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Blood Pressure-Lowering Profiles and Clinical Effects of Angiotensin Receptor Blockers Versus Calcium Channel Blockers.
Blood pressure-lowering drugs have different blood pressure-lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg (Pvalues <0.0001). The higher risks of myocardial infarction and stroke in the valsartan group was attenuated after adjustment for mean and variability of systolic blood pressure, from HR, 1.19 (95% CI, 1.02-1.39) to 1.11 (0.96-1.30) and from HR, 1.13 (0.96-1.33) to 1.00 (0.85-1.18), respectively. The lower risk of congestive heart failure in the valsartan group was accentuated after adjustment, from HR, 0.86 (0.74-1.00) to 0.76 (0.65-0.89). A smaller effect was seen on risk of death, from 1.01 (0.92-1.12) to 0.94 (0.85-1.04). In conclusion, the higher risks of myocardial infarction and stroke in patients randomized to valsartan versus amlodipine were related to the drugs' different blood pressure modulating profiles. The risk of congestive heart failure with valsartan was lower, independent of the less favorable blood pressure modulating profile.
Predictors of mental health and academic outcomes in first-year university students: Identifying prevention and early-intervention targets.
BACKGROUND: Although there is growing interest in mental health problems in university students there is limited understanding of the scope of need and determinants to inform intervention efforts. AIMS: To longitudinally examine the extent and persistence of mental health symptoms and the importance of psychosocial and lifestyle factors for student mental health and academic outcomes. METHOD: Undergraduates at a Canadian university were invited to complete electronic surveys at entry and completion of their first year. The baseline survey measured important distal and proximal risk factors and the follow-up assessed mental health and well-being. Surveys were linked to academic grades. Multivariable models of risk factors and mental health and academic outcomes were fit and adjusted for confounders. RESULTS: In 1530 students surveyed at entry to university 28% and 33% screened positive for clinically significant depressive and anxiety symptoms respectively, which increased to 36% and 39% at the completion of first year. Over the academic year, 14% of students reported suicidal thoughts and 1.6% suicide attempts. Moreover, there was persistence and overlap in these mental health outcomes. Modifiable psychosocial and lifestyle factors at entry were associated with positive screens for mental health outcomes at completion of first year, while anxiety and depressive symptoms were associated with lower grades and university well-being. CONCLUSIONS: Clinically significant mental health symptoms are common and persistent among first-year university students and have a negative impact on academic performance and well-being. A comprehensive mental health strategy that includes a whole university approach to prevention and targeted early-intervention measures and associated research is justified.
Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental aetiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioural phenotype (e.g. Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behaviour across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy amongst many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. Whilst multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g. frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify pre-existing pathophysiological theories.
© 2020 Elsevier Inc. Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.
<jats:p> <jats:bold>Background:</jats:bold> Why some but not all patients with severe AS (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and/or flux is associated with this transition. </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> 102 participants were recruited to five groups: moderate AS (ModAS, n=13), severe AS, LVEF ≥55% (SevAS-pEF, n=37), severe AS, LVEF<55% (SevAS-rEF, n=15), healthy volunteers with non-hypertrophied hearts with normal systolic function (NHv, n=30), and patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (NHbx, n=7). All underwent CMR imaging and <jats:sup>31</jats:sup> P magnetic resonance spectroscopy (MRS) for myocardial energetics. LV biopsies (AS and NHBx) were analysed for; CK total activity, CK isoforms, citrate synthase (CS) activity and total creatine. Using serial block-face scanning electron microscopy, mitochondria-sarcomere diffusion distances were calculated. </jats:p> <jats:p> <jats:bold>Results:</jats:bold> In the absence of failure, CK flux was lower in the presence of AS (by 32%, p=0.04), driven primarily by reduction in PCr/ATP (by 17%, p <0.001), with CK k <jats:sub>f</jats:sub> unchanged (p=0.46),and is present in ModAS. Although lowest in the SevAS-rEF group, CK flux was not different to the SevAS-pEF group (p>0.99). Accompanying the fall in CK flux, total CK and CS activities, and absolute activities of MtCK and CK-MM were also lower (p<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, p=.003). </jats:p> <jats:p> <jats:bold>Conclusions:</jats:bold> Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo MRS measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, but where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS, and suggest a fall in CK flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with AS severity this could increase susceptibility to systolic failure. As such, targeting CK capacity and/or flux may be a therapeutic strategy to prevent/treat systolic failure in AS. </jats:p>
