Childhood trauma, antipsychotic medication, and symptom remission in first-episode psychosis.

BACKGROUND: To what extent psychotic symptoms in first-episode psychosis (FEP) with a history of childhood interpersonal trauma (CIT) are less responsive to antipsychotic medication is not known. In this longitudinal study, we compare symptom trajectories and remission over the first 2 years of treatment in FEP with and without CIT and examine if differences are linked to the use of antipsychotics. METHODS: FEP (N = 191) were recruited from in- and outpatient services 1997-2000, and assessed at baseline, 3 months, 1 and 2 years. Inclusion criteria were 15-65 years, actively psychotic with a DSM-IV diagnosis of psychotic disorder and no previous adequate treatment for psychosis. Antipsychotic medication is reported as defined daily dosage (DDD). CIT (<18) was assessed with the Brief Betrayal Trauma Survey, and symptomatic remission based on scores from the Positive and Negative Syndrome Scale. RESULTS: CIT (n = 63, 33%) was not associated with symptomatic remission at 2 years follow-up (71% in remission, 14% in relapse), or time to first remission (CIT 12/ no-CIT 9 weeks, p = 0.51). Those with CIT had significantly more severe positive, depressive, and excited symptoms. FEP with physical (N = 39, 20%) or emotional abuse (N = 22, 14, 7%) had higher DDD at 1 year (p < 0.05). Mean DDD did not excerpt a significant between-group effect on symptom trajectories of positive symptoms. CONCLUSION: Results indicate that antipsychotic medication is equally beneficial in the achievement of symptomatic remission in FEP after 2 years independent of CIT. Still, FEP patients with CIT had more severe positive, depressive, and excited symptoms throughout.

Digital phenotyping by wearable-driven artificial intelligence in older adults and people with Parkinson's disease: Protocol of the mixed method, cyclic ActiveAgeing study.

BACKGROUND: Active ageing is described as the process of optimizing health, empowerment, and security to enhance the quality of life in the rapidly growing population of older adults. Meanwhile, multimorbidity and neurological disorders, such as Parkinson's disease (PD), lead to global public health and resource limitations. We introduce a novel user-centered paradigm of ageing based on wearable-driven artificial intelligence (AI) that may harness the autonomy and independence that accompany functional limitation or disability, and possibly elevate life expectancy in older adults and people with PD. METHODS: ActiveAgeing is a 4-year, multicentre, mixed method, cyclic study that combines digital phenotyping via commercial devices (Empatica E4, Fitbit Sense, and Oura Ring) with traditional evaluation (clinical assessment scales, in-depth interviews, and clinical consultations) and includes four types of participants: (1) people with PD and (2) their informal caregiver; (3) healthy older adults from the Helgetun living environment in Norway, and (4) people on the Helgetun waiting list. For the first study, each group will be represented by N = 15 participants to test the data acquisition and to determine the sample size for the second study. To suggest lifestyle changes, modules for human expert-based advice, machine-generated advice, and self-generated advice from accessible data visualization will be designed. Quantitative analysis of physiological data will rely on digital signal processing (DSP) and AI techniques. The clinical assessment scales are the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), Apathy Evaluation Scale (AES), and the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A qualitative inquiry will be carried out with individual and focus group interviews and analysed using a hermeneutic approach including narrative and thematic analysis techniques. DISCUSSION: We hypothesise that digital phenotyping is feasible to explore the ageing process from clinical and lifestyle perspectives including older adults and people with PD. Data is used for clinical decision-making by symptom tracking, predicting symptom evolution, and discovering new outcome measures for clinical trials.

Cingulate circuits are associated with escalation of heroin use and naloxone-induced increases in heroin self-administration.

