A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.

The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

Recovery from aphasia in the first year after stroke.

Most individuals who experience aphasia after a stroke recover to some extent, with the majority of gains taking place in the first year. The nature and time course of this recovery process is only partially understood, especially its dependence on lesion location and extent, which are the most important determinants of outcome. The aim of this study was to provide a comprehensive description of patterns of recovery from aphasia in the first year after stroke. We recruited 334 patients with acute left hemisphere supratentorial ischaemic or haemorrhagic stroke and evaluated their speech and language function within 5 days using the Quick Aphasia Battery (QAB). At this initial time point, 218 patients presented with aphasia. Individuals with aphasia were followed longitudinally, with follow-up evaluations of speech and language at 1 month, 3 months, and 1 year post-stroke, wherever possible. Lesions were manually delineated based on acute clinical MRI or CT imaging. Patients with and without aphasia were divided into 13 groups of individuals with similar, commonly occurring patterns of brain damage. Trajectories of recovery were then investigated as a function of group (i.e. lesion location and extent) and speech/language domain (overall language function, word comprehension, sentence comprehension, word finding, grammatical construction, phonological encoding, speech motor programming, speech motor execution, and reading). We found that aphasia is dynamic, multidimensional, and gradated, with little explanatory role for aphasia subtypes or binary concepts such as fluency. Patients with circumscribed frontal lesions recovered well, consistent with some previous observations. More surprisingly, most patients with larger frontal lesions extending into the parietal or temporal lobes also recovered well, as did patients with relatively circumscribed temporal, temporoparietal, or parietal lesions. Persistent moderate or severe deficits were common only in patients with extensive damage throughout the middle cerebral artery distribution or extensive temporoparietal damage. There were striking differences between speech/language domains in their rates of recovery and relationships to overall language function, suggesting that specific domains differ in the extent to which they are redundantly represented throughout the language network, as opposed to depending on specialized cortical substrates. Our findings have an immediate clinical application in that they will enable clinicians to estimate the likely course of recovery for individual patients, as well as the uncertainty of these predictions, based on acutely observable neurological factors.

Gluteal compartment syndrome: who is most at risk?

PURPOSE: Gluteal compartment syndrome (GCS) is a rare but devastating condition with a paucity of literature to help guide diagnosis and management. This study aims to identify and describe the risk factors and patient characteristics associated with GCS to facilitate early diagnosis. METHODS: This is a retrospective case series of patients undergoing gluteal compartment release between 2015 and 2022 at an academic Level I trauma center. Chart reviews were performed to extract data on patient demographics, presenting symptoms, risk factors, operative findings, and postoperative outcomes. RESULTS: 14 cases of GCS were identified. 12 (85.7%) were male, with a mean age of 39.4 ± 13 years and a mean BMI of 25.1 ± 4.1 kg/m2. 12 (85.7%) patients did not present as traumas and only 3 had ≥ 1 fracture. 9 patients reported drug use. Hemoglobin (Hgb) (11.7 ± 4 g/dL) was generally low (5 had Hgb < 10 g/dL). Creatine kinase (49,617 ± 60,068 units/L) was consistently elevated in all cases, and lactate (2.8 ± 1.6 mmol/L) was elevated in 9. 13 had non-viable muscle requiring debridement. Postoperatively, the mean ICU length of stay was 12 ± 23 days. 2 patients died during admission and all remaining patients required discharge to rehabilitation facilities. CONCLUSION: GCS is more likely to present in a young to middle-aged, otherwise healthy, male using drugs who is either found down or experienced an iatrogenic injury. Recognizing that GCS is different from that of the leg, in terms of etiology, may help avoid delays in diagnosis and treatment.

Vascular space occupancy asymmetric spin echo (VASO-ASE) for non-invasive quantification of cerebral oxygen extraction fraction.

