by
Leonard J Appleman;
Jan H Beumer;
Yixing Jiang;
Yan Lin;
Fei Ding;
Shannon Puhalla;
Leigh Swartz;
Taofeek Owonikoko;
R. Harvey;
Ronald Stoller;
Daniel P Petro;
Hussein A Tawbi;
Athanassios Argiris;
Sandra Strychor;
Marie Pouquet;
Brian Kiesel;
Alice P Chen;
David Gandara;
Chandra P Belani;
Edward Chu;
Suresh Ramalingam
Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1–7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard “3 + 3” design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC–MS/MS and AAS during cycles 1 and 2. Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1–16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.
Acne vulgaris is a common skin disease affecting adolescents and young adults of all ethnic groups, negatively impacting self-esteem, self-confidence, and social life. The Gram-positive bacteria Cutibacterium acnes colonizes the sebum-rich follicle and contributes to inflammation of the pilosebaceous gland. Long-term antibiotic therapies targeting C. acnes lead to the development of antimicrobial resistance, and novel acne vulgaris therapies are needed. This study investigated the C. acnes inhibitory activity of Callicarpa americana leaves, a native Southeastern United States shrub historically used by Native Americans to treat fever, stomachache, and pruritis. Flash chromatography fractions of the ethyl acetate-soluble C. americana ethanol leaf extract (649C-F9 and 649C-F13) exhibited MICs ranging from 16 to 32 µg ml−1 and IC50 range of 4-32 μg ml−1 against a panel of 10 distinct C. acnes isolates. Cytotoxicity against an immortalized human keratinocyte cell line (HaCaTs) skin was detected at more than eight times the dose required for growth inhibitory activity (IC50 of 256 μg ml−1 for 649C-F9 and IC50 of >512 μg ml−1 for 649C-F13). This work highlights the potential of C. americana leaf extracts as a cosmeceutical ingredient for the management of acne vulgaris. Further research is necessary to assess its mechanism of action and in vivo efficacy.
Background-—Current literature examining the prospective relationship between depression and other measures of negative affect with atrial fibrillation (AF) are limited. We determined the relationships of depression, anger, anxiety, and chronic stress with incident AF in a multiethnic cohort of middle-and older-aged adults. Methods and Results-—This analysis included 6644 MESA (Multi-Ethnic Study of Atherosclerosis) study participants who were free of AF at baseline. Depressive symptoms were assessed at baseline and defined as either a 20-item Center for Epidemiologic Studies Depression Scale score ≥16 or use of antidepressant medications. The Spielberger Trait Anger Scale, Spielberger Trait Anxiety Scale, and Chronic Burden Scale were also administered at baseline to assess anger, anxiety, and chronic stress, respectively. The primary outcome was incident AF, identified by follow-up study visit ECGs, hospital discharge diagnoses, or Medicare claims data. A total of 875 (13%) incident AF cases were detected over a median follow-up of nearly 13 years. A Center for Epidemiologic Studies Depression Scale score ≥16 (referent, Center for Epidemiologic Studies Depression Scale score <2) and antidepressant use were associated with a 34% and 36% higher risk of AF, respectively, in separate adjusted Cox proportional hazards analyses (hazard ratio, 1.34; 95% CI 1.04–1.74 for Center for Epidemiologic Studies Depression Scale ≥16; hazard ratio, 1.36; 95% CI, 1.04–1.77 for antidepressant use). No significant associations were observed for anger, anxiety, or chronic stress with development of AF. Conclusions-—Depressive symptoms are associated with an increased risk of incident AF. Further study into whether improving depressive symptoms reduces AF incidence is important.
by
Cortney R. Ballengee;
Subramaniam Kugathasan;
Jarod Prince;
Kajari Mondal;
Ryan W. Stidham;
Chunyan Liu;
Mi-Ok Kim;
Robert Baldassano;
Marla Dubinsky;
James Markowitz;
Neal Leleiko;
Jeffrey Hyams;
Lee Denson
Background & Aims: There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2). Methods: We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal–Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups. Results: The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71–0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55–0.83) and a specificity value of 0.83 (95% CI, 0.67–0.93). Conclusions: We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00790543.