Opioid use disorder (OUD) is defined as a compulsion to seek and take opioids, loss of control over intake and the development of a negative emotional state when access to opioids is denied. Using functional magnetic resonance imaging (fMRI) data in a rat model of OUD, we demonstrate that the escalation of heroin self-administration (SA) and the increased heroin SA following an injection of an opioid receptor antagonist (naloxone) are associated with changes in distinct brain circuits, centered on the cingulate cortex (Cg). Here, SA escalation score was negatively associated with changes in resting state functional connectivity (rsFC) between the Cg and the dorsal striatum. Conversely, increased heroin SA following naloxone injection, was associated with increased connectivity between the Cg and the extended amygdala and hypothalamus. Naloxone-induced increased SA was also positively associated with changes in the amplitude of low frequency fluctuations within the Cg, a measure of spontaneous neuronal activity. Characterizing the distinct brain circuit and behavior changes associated with different facets of addiction increases our understanding of OUD and may provide insight into addiction prevention and treatment.

The health impact of smokeless tobacco products: a systematic review.

INTRODUCTION: The objective was to systematically review studies on health outcomes from smokeless tobacco (SLT) products. METHODS: We analysed published literature on the health outcomes from SLT use between 01/01/2015 to 01/02/2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol using PubMed, Embase, Scopus, and Google Scholar. RESULTS: Of 53 studies included, six were global, 32 from Asia, Middle East and Africa (AMEA), nine from USA and six from Europe. 'Poor'-rated studies predominated (23;43%), in particular, for global (4;66%) and AMEA (16;50%). Health outcomes differed between SLT-products and regions; those in AMEA were associated with higher mortality (overall, cancer, Coronary heart disease (CHD), respiratory but not cardiovascular disease (CVD)), and morbidity (CVD, oral and head and neck cancers), with odds ratios up to 38.7. European studies showed no excess mortality (overall, CVD, from cancers) or morbidity (ischemic heart disease (IHD), stroke, oral, head and neck, pancreatic or colon cancers) from several meta-analyses; single studies reported elevated risk of rectal cancer and respiratory disorders. Pooled study data showed protection against developing Parkinson's disease. US studies showed mixed results for mortality (raised overall, CHD, cancer and smoking-related cancer mortality; no excess risk of respiratory or CVD mortality). Morbidity outcomes were also mixed, with some evidence of increased IHD, stroke and cancer risk (oral, head and neck). No studies reported on switching from cigarettes to SLT-products. CONCLUSION: Our review demonstrates stark differences between different SLT-products in different regions, ranging from zero harm from European snus to greatly increased health risks in AMEA. The literature on the safety profile for SLT-products for harm reduction is incomplete and potentially misinforming policy and regulation.

The skeletal consequences of epidural steroid injections: a literature review.

This literature review summarized studies that evaluated the effects of epidural steroid injections (ESIs) on skeletal health. While evidence is limited, studies suggest that ESIs may cause bone loss. Better understanding of these skeletal consequences will help foster strategies to prevent bone loss in the growing population of patients receiving ESIs. PURPOSE: Approximately nine million epidural steroid injections (ESIs) are administered annually in the United States to treat radicular back pain. ESIs often provide pain relief and functional improvement. While the overall incidence of adverse events resulting from ESIs is low, their effects on the skeleton are poorly understood. This is an important consideration given the profound skeletal impact of other forms of glucocorticoids. METHODS: Ovid MEDLINE and PubMed search results since 2010, including older, frequently referenced publications were reviewed. RESULTS: Systemic absorption of glucocorticoids occurs after ESI, which can cause hyperglycemia and endogenous cortisol suppression. The majority of studies investigating the skeletal effects of ESIs are retrospective. Several have found a relationship between low areal bone mineral density (BMD) by dual-energy x-ray absorptiometry and ESI exposure, but this finding is not uniform. Recently a dose-response relationship between ESI exposure and low spine volumetric BMD by computed tomography has been reported. Few studies have investigated the relationship between ESI exposure and fracture risk. Results of these studies are conflicting, and most have not been adequately powered to detect fracture outcomes. CONCLUSIONS: While evidence is limited, studies suggest that ESIs may cause bone loss, particularly those investigating volumetric BMD. Larger doses appear to confer greater risk. Further prospective studies are needed to investigate the relationship between ESI and fracture risk. Better understanding of the skeletal consequences of ESIs will help foster strategies to prevent bone loss in the growing population of patients receiving this treatment.

Risk factors for multi-joint disease in patients with glucocorticoid-induced osteonecrosis.