BACKGROUND: X-linked retinitis pigmentosa (XLRP) due to mutations in the RPGR gene is a very severe form of RP, resulting in rapid disease progression and retinal dysfunction. Female carriers do not usually report symptoms. However, it has reported that carriers of XLRP can have a significant visual and retinal impairment. OBJECTIVES: To report a detailed description of 3 cases of severely affected females who presented with a "male" phenotype and have posed challenges at diagnosis, due to the apparent autosomal dominant family history. METHOD: Autofluorescence imaging (AF), colour imaging and optical coherence tomography (OCT) were performed. Confirmation of the genetic mutation was obtained by Sanger genetic sequencing. In 1 patient an X-inactivation analysis was performed to detect the X-inactivation ratio, as the percentage of cells tested in which each allele is active. RESULTS: All the patients started suffering from night blindness in early childhood. Colour, fundus AF and OCT images showed the typical pattern of degeneration reported in men. One patient underwent retina implant surgery due to the severe atrophy. CONCLUSIONS: This is a small selection of females with a severe phenotype that do not differ from the typical male phenotype. In our opinion gene therapy surgery should be warranted in this scenario.
Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.
Sleep quantity and quality are both important for optimal development and functioning during youth. Yet few studies have examined the effects of insomnia symptoms and objective short sleep duration on memory performance among adolescents and young adults. One-hundred and ninety participants (female: 61.6%) aged from 12 to 24 years completed this study. All participants underwent a clinical interview, a 7-day actigraphic assessment, a battery of self-report questionnaires and cognitive tests to assess working memory and episodic memory. Insomnia symptoms were defined as a score ≥ 9 on the Insomnia Severity Index, and objective short sleep duration was defined as average total sleep time less than 7 hr for those aged 12-17 years, and 6 hr for those aged 18 years and above as assessed by actigraphy. Insomnia symptoms were significantly associated with worse self-perceived memory (p < .05) and poorer performance on the digit span task (p < .01), but not the dual N-back task and verbal learning task. There was no significant difference in any of the memory measures between participants with objective short sleep duration and their counterparts. No interaction effect was found between insomnia and short sleep duration on any of the objective memory outcomes. Insomnia symptoms, but not objective short sleep duration, were associated with poorer subjective memory and objective working memory performance in youths. Further studies are needed to investigate the underlying mechanisms linking insomnia and memory impairments, and to delineate the long-term impacts of insomnia on other aspects of neurocognitive functioning in youth.
Wearability testing of ambulatory vital sign monitoring devices: a prospective observational cohort study. (Preprint)
<sec> <title>BACKGROUND</title> <p>Timely recognition of the deteriorating patient remains challenging. Ambulatory monitoring systems (AMS) may provide support to current monitoring practices; however they need to be thoroughly tested before implementation in the clinical environment.</p> </sec> <sec> <title>OBJECTIVE</title> <p>The objective of this study is to assess the wearability of a selection of commercially available AMS to inform a future prospective study of ambulatory vital signs monitors in an acute hospital ward.</p> </sec> <sec> <title>METHODS</title> <p>Five pulse oximeters (4 with finger probe and 1 wrist worn only) and 2 chest patches were selected to be part of this study; participants wore each device up to 72 hours and completed one wearability questionnaire per device.</p> </sec> <sec> <title>RESULTS</title> <p>Quantitative scores and feedback were collected in 70 completed questionnaires from 20 healthy volunteers, with each device tested approximately 10 times. For the Comfort Rating Scale (CRS), the Wavelet Health device seemed to be the superior pulse oximeter (p < 0.001). There were no statistically significant differences between the chest patches in the CRS total score; however the VitalPatch was superior in the Attachment section (p = 0.043). General pain and discomfort scores and total percentage of time worn are also reflective of these.</p> </sec> <sec> <title>CONCLUSIONS</title> <p>Our results suggest that participants prefer to wear wrist-worn pulse oximeters without a probe compressing the fingertip and the smaller chest patch. A compromise between wearability, reliability and accuracy should be made for successful and practical integration of AMS in the hospital environment.</p> </sec>