PURPOSE: Asymmetric spin echo (ASE) MRI is a method for measuring regional oxygen extraction fraction (OEF); however, extravascular tissue models have been shown to under-estimate OEF. The hypothesis investigated here is that the addition of a vascular-space-occupancy (VASO) pre-pulse will more fully suppress blood water signal and provide global OEF values more consistent with physiological expectation and 15 O positron emission tomography (PET)-validated T2 -relaxation-under-spin-tagging (TRUST) OEF measures. METHODS: Healthy adults (n = 14; age = 27.7 ± 5.2 y; sex = 7/7 male/female) were scanned at 3.0T. Multi-echo ASE without inter-readout refocusing (ASERF- ), multi-echo ASE with inter-readout refocusing (ASERF+ ), and single-echo VASO-ASE were acquired twice each with common spatial resolution = 3.44 × 3.44 × 3.0 mm and τ = 0-20 ms (interval = 0.5 ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG  = 10 ms; effective TEs = 0, 40, 80, and 160 ms; spatial resolution = 3.4 × 3.4 × 5 mm). OEF intraclass-correlation-coefficients (ICC), summary statistics, and group-wise differences were assessed (Wilcoxon rank-sum; significance: two-sided p < 0.05). RESULTS: ASERF+ (OEF = 36.8 ± 1.9%) and VASO-ASE (OEF = 34.4 ± 2.3%) produced OEF values similar to TRUST (OEF = 36.5 ± 4.6%, human calibration model; OEF = 32.7 ± 4.9%, bovine calibration model); however, ASERF- yielded lower OEF (OEF = 26.1 ± 1.0%; p < 0.01) relative to TRUST. VASO-ASE (ICC = 0.61) yielded lower ICC compared to other ASE variants (ICC >0.89). CONCLUSION: VASO-ASE and TRUST provide similar OEF values; however, VASO-ASE spatial coverage and repeatability improvements are required.

What Factors Are Associated With Delayed Wound Closure in Open Reduction and Internal Fixation of Adult Both-bone Forearm Fractures?

BACKGROUND: Delayed wound closure is often used after open reduction and internal fixation (ORIF) of both-bone forearm fractures to reduce the risk of skin necrosis and subsequent infection caused by excessive swelling. However, no studies we are aware of have evaluated factors associated with the use of delayed wound closure after ORIF. QUESTIONS/PURPOSES: (1) What proportion of patients undergo delayed wound closure after ORIF of adult both-bone forearm fractures? (2) What factors are associated with delayed wound closure? METHODS: The medical records of all patients who underwent ORIF with plate fixation for both-bone fractures by the adult orthopaedic trauma service at our institution were considered potentially eligible for analysis. Between January 2010 and April 2022, we treated 74 patients with ORIF for both-bone forearm fractures. Patients were excluded if they had fractures that were fixed more than 2 weeks from injury (six patients), if their fracture was treated with an intramedullary nail (one patient), or if the patient experienced compartment syndrome preoperatively (one patient). No patients with Gustilo-Anderson Type IIIB and C open fractures were included. Based on these criteria, 89% (66 of 74) of the patients were eligible. No further patients were excluded for loss of follow-up because the primary endpoint was the use of delayed wound closure, which was performed at the time of ORIF. However, one further patient was excluded for having bilateral forearm fractures to ensure that each patient had a single fracture for statistical analysis. Thus, 88% (65 of 74) of patients were included in the analysis. These patients were captured by an electronic medical record search of CPT code 25575. The mean ± SD age was 34 ± 15 years and mean BMI was 28 ± 7 kg/m 2 . The mean follow-up duration was 4 ± 5 months. The primary endpoint was the use of delayed wound closure, which was determined at the time of definitive fixation if tension-free closure could not be achieved. All surgeons used a volar Henry or modified Henry approach and a dorsal subcutaneous approach to the ulna for ORIF. Univariate logistic regression was used to identify which factors might be associated with delayed wound closure. A multivariable logistic regression analysis was then performed for male gender, open fractures, age, and BMI. RESULTS: Twenty percent (13 of 65) of patients underwent delayed wound closure, 18% (12 of 65) of which occurred in patients who had high-energy injuries and 14% (nine of 65) in patients who had open fractures. Being a man (adjusted odds ratio 9.9 [95% confidence interval 1 to 87]; p = 0.04) was independently associated with delayed wound closure, after adjusting for open fractures, age, and BMI. CONCLUSION: One of five patients had delayed wound closure after ORIF of both-bone forearm fractures. Being a man was independently associated with greater odds of delayed wound closure. Surgeons should counsel all patients with these fractures about the possibility of delayed wound closure, with particular attention to men with high-energy and open fractures. Future larger-scale studies are necessary to confirm which factors are associated with the use of delayed wound closure in ORIF of both-bone fractures and its effects on fracture healing. LEVEL OF EVIDENCE: Level III, therapeutic study.

Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.

OBJECTIVE: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T1-weighted imaging for quantifying gray matter volumes and T2-weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (ß=-3.6 [mm3/y]/[m/s]; [95% CI, -7.2 to -0.02] P=0.049) and occipital lobe (ß=-34.2 [mm3/y]/[m/s]; [95% CI, -67.8 to -0.55] P=0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (ß=17.0 [mm3/y]/[m/s]; [95% CI, 7.2-26.9] P<0.001). All associations may be driven by outliers. CONCLUSIONS: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Mixed methods analysis of factors influencing change in clinical behaviours of non-physician anaesthetists in Kenya following obstetric anaesthesia training.

Maternal mortality rates in low-middle income countries remain high, with sub-Saharan Africa accounting for two-thirds of global maternal deaths. Inadequate staff training is one of the main contributors to anaesthesia-related deaths and the Association of Anaesthetists developed the Safe Anaesthesia from Education course in collaboration with the World Federation of Societies of Anaesthesiologists to address this training gap. We aimed to evaluate the impact of this course among Kenyan participants. Mixed methodologies and secondary analyses of anonymised data were used to study translation of learning into practice. In total, 103 participants from 66 facilities who attended courses between 2016 and 2017 were analysed. Ninety (87%) participants who were followed up completed knowledge tests. Baseline median (IQR [range]) knowledge test score was 41 (37-43 [21-46]). There was a significant improvement in median (IQR [range]) knowledge test score immediately post-course (43 (41-45 [33-48]); p < 0.001) which was sustained at 3-6 month follow-up (43 (41-45 [32-50]); p < 0.001 compared with baseline). Eighty-four of the 103 participants were observed in their workplace and capability, opportunity and motivation-behaviour framework was used to study the barriers and facilitators to practice change. Psychological capability and reflective motivation were the main factors enabling positive behaviour change such as team communication and pre-operative assessment, whereas physical and social opportunity accounted for the main barriers to behaviours such as performing the surgical safety checklist. Our study demonstrates that the Safe Anaesthesia from Education obstetric course is relevant in the low-resource setting and may lead to knowledge translation in clinical practice.

Development of a brief learning environment measure for use in healthcare professions education: the Healthcare Education Micro Learning Environment Measure (HEMLEM).

BACKGROUND: The learning environment impacts many aspects of healthcare education, including student outcomes. Rather than being a single and fixed phenomenon, it is made up of multiple micro learning environments. The standard clinical learning environment measurement tools do not consider such diversity and may fail to adequately capture micro learning environments. Moreover, the existing tools are often long and may take a prohibitive amount of time to complete properly. This may have a negative impact on their usefulness in educational improvement strategies. In addition, there is no universal tool available which could be utilised across several healthcare student groups and placement settings. AIM: To create an evidence-based measurement tool for assessing clinical micro learning environments across several healthcare profession student groups. METHODS: The measurement tool was developed through a step-wise approach: 1) literature review with iterative analysis of existing tools; 2) generation of new items via thematic analysis of student experiences; 3) a Delphi process involving healthcare educators; 4) piloting of the prototype; and 5) item reduction. RESULTS: The literature review and experiential data from healthcare students resulted in 115 and 43 items respectively. These items were refined, leaving 75 items for the Delphi process, which produced a prototype with 57 items. This prototype was then completed by 257 students across the range of healthcare professions, with item reduction resulting in a 12-item tool. CONCLUSION: This paper describes a mixed methods approach to developing a brief micro learning environment measurement tool. The generated tool can be used for measuring student perceptions of clinical environments across several healthcare professions. Further cross-cultural and cross-professional validation studies are needed to support widespread use, possibly through mobile application.

Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.

BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72±7 years; 59% male) or mild cognitive impairment (n=115; age, 73±7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 ( APOE ε4) status, and regional tissue volume. Models were repeated testing PWV× APOE ε4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation. RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (ß=-0.43; P=0.04) and higher CVR in the whole brain (ß=0.11; P=0.02), frontal lobes (ß=0.12; P<0.05), temporal lobes (ß=0.11; P=0.02), and occipital lobes (ß=0.14; P=0.01). Among APOE ε4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole-brain CBF (ß=-1.16; P=0.047), lower temporal lobe CBF (ß=-1.81; P=0.004), and higher temporal lobe CVR (ß=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (ß=-0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE ε4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (ß=-1.20; P=0.02). CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis.

Kawasaki disease (KD) vasculitis is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin, and is the most common cause of acquired heart disease among children in the United States. While  histological evidence of myocarditis can be found in all patients with acute KD, only a minority of patients are clinically symptomatic and a subset demonstrate echocardiographic evidence of impaired myocardial function, as well as increased left ventricular mass, presumed to be due to myocardial edema and inflammation. Up to a third of KD patients fail to respond to first-line therapy with intravenous immunoglobulin (IVIG), and the use of interleukin (IL)-1 receptor antagonist (IL-1Ra, anakinra) is currently being investigated as an alternative therapeutic approach to treat IVIG-resistant patients. In this study, we sought to investigate the effect of IL-1Ra on myocardial dysfunction and its relation to myocarditis development during KD vasculitis. We used the Lactobacillus casei cell-wall extract (LCWE)-induced murine model of KD vasculitis and investigated the effect of IL-1Ra pretreatment on myocardial dysfunction during KD vasculitis by performing histological, magnetic resonance imaging (MRI) and echocardiographic evaluations. IL-1Ra pretreatment significantly reduced KD-induced myocardial inflammation and N-terminal pro B-type natriuretic peptide (NT-proBNP) release. Both MRI and echocardiographic studies on LCWE-injected KD mice demonstrated that IL-1Ra pretreatment results in an improved ejection fraction and a normalized left ventricular function. These findings further support the potential beneficial effects of IL-1Ra therapy in preventing the cardiovascular complications in acute KD patients, including the myocarditis and myocardial dysfunction associated with acute KD.

Population-based study of the prevalence and management of self-reported high pain scores in patients with non-resected pancreatic adenocarcinoma.

BACKGROUND: Pain is a common debilitating symptom in pancreatic adenocarcinoma. This cohort study examined the use of, and factors associated with, pain-directed interventions for a high pain score in patients with non-curable pancreatic adenocarcinoma. METHODS: Administrative databases were linked and patients with non-resected pancreatic adenocarcinoma diagnosed between 2010 and 2016, who reported one or more Edmonton Symptom Assessment System (ESAS) score, were identified. A high pain score was defined as an ESAS score of at least 4. Outcomes were pain-directed interventions: opiates (in patients aged 65 years or more with universal drug coverage), nerve block and radiation therapy for a high pain score. Reduction in pain score of at least 1 point after pain-directed intervention was also evaluated. Modified Poisson regression was used to examine factors associated with pain-directed intervention. RESULTS: Among 2623 patients with a median age of 67 years, 1223 (46·6 per cent) were women, and 1621 (61·8 per cent) reported a high pain score at a median of 38 days after diagnosis. Of those with a high pain score, 75·6 per cent (688 of 910) received opiates, 13·5 per cent (219 of 1621) radiation and 1·2 per cent (19 of 1621) nerve block. The pain score decreased in 62·1 per cent of patients after administration of opiates, 73·4 per cent after radiation and all patients after nerve block. In multivariable analysis, no patient factor (age, sex, co-morbidity burden, rurality, income quintile) was associated with receipt of non-opiate pain-directed intervention for a high pain score. In patients aged at least 65 years, advanced age was associated with lower odds of opiate use. CONCLUSION: Opiates are the most common pain-directed intervention for non-curable pancreatic adenocarcinoma, whereas radiation therapy and nerve blocks are seldom used. The lack of association between pain-directed interventions and patient factors points toward practice-driven patterns.