This study investigated risk factors for osteonecrosis involving multiple joints (MJON) among glucocorticoid-treated patients. The best predictor of MJON was cumulative oral glucocorticoid dose. Risk of MJON was 12-fold higher in patients who had a second risk factor for osteonecrosis. Further research is needed into strategies for prevention of MJON. INTRODUCTION: Osteonecrosis (ON) is a debilitating musculoskeletal condition in which bone cell death can lead to mechanical failure. When multiple joints are affected, pain and disability are compounded. Glucocorticoid treatment is one of the most common predisposing factors for ON. This study investigated risk factors for ON involving multiple joints (MJON) among glucocorticoid-treated patients. METHODS: Fifty-five adults with glucocorticoid-induced ON were prospectively enrolled. MJON was defined as ON in ≥ three joints. Route, dose, duration, and timing of glucocorticoid treatment were assessed. RESULTS: Mean age of enrolled subjects was 44 years, 58% were women. Half had underlying conditions associated with increased ON risk: systemic lupus erythematosus (29%), acute lymphoblastic leukemia (11%), HIV (9%), and alcohol use (4%). Mean daily oral dose of glucocorticoids was 29 mg. Average cumulative oral dose was 30 g over 5 years. The best predictor of MJON was cumulative oral glucocorticoid dose. For each increase of 1,000 mg, risk of MJON increased by 3.2% (95% CI 1.03, 1.67). Glucocorticoid exposure in the first 6 months of therapy, peak dose (oral or IV), and mean daily dose did not independently increase risk of MJON. The risk of MJON was 12-fold in patients who had a second risk factor (95% CI 3.2, 44.4). CONCLUSIONS: Among patients with glucocorticoid-induced ON, cumulative oral dose was the best predictor of multi-joint disease; initial doses of IV and oral glucocorticoids did not independently increase risk. Further research is needed to better define optimal strategies for prevention and treatment of MJON.

Nicotine addiction: Translational insights from circuit neuroscience.

Contemporary neuroscience aims to understand how neuronal activity produces internal processes and observable behavioral states. This aim crucially depends on systems-level, circuit-based analyses of the working brain, as behavioral states arise from information flow and connectivity within and between discrete and overlapping brain regions, forming circuits and networks. Functional magnetic resonance imaging (fMRI), offers a key to advance circuit neuroscience; fMRI measures inter and intra- regional circuits at behaviorally relevant spatial-temporal resolution. Herein, we argue that cross-sectional observations in human populations can be best understood via mechanistic and causal insights derived from brain circuitry obtained from preclinical fMRI models. Using nicotine addiction as an exemplar of a circuit-based substance use disorder, we review fMRI-based observations of a circuit that was first shown to be disrupted among human smokers and was recently replicated in rodent models of nicotine dependence. Next, we discuss circuits that predispose to nicotine dependence severity and their interaction with circuits that change as a result of chronic nicotine administration using a rodent model of dependence. Data from both clinical and preclinical fMRI experiments argue for the utility of fMRI studies in translation and reverse translation of a circuit-based understanding of brain disease states. We conclude by discussing the future of circuit neuroscience and functional neuroimaging as an essential bridge between animal models and human populations to the understanding of brain function in health and disease.

Maternal use of folic acid and multivitamin supplements and infant risk of birth defects in Norway, 1999-2013.

The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.

Low volumetric bone density is a risk factor for early complications after spine fusion surgery.

This study aims to investigate lumbar spine (LS) volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. INTRODUCTION: Lumbar spine (LS) fusion surgery is increasingly performed worldwide. Complications after fusion result in significant morbidity and healthcare costs. Multiple factors, including osteoporosis, have been suggested to contribute to risk of complications and re-operation. However, most studies have used DXA, which is subject to artifact in patients with spine pathology, and none have investigated the relationship between BMD and timing of post-operative complications. This study aims to investigate LS volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. METHODS: We evaluated a cohort of 359 patients who had initial LS fusion surgery at our institution, had pre-operative LS CTs and post-operative imaging available for review. Demographic factors, smoking status, vBMD, and details of surgical procedure were related to likelihood and timing of post-operative complications. RESULTS: Mean age was 60 ± 14 years, vBMD 122 ± 37 g/cm3. Median follow-up was 11 months. Skeletal complications occurred in 47 patients (13%); 34 patients (10%) required re-operation. Low vBMD (directly measured and estimated using HU) and smoking were associated with increased risk of skeletal complications. Each increase in baseline vBMD of 10 g/cm3 decreased the complication hazard and increased the complication-free duration in time-to-event analysis (hazard ratio 0.91, 95% CI 0.83-0.98, p < 0.02). CONCLUSIONS: Low vBMD was a significant risk factor for early post-operative complications in patients undergoing LS fusion. Prospective studies are needed to confirm these findings and to elucidate the optimal timing for follow-up and strategies for prevention of post-operative complications in this population.

