Age-related estimates of aggregate g-ratio of white matter structures assessed using quantitative magnetic resonance neuroimaging.

The g-ratio, defined as the inner-to-outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g-ratio in the context of normative aging; characterizing regional and time-dependent cerebral changes in g-ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age-related differences in aggregate g-ratio, that is, g-ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U-shaped, relationship between aggregate g-ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age-related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g-ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g-ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g-ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations.

Is There Any Clinical Utility to Genetic Testing for Patients With Congenital Heart Disease?

Genetic diagnosis is becoming increasingly sophisticated, with the ability to identify even fine differences in patients with a wide variety of congenital heart lesions. Although we have an incomplete understanding of the clinical consequences of most genetic findings, some categories of mutations can have important implications for disease recurrence and prognosis. Consideration of the biology underlying a genetic deficiency, when known, can be useful in the clinical management of some patients.

Veterinarians' attitudes and practices regarding opioid-related vet shopping practices in tri-state Appalachian counties: an exploratory study.

BACKGROUND: The opioid crisis continues to grow in the United States with 46,700 drug overdose deaths due to opioids in 2017 alone. Vet shopping, the practice of soliciting veterinarians for prescription medications, has been receiving national media attention in recent years. A 2014 review of Prescription Monitoring Drug Programs found less than 10 veterinary shoppers nationwide. Still much is unknown about the role of vet shopping and the opioid crisis. This study sought to understand the practice of vet shopping through the eyes of veterinarians practicing in Appalachian counties within the states of Kentucky, Tennessee, and Virginia, United States. RESULTS: Fourteen veterinarians were asked a set of 13 questions related to vet shopping. Results indicated that 13 veterinarians in the study had heard of the phenomenon of vet shopping and eight veterinarians had personally encountered vet shopping in their practices. Qualitative analysis of the interviews identified six key themes including a need for interprofessional communication and how important a valid veterinary-client-patient-relationship is within the profession. CONCLUSIONS: The study hopefully sheds some light on the how often vet shopping is encountered in practice, concerns of veterinarians regarding vet shopping, and potential areas for improvement.

A Guide for Understanding Health Education and Promotion Programs.

Planning, Implementing & Evaluating Health Promotion Programs: A Primer is a versatile and comprehensive resource on the theoretical and practical underpinnings of successful health promotion programs. The requirements for effective health promotion program development are presented with frequent use of practical planning examples, pedagogical devices, and expert rationale. Ideal for undergraduate and graduate students in health education, promotion, and planning courses, this 15-chapter textbook is organized in a manner that specifically addresses the responsibilities and competencies required of health education specialists as published in the Health Education Specialist Practice Analysis of 2015. The authors of this textbook are leaders in the field and provide readers with the skills necessary to carry out the full process of health promotion program execution, while also offering direct preparation for CHES and MCHES licensing exams.

Exercise restriction is not associated with increasing body mass index over time in patients with anomalous aortic origin of the coronary arteries.

Anomalous aortic origin of the coronary arteries is associated with exercise-induced ischaemia, leading some physicians to restrict exercise in patients with this condition. We sought to determine whether exercise restriction was associated with increasing body mass index over time. From 1998 to 2015, 440 patients ⩽30 years old were enrolled into an inception cohort. Exercise-restriction status was documented in 143 patients. Using linear mixed model repeated-measures regression, factors associated with increasing body mass index z-score over time, including exercise restriction and surgical intervention as time-varying covariates, were investigated. The 143 patients attended 558 clinic visits for which exercise-restriction status was recorded. The mean number of clinic visits per patient was 4, and the median duration of follow-up was 1.7 years (interquartile range (IQR) 0.5-4.4). The median age at first clinic visit was 10.3 years (IQR 7.1-13.9), and 71% (101/143) were males. All patients were alive at their most recent follow-up. At the first clinic visit, 54% (78/143) were exercise restricted, and restriction status changed in 34% (48/143) during follow-up. The median baseline body mass index z-score was 0.2 (IQR 0.3-0.9). In repeated-measures analysis, neither time-related exercise restriction nor its interaction with time was associated with increasing body mass index z-score. Surgical intervention and its interaction with time were associated with decreasing body mass index z-score. Although exercise restriction was not associated with increasing body mass index over time, surgical intervention was associated with decreasing body mass index z-score over time in patients with anomalous aortic origin of the coronary arteries.