ANTECEDENTES: El dolor es un síntoma debilitante frecuente en el adenocarcinoma de páncreas. Este estudio de cohortes examinó el uso de las intervenciones dirigidas para el tratamiento del dolor y los factores asociados a las mismas en pacientes con adenocarcinoma pancreático incurable que presentaban puntuaciones altas de dolor. MÉTODOS: Se revisaron las bases de datos administrativas y se identificaron los pacientes con adenocarcinoma pancreático no resecado diagnosticados entre 2010-2016 con puntuaciones > 1 del Sistema de Evaluación de Síntomas de Edmonton (Edmonton Symptom Assessment System, ESAS). La puntuación alta de dolor se definió como ESAS > 4. Los resultados evaluados fueron las intervenciones dirigidas contra el dolor: opiáceos (en pacientes mayores de 65 años con cobertura universal de medicamentos), bloqueo nervioso y radioterapia en el caso de puntuación alta del dolor. También se evaluó la reducción en la puntuación del dolor (> 1 punto) después de la intervención dirigida contra el dolor. Los factores asociados a la intervención contra el dolor se analizaron mediante una regresión de Poisson modificada. RESULTADOS: De los 2.623 pacientes con una mediana de edad de 67 años, 1.223 (46,6%) eran mujeres, y 1.621 (61.8%) presentaron una puntuación alta de dolor con una mediana de 38 días desde el momento del diagnóstico. De aquellos con puntuación alta de dolor, el 75,6% recibió opiáceos (n = 688/910), el 13,5% radiación (n = 219/1.621) y el 1,2% bloqueo nervioso (n = 19/1.621). La puntuación del dolor disminuyó en el 62,2% después del tratamiento con los opiáceos, en el 73,8% después de la radiación y en el 100% después del bloqueo nervioso. En el análisis multivariable, ningún factor relacionado con el paciente (edad, sexo, comorbilidades, vivir en una zona rural, quintil de ingresos) se asoció con una intervención dirigida contra dolor sin opiáceos en los casos de puntuación alta del dolor. En pacientes mayores de 65 años, la edad avanzada se asoció con menor probabilidad de uso de opiáceos. CONCLUSIÓN: Mientras que los opiáceos son la intervención dirigida contra dolor más común para el adenocarcinoma pancreático no resecable, la radioterapia y el bloqueo nervioso rara vez se usan. La falta de asociación de las intervenciones dirigidas contra el dolor con los factores del paciente apunta hacia el uso de patrones terapéuticos basados ​​en la práctica clínica.

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.

BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

Vessel wall and lumen characteristics with age in healthy participants using 3T intracranial vessel wall magnetic resonance imaging.

BACKGROUND: Intracranial vessel wall imaging (VWI) at a clinical field strength of 3T has become more widely available. However, how vessel measurements change with age and sex, over an age range spanning a typical lifespan, are needed. PURPOSE/HYPOTHESIS: To assess for identifiable changes in arterial wall thickness, outer vessel wall diameter, and lumen diameter with age cross-sectionally in healthy controls without cerebrovascular disease risk factors at the spatial resolution afforded by currently recommended 3T VWI approaches. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy subjects (n = 82; age = 8-79 years). FIELD STRENGTH/SEQUENCE: 3T intracranial VWI, angiography, and T1 -weighted anatomical imaging. ASSESSMENT: Two readers measured lumen and outer wall diameters of the supraclinoid internal carotid artery (ICA) and distal basilar artery. Wall thickness and intraclass correlation coefficients (ICCs) were calculated. STATISTICAL TESTS: Separate linear regressions were performed to understand the relationship between wall measurements (lumen diameter, outer vessel wall diameter, and wall thickness) and age, gender, side (left or right); significance: two-sided P < 0.05. RESULTS: Readers showed excellent agreement for lumen and outer wall diameters (ICC 0.83-094). Linear regression of supraclinoid ICA wall measurements showed a statistically significant increase in wall thickness (P = 0.00051) and outer vessel wall diameter (P = 0.030) with age. ICA lumen and outer vessel wall diameters were statistically greater in males vs. females (lumen diameter 3.69 ± 0.41 vs. 3.54 ± 0.35 mm, P = 0.026; outer wall diameter 5.78 ± 0.52 vs. 5.56 ± 0.44 mm, P = 0.0089) with a trend toward increase in wall thickness (1.05 ± 0.12 vs. 1.01 ± 0.10 mm, P = 0.055). No significant difference was found in basilar artery wall thickness (P = 0.45, P = 0.72), lumen diameter (P = 0.15, P = 0.42), or outer vessel wall diameter (P = 0.34, P = 0.41) with age or gender, respectively. DATA CONCLUSION: Intracranial vessel wall measurements were shown to be consistent between readers. At the available spatial resolution of 3T intracranial VWI sequences, supraclinoid ICA vessel wall thickness and outer vessel wall diameter appear to mildly increase with age. There was no detectable change in basilar artery vessel wall characteristics with age. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1452-1460.