Accurate identification of in vivo nonlinear, anisotropic mechanical properties of the aortic wall of individual patients remains to be one of the critical challenges in the field of cardiovascular biomechanics. Since only the physiologically loaded states of the aorta are given from in vivo clinical images, inverse approaches, which take into account of the unloaded configuration, are needed for in vivo material parameter identification. Existing inverse methods are computationally expensive, which take days to weeks to complete for a single patient, inhibiting fast feedback for clinicians. Moreover, the current inverse methods have only been evaluated using synthetic data. In this study, we improved our recently developed multi-resolution direct search (MRDS) approach and the computation time cost was reduced to 1~2 hours. Using the improved MRDS approach, we estimated in vivo aortic tissue elastic properties of two ascending thoracic aortic aneurysm (ATAA) patients from pre-operative gated CT scans. For comparison, corresponding surgically-resected aortic wall tissue samples were obtained and subjected to planar biaxial tests. Relatively close matches were achieved for the in vivo-identified and ex vivo-fitted stress-stretch responses. It is hoped that further development of this inverse approach can enable an accurate identification of the in vivo material parameters from in vivo image data.
Background: Medicare has a voluntary episodic payment model for Medicare beneficiaries that bundles payment for the index acute myocardial infarction (AMI) hospitalization and all post-discharge services for a 90-day follow-up period. The purpose of this study is to report on the types and frequency of readmissions and identify demographic and clinical factors associated with readmission of Medicare beneficiaries that survived their AMI hospitalization. Methods and Results: This retrospective study used the Inpatient Standard Analytical File for 2014. There were 143 286 Medicare beneficiaries with AMI who were discharged alive from 3619 hospitals. All readmissions occurring in any hospital within 90 days of the index AMI discharge date were identified. Of 143 286 Medicare beneficiaries discharged alive from their index AMI hospitalization, 28% (40 145) experienced at least 1 readmission within 90 days and 8% (11 477) had >1 readmission. Readmission rates were higher among Medicare beneficiaries who did not undergo a percutaneous coronary intervention in their index AMI admission (34%) compared with those that underwent a percutaneous coronary intervention (20.2%). Using all Medicare beneficiary's index AMI, 27 comorbid conditions were significantly associated with the likelihood of a Medicare beneficiary having a readmission during the follow-up period. The strongest clinical characteristics associated with readmissions were dialysis dependence, type 1 diabetes mellitus, and heart failure. Conclusions: This study provides benchmark information on the types of hospital readmissions Medicare beneficiaries experience during a 90-day AMI bundle. This paper also suggests that interventions are needed to alleviate the need for readmissions in high-risk populations, such as, those managed medically and those at risk of heart failure.
by
Maryam Y. Naim;
Heather M. Griffis;
Rita Burke;
Bryan McNally;
Lihai Song;
Robert A. Berg;
Vinay M. Nadkarni;
Kimberly Vellano;
David Markenson;
Richard N. Bradley;
Joseph W. Rossano
Background: Whether racial and neighborhood characteristics are associated with bystander cardiopulmonary resuscitation (BCPR) in pediatric out-of-hospital cardiac arrest (OHCA) is unknown. Methods and Results: An analysis was conducted of CARES (Cardiac Arrest Registry to Enhance Survival) for pediatric nontraumatic OHCAs from 2013 to 2017. An index (range, 0–4) was created for each arrest based on neighborhood characteristics associated with low BCPR (>80% black; >10% unemployment; <80% high school; median income, <$50 000). The primary outcome was BCPR. BCPR occurred in 3399 of 7086 OHCAs (48%). Compared with white children, BCPR was less likely in other races/ethnicities (black: adjusted odds ratio [aOR], 0.59; 95% CI, 0.52–0.68; Hispanic: aOR, 0.78; 95% CI, 0.66–0.94; and other: aOR, 0.54; 95% CI, 0.40–0.72). Compared with arrests in neighborhoods with an index score of 0, BCPR occurred less commonly for arrests with an index score of 1 (aOR, 0.80; 95% CI, 0.70–0.91), 2 (aOR, 0.75; 95% CI, 0.65–0.86), 3 (aOR, 0.52; 95% CI, 0.45–0.61), and 4 (aOR, 0.46; 95% CI, 0.36–0.59). Black children had an incrementally lower likelihood of BCPR with increasing index score while white children had an overall similar likelihood at most scores. Black children with an index of 4 were approximately half as likely to receive BCPR compared with white children with a score of 0. Conclusions: Racial and neighborhood characteristics are associated with BCPR in pediatric OHCA. Targeted CPR training for nonwhite, low-education, and low-income neighborhoods may increase BCPR and improve pediatric OHCA outcomes.