Targeted Systemic Therapies for Adults with Atopic Dermatitis: Selecting from Biologics and JAK Inhibitors.

Therapeutic options for people with moderate or severe atopic dermatitis refractory to topical therapy have rapidly expanded in recent years. These new targeted immunomodulatory agents-biologics and Janus kinase (JAK) inhibitors-have each demonstrated high levels of efficacy and acceptable safety in mostly placebo-controlled clinical trials for atopic dermatitis, but there is no universally applicable algorithm to help choose between them for a given patient. Hence, patients and physicians should utilize shared decision making, discussing efficacy, safety, mode of delivery, monitoring, costs, speed of onset, and other factors to reach individualized treatment decisions. In this review, we try to aid shared decision making by summarizing the efficacy, safety, and monitoring of biologics and oral JAK inhibitors for adults with atopic dermatitis. Network meta-analyses suggest that higher doses of abrocitinib and upadacitinib are more effective than biologics. They also show that, among biologics, dupilumab is likely more effective than tralokinumab and lebrikizumab. Biologics are generally considered safer than JAK inhibitors, although concerns about JAK inhibitors are mainly extrapolated from older generation JAK inhibitors used in higher-risk populations. We also outline evidence and considerations for choosing and using systemic immunomodulatory treatments for special populations including pregnant individuals, those with human immunodeficiency virus (HIV), hepatitis B and C, end stage kidney disease, and older adults.

Ross Procedure in Children: The Society of Thoracic Surgeons Congenital Heart Surgery Database Analysis.

BACKGROUND: Single-center studies have demonstrated excellent results for the Ross procedure in children. We aimed to evaluate national variation in clinical outcomes using The Society of Thoracic Surgeons Congenital Heart Surgery Database. METHODS: The database was used to identify 2805 children undergoing the Ross procedure from 2000 through 2018, comprising 163 neonates (<30 days, 5.8%), 448 infants (30-365 days, 16.0%), 1444 children (1-12 years, 51.5%), and 750 teenagers (13-17 years, 26.7%). Centers were divided into terciles by procedural volume. Multivariable logistic regression was used to identify predictors of a composite outcome of operative mortality, neurologic deficit, or renal failure requiring dialysis. RESULTS: Neonates and infants were more likely to present with aortic stenosis than children and teenagers (61.7% [n = 377] vs 34.6% [n = 760]; P < .01) and have risk factors including preoperative shock (9.2% [n = 56] vs 0.4% [n = 8]; P < .01). Operative mortality was 24.1% (n = 39) in neonates, 11.2% (n = 50) in infants, 1.5% (n = 21) in children , and 0.8% (n = 6) in teenagers (P < .01). Independent predictors of the composite outcome in children aged <1 year included neonatal age (odds ratio [OR], 3.0; 95% CI, 1.9-4.8), low-volume center (OR, 2.1; 95% CI, 1.1-3.9), and procedure year (OR, 0.7; 95% CI, 0.5-0.9 per 5 years). In children aged ≥1 year, no association was found between center volume, procedure year, and outcome. CONCLUSIONS: The Ross procedure is being performed with low mortality in children aged ≥1 year throughout North America. High-volume centers have improved outcomes in children aged <1 year, who have different anatomic characteristics and risk profiles.

Predisposing, enabling and reinforcing factors associated with opioid addiction helping behaviour in tri-state Appalachian counties: application of the PRECEDE-PROCEED model-cross-sectional analysis.

