleeds, nor does it address the return to competition for combat sports athletes who have suffered such an injury. These more severe forms of brain injuries are beyond the scope of this statement. This consensus statement does not address neuroimaging guidelines in combat sports.
Effect of Stress Ball Use or Hand-holding on Anxiety During Skin Cancer Excision
Authors: Arianna F. Yanes, Alexandra Weil, Karina C. Furlan, Emily Poon, Murad Alam
Journal: JAMA Dermatology (2018)

Patients undergoing skin surgery under local anesthesia can experience anxiety. Adjuvant intraoperative anxiety reduction methods may help.To assess whether hand-holding or holding a stress ball reduces patient anxiety during excisional surgery of head or neck skin cancer with the patient under local anesthesia and to measure pain and patient satisfaction.In this nonblinded, single-center randomized clinical trial, performed from January 24 through April 26, 2017, at a dermatology outpatient service in an urban, academic medical center, a consecutive sample of 135 adults who required excisional removal of nonmelanoma skin cancer of the head or neck was randomized and studied.Participants were randomized 1:1:1 to 3 groups: hand-holding, stress ball, or control (treatment as usual). Participants in the hand-holding group had a female researcher hold one of their hands during administration of anesthesia and extirpation, and those in the stress ball group held a round compressible ball and squeezed it as desired during the same period.The primary outcome was anxiety, measured by a visual analog scale (VAS), 6-item State Trait Anxiety Inventory (STAI), and physiologic measures (blood pressure and heart rate). Secondary outcomes were pain during the procedure and overall participant satisfaction. In addition, participants were asked how many hours they spent researching the procedure before surgery.A total of 135 participants, 45 per study arm, were enrolled (mean [SD] age, 65.5 [13.9] years; 84 [62.2%] male; 134 [99.3%] white). There were no withdrawals or dropouts. Anxiety decreased over time in all groups, but no significant differences were found in the 3 anxiety measures across the 3 groups (VAS anxiety score before: control group, 3.11; hand-holding group, 3.04; stress ball group, 3.09 [P > .99]; VAS anxiety score during: control group, 1.89; hand-holding group, 2.31; stress ball group, 2.47 [P = .55]; STAI score: control group, 8.91; hand-holding group, 8.93; stress ball group, 8.76 [P = .96]). The 3 groups also did not significantly differ in postprocedure pain scores (control group, 0.78; hand-holding group, 0.64; stress ball group, 0.67; P = .85). Almost all participants (134 [99.2%]) were very satisfied. Participants who had done research had higher preoperative VAS anxiety scores (researched, 3.84; did not research, 2.62; P = .04).Hand-holding and squeezing a stress ball do not appear to provide incremental anxiety reduction in patients during excisional skin cancer surgery. It is possible that some subgroups may respond better or that patients may respond better when able to select and tailor their preferred anxiety reduction method.ClinicalTrials.gov identifier: NCT02816996.
Characteristics and survival of African American (AA) newly diagnosed multiple myeloma (NDMM) patients (Pts): A report from the Connect MM Registry.
Authors: Kathleen Toomey, Cristina Gasparetto, Jatin J. Shah, Rafat Abonour, Jayesh Mehta, Mohit Narang, Howard R. Terebelo, James W. Hardin, Shankar Srinivasan, Gail Larkins, Rosanna J. Ricafort, Yasir M. Nagarwala, Robert M. Rifkin
Journal: Journal of Clinical Oncology (2015)