by
Maryann G. Delea;
Jedidiah S. Snyder;
Mulusew Belew;
Bethany Caruso;
Joshua V. Garn;
Gloria D. Sclar;
Mulat Woreta;
Kassahun Zewudie;
Abebe Gebremariam;
Matthew Freeman
Background: Unimproved water, sanitation, and hygiene (WASH) behaviors are key drivers of infectious disease transmission and influencers of mental well-being. While WASH is seen as a critical enabler of health, important knowledge gaps related to the content and delivery of effective, holistic WASH programming exist. Corresponding impacts of WASH on mental well-being are also underexplored. There is a need for more robust implementation research that yields information regarding whether and how community-based, demand-side interventions facilitate progressive and sustained adoption of improved sanitation and hygiene behaviors and downstream health impacts. The purpose of this protocol is to detail the rationale and design of a cluster-randomized trial evaluating the impact of a demand-side sanitation and hygiene intervention on sustained behavior change and mental well-being in rural and peri-urban Amhara, Ethiopia. Methods: Together with partners, we developed a theoretically-informed, evidence-based behavioral intervention called Andilaye. We randomly selected and assigned 50 sub-districts (kebeles) from three purposively selected districts (woredas); half to receive the Andilaye intervention, and half the standard of care sanitation and hygiene programming (i.e., community-led total sanitation and hygiene [CLTSH]). During baseline, midline, and endline, we will collect data on an array of behavioral factors, potential moderators (e.g., water and sanitation insecurity, collective efficacy), and our primary study outcomes: sanitation and hygiene behaviors and mental well-being. We will perform a process evaluation to assess intervention fidelity and related attributes. Discussion: While CLTSH has fostered sanitation and hygiene improvements in Ethiopia, evidence of behavioral slippage, or regression to unimproved practices in communities previously declared open defecation free exists. Other limitations of CLTSH, such as its focus on disgust, poor triggering, and over-saturation of Health Extension Workers have been documented. We employed rigorous formative research and practically applied social and behavioral theory to develop Andilaye, a scalable intervention designed to address these issues and complement existing service delivery within Ethiopia's Health Extension Program. Evidence from this trial may help address knowledge gaps related to scalable alternatives to CLTSH and inform sanitation and hygiene programming and policy in Ethiopia and beyond. Trial registration: This trial was registered with clinicaltrials.gov (NCT03075436) on March 9, 2017.
Background: The gut is hypothesized to be the "motor" of critical illness. Under basal conditions, the gut plays a crucial role in the maintenance of health. However, in critical illness, all elements of the gut are injured, potentially worsening multiple organ dysfunction syndrome. Main body: Under basal conditions, the intestinal epithelium absorbs nutrients and plays a critical role as the first-line protection against pathogenic microbes and as the central coordinator of mucosal immunity. In contrast, each element of the gut is impacted in critical illness. In the epithelium, apoptosis increases, proliferation decreases, and migration slows. In addition, gut barrier function is worsened via alterations to the tight junction, resulting in intestinal hyperpermeability. This is associated with damage to the mucus that separates the contents of the intestinal lumen from the epithelium. Finally, the microbiome of the intestine is converted into a pathobiome, with an increase in disease-promoting bacteria and induction of virulence factors in commensal bacteria. Toxic factors can then leave the intestine via both portal blood flow and mesenteric lymph to cause distant organ damage. Conclusion: The gut plays a complex role in both health and critical illness. Here, we review gut integrity in both health and illness and highlight potential strategies for targeting the intestine for therapeutic gain in the intensive care unit.
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Asha Moudgil;
Vikas R. Dharnidharka;
Daniel I. Feig;
Barry Warshaw;
Vidya Perera;
Bindu Murthy;
Mustimbo Roberts;
Martin S. Polinsky;
Robert B. Ettenger
Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12-17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein-Barr virus were enrolled; all completed the 6-month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C max ] and area under the serum concentration-time curve from time zero extrapolated to infinity [AUC 0-INF ] were 20% and 25%, respectively). Mean half-life (T 1/2 ) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady-state (V ss ) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.