OBJECTIVES: The overdose epidemic was designated a 'Public Health Emergency' in the USA on 26 October 2017, bringing attention to the severity of this public health problem. The Appalachian region remains substantially impacted by the effects from years of overprescription of opioids, and subsequently opioid non-medical use and addiction. This study aims to examine the utility of the PRECEDE-PROCEED model constructs (ie, predisposing, reinforcing and enabling factors) to explain opioid addiction helping behaviour (ie, helping someone who has an opioid addiction) among members of the public living in tri-state Appalachian counties. DESIGN: Cross-sectional study. SETTING: Rural county in the Appalachian region of the USA. PARTICIPANTS: A total of 213 participants from a retail mall in a rural Appalachian Kentucky county completed the survey. Most participants were between the ages of 18 and 30 years (n=68; 31.9%) and identified as men (n=139; 65.3%). PRIMARY OUTCOME MEASURE: Opioid addiction helping behaviour. RESULTS: The regression model was significant (F (6, 180)=26.191, p<0.001) and explained 44.8% of the variance in opioid addiction helping behaviour (R2=0.448). Attitude towards helping someone with opioid addiction (B=0.335; p<0.001), behavioural skills (B=0.208; p=0.003), reinforcing factors (B=0.190; p=0.015) and enabling factors (B=0.195; p=0.009) were all significantly associated with opioid addiction helping behaviour. CONCLUSIONS: PRECEDE-PROCEED model constructs have utility to explain opioid addiction helping behaviour among individuals in a region greatly impacted by the overdose epidemic. This study provides an empirically tested framework for future programmes addressing helping behaviour related to opioid non-medical use.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling.

MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.

Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac surgery.

Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.

Cerebral aggregate g-ratio mapping using magnetic resonance relaxometry and diffusion tensor imaging to investigate sex and age-related differences in white matter microstructure.

Axonal demyelination is a cardinal feature of aging and age-related diseases. The g-ratio, mathematically defined as the inner-to-outer diameter of a myelinated axon, is used as a structural index of optimal axonal myelination and has been shown to represent a sensitive imaging biomarker of microstructural integrity. Several magnetic resonance imaging (MRI) methods for whole-brain mapping of aggregate g-ratio have been introduced. Computation of the aggerate g-ratio requires estimates of the myelin volume fraction (MVF) and the axonal volume fraction (AVF). While accurate determinations of MVF and AVF can be obtained through multicomponent relaxometry or diffusion analyses, respectively, these methods require lengthy acquisition times making their implementation challenging in a clinical context. Therefore, any attempt to overcome this drawback is needed. Expanding on our previous work, we introduced a new MRI method for whole-brain mapping of aggregate g-ratio. This new approach is based on the use of a single-shell diffusion for AVF determination, reducing the acquisition time by approximately ~10 min from our recently introduced approach, while offering the possibility to investigate g-ratio differences in previous studies with existing data for MVF mapping and single-shell diffusion data for AVF mapping. Our comparison analysis indicates that our newly derived aggregate g-ratio values were similar to those derived from our previous method, which requires a longer acquisition time. Further, in agreement with our previous observations, we found quadratic U-shaped relationships between aggregate g-ratio and age in this much larger study cohort. However, our results show that sexual dimorphism in g-ratio was not significant in any brain region investigated.

Resident education in congenital heart surgery does not compromise outcomes.

