Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We ...sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal).
CMR was performed in 230 genotyped HCM patients (48 ± 15 years, 69% male), 30 genotype-positive/phenotype-negative (G+/P-) family members (32 ± 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical-basal muscle bundle, which was resected in all patients.
Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status.
Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. ...Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.
JCO
The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional ...pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy-General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival (
= .53), disease-free survival (
= .21), or locoregional failure (
= .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT
15.1% CRT,
= .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT
8.6% CRT,
= .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT
-6.0, standard deviation = 14.3, CRT,
= .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.
Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this ...functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.
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•HSCs fail to recover functional potency after inflammatory/infection challenge•Discrete challenges have a cumulative effect, even if separated by weeks or months•Inflammation in early life accelerates the cellular and molecular aging of HSCs•Mice exposed to inflammation develop features of aged human hematopoiesis
Inflammation and infection acutely suppress HSC function. However, the long-term ramifications of such challenges are unclear. This study demonstrates that murine HSCs fail to recover functional potency up to 1 year post-inflammatory/infection challenge, meaning that such events can have accumulative effects over a lifetime; this promotes acquisition of the aged state.
Heterozygosity of
(
) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct ...allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines
heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where
heterozygote advantage occurs.
Men with high-risk features (extraprostatic extension or high Gleason grade) face a high risk of prostate cancer recurrence after radical prostatectomy. Clinical trials of adjuvant systemic therapy ...for such patients have been limited.
The SWOG (Southwest Oncology Group) S9921 study randomly assigned 983 men with high-risk features at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and bicalutamide for 2 years.
Although the final primary treatment comparison results are not ready for publication, this article reports results in the ADT-alone control arm with a median follow-up of 4.4 years. For these 481 men, the estimated 5-year biochemical failure-free survival is 92.5% (95% CI, 90 to 95), and 5-year overall survival is 95.9% (95% CI, 93.9 to 97.9).
The results of this trial, taken in context, make a compelling argument for counseling all high-risk patients with prostate cancer about adjuvant ADT. This article discusses the challenges in the design and implementation of clinical trials to take the next step forward in adjuvant therapy for prostate cancer because of the excellent survival achieved with currently available therapies and highlights the need for better molecular markers to personalize care.
Research suggests that children with conduct problems (CP) and callous-unemotional (CU) traits show a diminished response to behavior therapy, perhaps due to a reward-oriented, punishment insensitive ...learning style. Children with CP and CU may benefit from personalizing behavioral treatment for them by emphasizing rewards and de-emphasizing punishments. This hypothesis was tested in a sample of 46 children (78.3% boys), ages 7.0 to 12.6 years (M = 9.3, SD = 1.4). All participants met criteria for ODD and ADHD and 63% also met criteria for CD. Participants were oversampled for high CU, but CU scores ranged from average to high. Children received four weeks of modified behavior therapy that emphasized rewards and de-emphasized punishments and four weeks of treatment as usual, which was standard behavior therapy that balanced rewards and punishments. Treatments were implemented in a summer treatment program and compared using a within-subjects design, with order of treatment counterbalanced. Disruptive behavior was equal or slightly higher in modified behavior therapy than in standard behavior therapy on point system measures, but lower on parent weekly ratings. End of treatment ratings showed both treatments produced significant improvements compared to pre-treatment ratings but did not differ from each other. Personalizing behavior therapy for children with CP and CU produced inconsistent findings relative to standard behavior therapy. Behavior therapy is likely to be a necessary part of treatment for children with CP and CU, but treatment personalization efforts may provide some benefit by addressing other deficits shown by these children.
Opioids prescribed for acute pain after total knee arthroplasty (TKA) play a contributing role in the number of opioid pills in circulation. At the height of an opioid epidemic in the United States, ...opioids are increasingly diverted, misused, and abused. Therefore, many states have enacted narcotic regulations in an attempt to curb opioid diversion and misuse. The purpose of this study is to evaluate the effect of stricter state prescribing regulations on opioid consumption following TKA.
In total, 165 opioid-naive patients undergoing primary unilateral TKA at a single institution with a standardized perioperative pain protocol were reviewed. Seventy-one patients (group 1) resided in a state with strict opioid regulations that limit the initial number of pills dispensed and refills, whereas 92 patients (group 2) resided in another state without quantity and refill regulations. Patient demographics were similar between the 2 groups. Mean age was 64 and mean body mass index was 32 kg/m2. Opioid consumption, quantity, and refill patterns were collected for 6 weeks following surgery.
The average oral morphine equivalents consumed during the 6 weeks postsurgery were significantly lower in group 1 at 446.3 ± 266.3 mg (range 10-992) compared to group 2 at 622.6 ± 313.7 mg (range 20-1416) (P < .001). The average oral morphine equivalent corresponds to 60 tablets of 5 mg oxycodone per patient in group 1 vs 84 tablets per patient in group 2. Fifty-nine (83%) patients in group 1 had stopped taking opioids within 6 weeks of surgery compared to 59 (64%) in group 2 (P = .04).
Based on our results, the institution of state regulations aimed at decreasing the quantity and refills of postoperative opioids led patients to consume less opioids following TKA. Many patients are prescribed more opioids than they require which increases their consumption and can increase the risk for diversion, addiction, and misuse.
Level III; retrospective comparative cohort study.
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