Nicotine dependence (trait) and acute nicotinic stimulation (state) modulate attention but not inhibitory control: converging fMRI evidence from Go-Nogo and Flanker tasks.

Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go-Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go-Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.

Heart failure in Norway, 2000-2014: analysing incident, total and readmission rates using data from the Cardiovascular Disease in Norway (CVDNOR) Project.

AIMS: To examine trends in heart failure (HF) hospitalization rates and risk of readmissions following an incident HF hospitalization. METHODS AND RESULTS: During 2000-2014, we identified in the Cardiovascular Disease in Norway Project 142 109 hospitalizations with HF as primary diagnosis. Trends of incident and total (incident and recurrent) HF hospitalization rates were analysed using negative binomial regression models. Changes over time in 30-day and 3-year risk of HF recurrences or cardiovascular disease (CVD)-related readmissions were analysed using Fine and Grey competing risk regression, with death as competing events. Age-standardized rates declined on average 1.9% per year in men and 1.8% per year in women for incident HF hospitalizations (both Ptrend < 0.001) but did not change significantly in either men or women for total HF hospitalizations. In men surviving the incident HF hospitalization, 30-day and 3-year risk of a HF recurrent event increased 1.7% and 1.2% per year, respectively. Similarly, 30-day and 3-year risk of a CVD-related hospitalization increased 1.5% and 1.0% per year, respectively (all Ptrend < 0.001). No statistically significant changes in the risk of HF recurrences or CVD-related readmissions were observed among women. In-hospital mortality for a first and recurrent HF episode declined over time in both men and women. CONCLUSIONS: Incident HF hospitalization rates declined in Norway during 2000-2014. An increase in the risk of recurrences in the context of reduced in-hospital mortality following an incident and recurrent HF hospitalization led to flat trends of total HF hospitalization rates.

Paraneoplastic Cerebellar Degeneration in Nasopharyngeal Carcinoma: a Unique Association.

Paraneoplastic cerebellar degeneration (PCD) is a rare disorder that is associated with lung or gynecological malignancies and Hodgkin lymphoma. Neurologic symptoms are commonly the initial presenting sign leading to the diagnosis of an underlying malignancy. We are presenting an Asian male with progressive lower extremity weakness with EBV-positive nasopharyngeal carcinoma (NPC) and anti-Yo antibodies. Peculiarly, transient diffuse leptomeningeal enhancement is seen on MR imaging. This is the first report of PCD associated with NPC and thus illustrates that PCD embodies a boarder set of disease than previously described.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

Stability and Change in Longitudinal Associations between Child Behavior Problems and Maternal Stress in Families with Preterm Born Children, Follow-Up after a RCT-Study.

The Tromsø Intervention Study on Preterms (TISP) randomized 146 preterm-born children either to the Mother-Infant Transaction Program (MITP) or to a preterm control group. Previously, significant reductions of child behavior problems and maternal stress have been reported in the intervention group. This follow-up study examines whether the MITP may have affected the longitudinal adaptation between mothers and their children from two until nine years, expressed as associations between different behavioral problems and parenting stress reported by mothers. Associations between internalizing, attentional, and social problems and different dimensions of parenting stress were analyzed in separate models that included effects of time and group status. The MITP did not influence the development of longitudinal associations as no significant three-way interaction (stress*group*time) was found. Significant stress by group interactions was only found in reports on children's attentional problems when analyzed with parent- or interaction-related stress. Mothers who had participated in the MITP reported weaker stress⁻behavior associations than control mothers. This effect was moderated by two independent variables, namely children's birthweight and years of maternal education for the parent⁻child difficult interaction stress.

Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance.

Patients with monoclonal gammopathy of undetermined significance (MGUS) had abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness at both the radius and tibia by high-resolution peripheral quantitative CT compared to matched controls. This is the first report demonstrating that patients with MGUS have microarchitectural deficits at multiple skeletal sites. INTRODUCTION: Fracture risk is elevated in patients with monoclonal gammopathy of undetermined significance (MGUS). However, the pathogenesis of bone disease in these patients is poorly understood. Prior work using high-resolution peripheral CT (HRpQCT) demonstrated abnormal microarchitecture at the radius, with predominantly cortical abnormalities. We hypothesized that patients with MGUS have abnormal microarchitecture at both radius and tibia compared to controls, reflecting global skeletal effects of the disease. METHODS: This case-control study enrolled 36 subjects; patients with MGUS (n = 12) were matched 1:2 by age, sex, and race to controls (n = 24). Areal BMD (aBMD) was measured by DXA, vBMD, and microarchitecture by HRpQCT, and whole bone stiffness by finite element analysis. Serum was drawn for markers of bone metabolism and inflammation. RESULTS: By DXA, MGUS patients had lower aBMD at the lumbar spine, femoral neck, and 1/3 radius. Markers of bone metabolism and inflammation did not differ. By HRpQCT at the radius, MGUS patients had lower total, trabecular and cortical density, lower trabecular number, and greater trabecular separation and heterogeneity. At the tibia, MGUS patients had lower total and trabecular density, lower trabecular number, greater separation and heterogeneity, and lower whole bone stiffness. CONCLUSIONS: Patients with MGUS had lower vBMD, cortical, and trabecular abnormalities at the radius compared to matched controls. At the tibia, trabecular abnormalities predominated. These results suggest that in addition to previously described cortical deficits, deterioration of trabecular bone may contribute to a generalized skeletal fragility in patients with MGUS.

Identifying symptoms using the drawings of 4-7 year olds with cancer.

PURPOSE: Symptom burden in children with cancer who are less than 8 years old is not well understood. Our research focuses on identifying how to structure a self-report instrument for younger children. Our aim was to describe how children with cancer, aged 4-7 years, express their symptoms through drawings. METHODS: Children were asked to make drawings of a day when they were "feeling bad or not good". Content of 18 children's drawings was analyzed. RESULTS: Four themes were established: physical symptoms, emotions, location and miscellaneous. Most of the drawings illustrated specific symptoms important to this age group, while also facilitating our understanding of how children with cancer view their symptoms. CONCLUSION: Having children draw pictures may help initiate communication regarding how they feel, and develop rapport between the interviewer and children.

Abnormal microarchitecture and stiffness in postmenopausal women using chronic inhaled glucocorticoids.

Postmenopausal (PM) women using inhaled glucocorticoids (IGCs) had substantial abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness using high resolution peripheral computed tomography (HRpQCT) compared to age- and race-matched controls. Abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs. INTRODUCTION: While oral glucocorticoids are well recognized to have destructive skeletal effects, less is known about the effects of IGCs. The detrimental skeletal effects of IGCs may be greatest in PM women, in whom they compound negative effects of estrogen loss and aging. The goal of this study was to evaluate microarchitecture and stiffness in PM women using chronic IGCs. METHODS: This case-control study compared PM women using IGCs for ≥ 6 months (n = 20) and controls matched for age and race/ethnicity (n = 60). Skeletal parameters assessed included areal BMD (aBMD) by DXA, trabecular and cortical vBMD and microarchitecture by HRpQCT of the radius and tibia, and whole bone stiffness by finite element analysis. RESULTS: By DXA, mean values in both groups were in the osteopenic range; hip aBMD was lower in IGC users (P < 0.04). By HRpQCT, IGC users had lower total, cortical, and trabecular vBMD at both radius and tibia (all P < 0.05). IGC users had lower cortical thickness, lower trabecular number, greater trabecular separation and heterogeneity at the radius (all P < 0.03), and greater heterogeneity at the tibia (P < 0.04). Whole bone stiffness was lower in IGC users at radius (P < 0.03) and tended to be lower at the tibia (P = 0.09). CONCLUSIONS: PM women using IGCs had substantial abnormalities in vBMD, microarchitecture, and stiffness compared to controls. These abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs.