OBJECTIVE: Most of all congenital cardiac surgical programs participate in public outcomes reporting. The primary end point is transparency. In this era, academic programs with surgical residents face the challenge of producing outstanding results while allowing residents to learn by doing. We sought to understand the effect of education on our surgical outcomes. METHODS: We collected data for all American Board of Thoracic Surgery index cases done at our institution over a 10-year period. We identified 3406 cases and categorized them into 2 groups according to primary surgeon: attending (2269) versus resident (1137). In a multivariable logistic regression model we examined the effect of operating surgeon on in-hospital mortality, major morbidity, and length of stay. We used propensity score matching subsequently to balance differences between cohorts, and multivariable logistic regression was repeated. RESULTS: Using the entire cohort, multivariable logistic regression model adjusted for age, sex, weight, lack of preoperative comorbidity, presence of preoperative respiratory failure, The Society of Thoracic Surgeons--European Association for Cardio-Thoracic Surgery category, and need for deep hypothermic circulatory arrest, showed a higher odds of survival in the resident cohort (odds ratio, 1.484; 95% confidence interval, 0.998-2.206; P = .05). Propensity score matching identified 1137 pairs of attending and resident cases with well-balanced preoperative variables. Logistic regression modeling using the matched cohort showed equivalent 30-day mortality, 30-day major morbidity, and length of stay. CONCLUSIONS: There was no difference in mortality, major morbidity, or length of stay when similar cases were compared that were operated on by attendings versus those by a resident. Effectively educating congenital heart surgeons without compromising an operation's quality requires thoughtful approach, including case selection and graded responsibility.

Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or Obesity.

BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD. METHODS: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03×10-11), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures. REGISTRATION: URL: https://clinicaltrials.gov; NCT01196182.

Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study.

OBJECTIVE: To determine the incidence, severity, and risk factors of acute kidney injury in children undergoing cardiac surgery for congenital heart defects. DESIGN: Prospective observational multicenter cohort study. SETTING: Three pediatric intensive care units at academic centers. PATIENTS: Three hundred eleven children between the ages of 1 month and 18 yrs undergoing pediatric cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined as a ≥50% increase in serum creatinine from the preoperative value. Secondary outcomes were length of mechanical ventilation, length of intensive care unit and hospital stays, acute dialysis, and in-hospital mortality. The cohort had an average age of 3.8 yrs and was 45% women and mostly white (82%). One-third had prior cardiothoracic surgery, 91% of the surgeries were elective, and almost all patients required cardiopulmonary bypass. Acute kidney injury occurred in 42% (130 patients) within 3 days after surgery. Children ≥2 yrs old and <13 yrs old had a 72% lower likelihood of acute kidney injury (adjusted odds ratio: 0.28, 95% confidence interval: 0.16, 0.48), and patients 13 yrs and older had 70% lower likelihood of acute kidney injury (adjusted odds ratio: 0.30, 95% confidence interval: 0.10, 0.88) compared to patients <2 yrs old. Longer cardiopulmonary bypass time was linearly and independently associated with acute kidney injury. The development of acute kidney injury was independently associated with prolonged ventilation and with increased length of hospital stay. CONCLUSIONS: Acute kidney injury is common after pediatric cardiac surgery and is associated with prolonged mechanical ventilation and increased hospital stay. Cardiopulmonary bypass time and age were independently associated with acute kidney injury risk. Cardiopulmonary bypass time may be a marker for case complexity.

Sex and age-related differences in cerebral blood flow investigated using pseudo-continuous arterial spin labeling magnetic resonance imaging.

Adequate cerebral blood flow (CBF) is essential to a healthy central nervous system (CNS). Previous work suggests that CBF differs between men and women, and declines with age and certain pathologies, but a highly controlled systematic study across a wide age range, and incorporating white matter (WM) regions, has not been undertaken. Here, we investigate age- and sex-related differences in CBF in gray matter (GM) and WM regions in a cohort (N = 80) of cognitively unimpaired individuals over a wide age range. In agreement with literature, we find that GM regions exhibited lower CBF with age. In contrast, WM regions exhibited higher CBF with age in various cerebral regions. We attribute this new finding to increased oligodendrocyte metabolism to maintain myelin homeostasis in the setting of increased myelin turnover with age. Further, consistent with prior studies, we found that CBF was higher in women than in men in all brain structures investigated. Our work provides new insights into the effects of age and sex on CBF. In addition, our results provide reference CBF values for the standard ASL protocol recommended by the ISMRM Perfusion Study Group and the European ASL in Dementia consortium. Thus, these results provide a foundation for further investigations of CNS perfusion in a variety of settings, including aging, cerebrovascular diseases, and dementias.