Cerebral blood flow territory instability in patients with atherosclerotic intracranial stenosis.

BACKGROUND: Stroke risk stratification in patients with symptomatic intracranial atherosclerotic arterial disease (ICAD) remains an important clinical objective owing to the high 14-19% recurrent stroke rate in these patients on standard-of-care medical management. There thus remains a need for hemodynamic markers that may allow for the selection of personalized therapies for high-risk symptomatic patients. PURPOSE: To determine if shifting of cerebral blood flow (CBF) territories in response to changes in cerebral perfusion pressure (CPP) may provide a marker for stroke risk in ICAD patients. STUDY TYPE: Prospective. POPULATION: Twenty ICAD patients who experienced a stroke within 45 days of study enrollment and 10 healthy controls. SEQUENCE: 3.0T MRI including anatomical imaging (T1 -weighted, T2 -weighted/FLAIR), 3D MR angiography, and normocapnic and hypercapnic vessel-encoded CBF-weighted arterial spin labeling. ASSESSMENT: Patients were scanned within 45 days of overt stroke and monitored (duration = 13.2 ± 4.4 months) for the endpoint of non-cardioembolic stroke or transient ischemic attack. Flow territory shifting (shifting index) was calculated from the first scan by determining whether a voxel shifted from its primary arterial source from normocapnia to hypercapnia. STATISTICAL TESTS: A Mann-Whitney U-test (significance: P < 0.05) was performed to determine whether patients meeting the endpoint had greater shifting indices relative to controls or patients not meeting the endpoint. RESULTS: Shifting indices (mean ± standard error) were significantly higher in patients meeting endpoint criteria relative to controls (P = 0.0057; adjusted P = 0.036) and patients not meeting endpoint criteria (P = 0.0047; adjusted P = 0.036). DATA CONCLUSION: Flow territory shifting may provide a marker of recurrent stroke risk in symptomatic ICAD patients on standard-of-care medical management therapies. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1441-1451.

How do members of a fire and rescue service perceive expanding their roles to deliver more health care services?

BACKGROUND: Increasingly, public sector workers are being required to expand their roles into public health. Fire and rescue services, as part of the Emergency Medical Response trial, are at the forefront of role expansion, with increasing capacity due to reducing numbers of fires in recent years. Firefighter roles, successfully implemented, include responding to cardiac arrests and conducting checks on health and wellbeing in people's own homes. In this study, we explored fire service members' perceptions about this role expansion, to increase understanding of how role expansion can be introduced and supported. METHODS: We interviewed 21 firefighters and team members about their perceptions of new roles. Interviews were conducted, transcribed and thematically analysed until reaching thematic saturation. RESULTS: Perspectives differed for responding to cardiac arrests and wellbeing checks. Cardiac arrests were seen as aligned with core roles and thus more acceptable. For both types of new role participants wanted more training and opportunities to provide feedback on implementation. CONCLUSIONS: How team members viewed role expansion depended on new role alignment with core role, training and being able to give feedback to management to shape future services.

The Safer Anaesthesia from Education (SAFE)® paediatric anaesthesia course: educational impact in five countries in East and Central Africa.