e19529 Background: MM incidence in AA is twice that of Caucasians (CA) yet differences in disease biology and healthcare utilization may impact treatment (Tx) and outcomes in AA pts. Connect MM is a prospective, observational, US, multicenter registry designed to characterize the natural history and management of pts with NDMM in the era of novel Tx. Methods: From September 2009 to December 2011, 1493 pts with NDMM (diagnosed ≤ 2 mo before study entry) were enrolled at 234 sites. We analyzed data collected through June 30, 2014. Baseline pt and disease characteristics and initial Tx were assessed by multivariate analysis with outcomes to evaluate the impact of ethnicity. Results: Of 1,493 pts, 198 (13%) were AA and 1,223 (82%) were CA. AA pts were younger than CA (median, 64 vs 67 y) and a lower proportion was male (49% vs 59%). Differences between AA and CA pts were noted for Hb < 10 g/dL (60% vs 42%), diabetes history (Hx; 31% vs 16%), creatinine (sCr) > 2 mg/dL (24% vs 17.6%), hypertension Hx (68% vs 55%), and IMWG high-risk cytogenetics (12.2% vs 17.3%). Of pts initially treated with transplant intent, 35% (27/77) of AA and 46% (255/558) of CA received autologous stem cell transplant (ASCT) during first-line Tx. Most common initial Tx for AA vs CA pts were bortezomib/dexamethasone (BORT/DEX; 22% vs 20%), lenalidomide/DEX (LEN/DEX; 20% vs 16%) and LEN/BORT/DEX (19% vs 22%). AA and CA pts had similar 3-y survival (66% vs 65.3%). In AA pts, upfront Tx with ASCT correlated with a lower risk of death; diabetes Hx and Cr > 2mg/dL with higher risk (Table). Conclusions: AA pts are diagnosed at a younger age and have similar OS compared with CA pts despite differences in clinical practices, comorbidities, income, and receipt of transplant. Further research in this cohort is warranted to better understand potential disparities in biology, Tx utilization and outcomes. Correlation of baseline characteristics and estimate of hazard ratios of death for AA patients. Univariate Analysis Multivariate Analysis Estimate (95% CI) P Value Estimate (95% CI) P Value Upfront ASCT 0.21 (0.06 - 0.67) 0.008 0.26 (0.08 - 0.87) 0.029 Diabetes Hx 1.89 (1.12 - 3.20) 0.018 1.95 (1.13 - 3.36) 0.016 sCr > 2 mg/dL 3.58 (2.11- 6.07) < 0.001 2.15 (1.05 - 4.39) 0.036
Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies
Authors: Michael R. Savona, Kathryn Kolibaba, Paul Conkling, Edwin C. Kingsley, Carlos Becerra, John C. Morris, Robert M. Rifkin, Eric Laille, Amy Kellerman, Stacey M. Ukrainskyj, Qian Dong, Barry S. Skikne
Journal: American Journal of Hematology (2018)

CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.
Long-Term Outcomes of Childhood Left Ventricular Noncompaction Cardiomyopathy
Authors: William Y. Shi, Margarita Moreno-Betancur, Alan W. Nugent, Michael Cheung, Steven Colan, Christian Turner, Gary F. Sholler, Terry Robertson, Robert Justo, Andrew Bullock, Ingrid King, Andrew M. Davis, Piers E.F. Daubeney, Robert G. Weintraub
Journal: Circulation (2018)

Long-term outcomes for childhood left ventricular noncompaction (LVNC) are uncertain. We examined late outcomes for children with LVNC enrolled in a national population-based study.The National Australian Childhood Cardiomyopathy Study includes all children in Australia with primary cardiomyopathy diagnosed before 10 years of age between 1987 and 1996. Outcomes for subjects with LVNC with a dilated phenotype (LVNC-D) were compared with outcomes for those with dilated cardiomyopathy. Propensity-score analysis was used for risk factor adjustment.There were 29 subjects with LVNC (9.2% of all cardiomyopathy subjects), with a mean annual incidence of newly diagnosed cases of 0.11 per 100 000 at-risk individuals. Congestive heart failure was the initial symptom in 24 of 29 subjects (83%), and 27 (93%) had LVNC-D. The median age at diagnosis was 0.3 (interquartile interval, 0.08-1.3) years. The median duration of follow-up was 6.8 (interquartile interval, 0.7-24.0) years for all subjects and 24.7 (interquartile interval, 23.3 - 27.7) years for surviving subjects. Freedom from death or transplantation was 48% (95% confidence interval [CI], 30-65) at 10 years after diagnosis and 45% (95% CI, 27-63) at 15 years. In competing-risk analysis, 21% of subjects with LVNC were alive with normal left ventricular systolic function, and 31% were alive with abnormal function at 15 years. Propensity-score matching between subjects with LVNC-D and those with dilated cardiomyopathy suggested a lower freedom from death/transplantation at 15 years after diagnosis in the subjects with LVNC-D (LVNC-D, 46% [95% CI, 26-66] versus dilated cardiomyopathy, 70% [95% CI, 42-97]; P=0.08). Using propensity-score inverse probability of treatment-weighted Cox regression, we found evidence that LVNC-D was associated with a greater risk of death or transplantation (hazard ratio, 2.3; 95% CI, 1.4-3.8; P=0.0012).Symptomatic children with LVNC usually present in early infancy with a predominant dilated phenotype. Long-term outcomes are worse than for matched children with dilated cardiomyopathy.