Duty of Notification and Aviation Safety-A Study of Fatal Aviation Accidents in the United States in 2015.

After the Germanwings accident, the French Safety Investigation Authority (BEA) recommended that the World Health Organization (WHO) and European Community (EC) develop clear rules for the duty of notification process. Aeromedical practitioners (AMEs) face a dilemma when considering the duty of notification and conflicts between pilot privacy and public and third-party safety. When balancing accountability, knowledge of the duty of notification process, legislation and the clarification of a doctor’s own set of values should be assessed a priori. Relatively little is known of the magnitude of this problem in aviation safety. To address this, the National Transportation Safety Board (NTSB) database was searched to identify fatal accidents during 2015 in the United States in which a deceased pilot used a prescribed medication or had a disease that potentially reduced pilot performance and was not reported to the AME. Altogether, 202 finalized accident reports with toxicology were available from (the year) 2015. In 5% (10/202) of these reports, the pilot had either a medication or a disease not reported to an AME which according to the accident investigation was causal to the fatal accident. In addition, the various approaches to duty of notification in aviation in New Zealand, Finland and Norway are discussed. The process of notification of authorities without a pilot’s express permission needs to be carried out by using a guidance protocol that works within legislation and professional responsibilities to address the pilot and the public, as well as the healthcare provider. Professional guidance defining this duty of notification is urgently needed.

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles.

BACKGROUND: Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias. METHODS AND RESULTS: We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long-term atrial fibrillation (AF) risk in a community-based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B-Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow-up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08-1.19, P<0.001) and 1.16 (95% confidence interval 1.10-1.22, P<0.001) per SD increment for log-transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01-1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk. CONCLUSIONS: Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346.

The PAr index, an indicator reflecting altered vitamin B-6 homeostasis, is associated with long-term risk of stroke in the general population: the Hordaland Health Study (HUSK).

Background: Vitamin B-6 homeostasis is altered during inflammation and immune activation. It is unknown whether altered vitamin B-6 homeostasis is associated with the risk of stroke. Objective: We investigated the relation between the ratio plasma 4-pyridoxic acid: (pyridoxal + pyridoxal-5'-phosphate) (PAr) as an indicator of altered vitamin B-6 homeostasis and the risk of stroke in the general population. Design: We conducted a prospective analysis of the community-based Hordaland Health Study (HUSK) in 6891 adults (born during 1925-1927 and 1950-1951) without known stroke at baseline (1998-1999). Participants were followed via linkage to the CVDNOR (Cardiovascular Disease in Norway) project and the Cause of Death Registry. HRs and 95% CIs were calculated using Cox proportional hazards analyses. Results: A total of 390 participants (193 men and 197 women) developed stroke over a median follow-up period of 11 y. Study participants with elevated PAr experienced a higher risk of incident stroke in an essentially linear dose-response fashion. The HR (95% CI) for the highest compared with the lowest quartile of PAr was 1.97 (1.42, 2.73; P-trend <0.001) for total stroke and 2.09 (1.42, 3.09; P-trend <0.001) for ischemic stroke after adjustment for age, sex, body mass index (BMI), smoking, education, physical activity, estimated glomerular filtration rate, hypertension, diabetes, total cholesterol, and statin use. PAr had greater predictive strength than did C-reactive protein, current smoking, diabetes, hypertension, estimated glomerular filtration rate, and physical activity. The associations were similar in subgroups stratified by age group, sex, BMI, current smoking, hypertension, diabetes, and statin use at baseline. Conclusions: Higher plasma PAr was independently associated with increased risk of incident stroke in all participants and across all subgroups stratified by conventional risk predictors. Our novel findings point to and expand the range of inflammation and immune activation processes that may be relevant for the pathogenesis and prevention of stroke. This trial was registered at clinicaltrials.gov as NCT03013725.