There is an urgent need to improve access to safe surgical and anaesthetic care for children living in many low- and middle-income countries. Providing quality training for healthcare workers is a key component of achieving this. The 3-day Safer Anaesthesia from Education (SAFE)® paediatric anaesthesia course was developed to address the specific skills and knowledge required in this field. We undertook a project to expand this course across five East and Central African countries (Ethiopia, Kenya, Malawi, Uganda and Zambia) and train local faculty. This study reports the outcomes from course evaluation data, exploring the impact on knowledge, skills and behaviour change in participants. Eleven courses were conducted in a 15-month period, with 381 participants attending. Fifty-nine new faculty members were trained. Knowledge scores (0-50 scale) increased significantly from mean (SD) 37.5 (4.7) pre-course to 43.2 (3.5) post-course (p < 0.0001). Skills scores (0-10 scale) increased significantly from 5.7 (2.0) pre-course to 8.0 (1.5) post-course (p < 0.0001). One hundred and twenty-six participants in Malawi, Uganda and Zambia were visited in their workplace 3-6 months later. Knowledge and skills were maintained at follow-up, with scores of 41.5 (5.0) and 8.3 (1.4), respectively (p < 0.0001 compared with pre-course scores). Content analysis from interviews with these participants highlighted positive behaviour changes in the areas of preparation, peri-operative care, resuscitation, management of the sick child, communication and teaching. This study indicates that the SAFE paediatric anaesthesia course is an effective way to deliver training, and could be used to help strengthen emergency and essential surgical care for children as a component of universal health coverage.

Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements.

BACKGROUND: Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo. PURPOSE: To evaluate experimentally how IC vessel wall and lumen measurements change in identical subjects when evaluated using the most commonly available blood and cerebrospinal fluid (CSF) flow suppression modules and VWI sequences. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy adults (n = 13; age = 37 ± 15 years) were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0T 3D T1 /proton density (PD)-weighted turbo-spin-echo (TSE) acquisition with post-readout anti-driven equilibrium module, with and without Delay-Alternating-with-Nutation-for-Tailored-Excitation (DANTE) was applied. DANTE flip angle (8-12°) and TSE refocusing angle (sweep = 40-120° or 50-120°) were varied. ASSESSMENT: Basilar artery and internal carotid artery (ICA) wall thicknesses, CSF signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal ratio (SR) were assessed. Measurements were made by two readers (radiology resident and board-certified neuroradiologist). STATISTICAL TESTS: A Wilcoxon signed-rank test was applied with corrected two-sided P < 0.05 required for significance (critical P = 0.008, 0.005, and 0.05 for SNR/CNR, SR, and wall thickness, respectively). RESULTS: A TSE pulse sweep = 40-120° and sweep = 50-120° provided similar (P = 0.55) CSF suppression. Addition of the DANTE preparation reduced CSF SNR from 17.4 to 6.7, thereby providing significant (P < 0.008) improvement in CSF suppression. The DANTE preparation also resulted in a significant (P < 0.008) reduction in vessel wall SNR, but variable vessel wall to CSF CNR improvement (P = 0.87). There was a trend for a difference in blood SNR with vs. without DANTE (P = 0.05). The outer vessel wall diameter and wall thickness values were lower (P < 0.05) with (basilar artery 4.45 mm, 0.81 mm, respectively) vs. without (basilar artery 4.88 mm, 0.97 mm, respectively) DANTE 8°. DATA CONCLUSION: IC VWI with TSE sweep = 40-120° and with DANTE flip angle = 8° provides the best CSF suppression and CNR of the approaches evaluated. However, improvements are heterogeneous, likely owing to intersubject vessel pulsatility and CSF flow variations, which can lead to variable flow suppression efficacy in these velocity-dependent modules. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1120-1128.

Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases.

BACKGROUND: Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. OBJECTIVE: We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. METHODS: We used longitudinal data on 30 060 children up to age 7 years from Geisinger Clinic's electronic health record to conduct a sex- and age-matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins and macrolides. RESULTS: There were 484 milk allergy cases, 598 non-milk food allergy cases and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (Odds Ratio; 95% Confidence interval) (1.78; 1.28-2.48), non-milk food allergy (1.65; 1.27-2.14), and other allergies (3.07; 2.72-3.46) compared with children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. CONCLUSIONS AND CLINICAL RELEVANCE: We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with paediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform paediatric treatment decisions.

Antibiotic use and childhood body mass index trajectory.

BACKGROUND/OBJECTIVES: Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large-scale, population-based, longitudinal studies of the full age range among mainly healthy children. SUBJECTS/METHODS: We used electronic health record data on 163 820 children aged 3-18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations-reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))-and whether these varied by age. RESULTS: Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use. CONCLUSIONS: We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies.

Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis.

Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014-2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. "Big Data" analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by "Big Data" analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of-concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat).