Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic ...component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 (GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes (ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.
Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to ...determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo.
Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up.
Nine English old-age psychiatry services.
A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+.
clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer.
(1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.
CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed.
Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine).
Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112).
Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group.
This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.
A previous modelling study predicted that the forces applied by the extensor muscles to stabilise the lumbar spine would be greater in spines that have a larger sagittal curvature (lordosis). Because ...the force‐generating capacity of a muscle is related to its size, it was hypothesised that the size of the extensor muscles in a subject would be related to the size of their lumbar lordosis. Magnetic resonance imaging (MRI) data were obtained, together with age, height, body mass and back pain status, from 42 female subjects. The volume of the extensor muscles (multifidus and erector spinae) caudal to the mid‐lumbar level was estimated from cross‐sectional area measurements in axial T1‐weighted MRIs spanning the lumbar spine. Lower lumbar curvature was determined from sagittal T1‐weighted images. A stepwise linear regression model was used to determine the best predictors of muscle volume. The mean lower lumbar extensor muscle volume was 281 cm3 (SD = 49 cm3). The mean lower lumbar curvature was 30 ° (SD = 7 °). Five subjects reported current back pain and were excluded from the regression analysis. Nearly half the variation in muscle volume was accounted for by the variables age (standardised coefficient, B = −3.2, P = 0.03) and lower lumbar curvature (B = 0.47, P = 0.002). The results support the hypothesis that extensor muscle volume in the lower lumbar spine is related to the magnitude of the sagittal curvature; this has implications for assessing muscle size as an indicator of muscle strength.
A wide range of 2-pyridyl and other difficult-to-access heterocyclic N-methyliminodiacetic acid boronates can be readily prepared from the corresponding bromides via a new method involving direct ...transligation of 2-heterocyclic trialkoxyborate salts with N-methyliminodiacetic acid (MIDA) at elevated temperatures.
A stretchable photodetector with enhanced, strain‐tunable photoresponsivity is developed based on crumpled graphene by engineering 2D graphene into 3D structures. This crumpled graphene photodetector ...demonstrates ≈400% enhanced photoresponsivity led by an order‐of‐magnitude enhanced extinction of graphene and 100% modulation in photoresponsivity with 200% applied strain. Finally, strain‐tunable, wavelength‐selective photodetection is shown by integrated colloidal photonic crystals–crumpled graphene photodetector devices.
Depression in mothers during pregnancy and in the postnatal period has been recognized to have wide-ranging adverse impacts on offspring. Our study examines some of the outcomes and long-term ...economic implications experienced by offspring who have been exposed to perinatal depression.
We analysed the effects of perinatal depression on child development outcomes of children at ages 11 and 16 years from the community-based South London Child Development Study. Economic consequences were attached to those outcomes through simple decision-analytic techniques, building on evidence from studies of epidemiology, health-related quality of life, public sector costs and employment. The economic analysis takes a life-course perspective from the viewpoints of the public sector, individual and society.
Additional risks that children exposed to perinatal depression develop emotional, behavioural or cognitive problems ranged from 5% to 21%. In addition, there was a high risk (24%) that children would have special educational needs. We present results in the form of cost consequences attached to adverse child outcomes. For each child exposed to perinatal depression, public sector costs exceeded £3030, costs due to reduced earnings were £1400 and health-related quality of life loss was valued at £3760.
Action to prevent or treat mothers' depression during pregnancy and after birth is likely to reduce public sector costs, increase earnings and improve quality of life for children who were exposed to the condition.
Abstract
Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel ...biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.
Background
Black and Hispanic patients are less likely to receive cardiac resynchronization therapy (CRT) than White patients. Medicaid expansion has been associated with increased access to ...cardiovascular care among racial and ethnic groups with higher prevalence of underinsurance. It is unknown whether the Medicaid expansion was associated with increased receipt of CRT by race and ethnicity.
Methods and Results
Using Healthcare Cost and Utilization Project Data State Inpatient Databases from 19 states and Washington, DC, we analyzed 1061 patients from early‐adopter states (Medicaid expansion by January 2014) and 745 patients from nonadopter states (no implementation 2013–2014). Estimates of change in census‐adjusted rates of CRT with or without defibrillator by race and ethnicity and Medicaid adopter status 1 year before and after January 2014 were conducted using a quasi‐Poisson regression model. Following the Medicaid expansion, the rate of CRT did not significantly change among Black individuals from early‐adopter states (1.07 95% CI, 0.78–1.48) or nonadopter states (0.79 95% CI, 0.57–1.09). There were no significant changes in rates of CRT among Hispanic individuals from early‐adopter states (0.99 95% CI, 0.70–1.38) or nonadopter states (1.01 95% CI, 0.65–1.57). There was a 34% increase in CRT rates among White individuals from early‐adopter states (1.34 95% CI, 1.05–1.70), and no significant change among White individuals from nonadopter states (0.77 95% CI, 0.59–1.02). The change in CRT rates among White individuals was associated with the timing of the Medicaid implementation (
P
=0.003).
Conclusions
Among states participating in Healthcare Cost and Utilization Project Data State Inpatient Databases, implementation of Medicaid expansion was associated with increase in CRT rates among White individuals residing in states that adopted the Medicaid expansion policy. Further work is needed to address disparities in CRT among Black and Hispanic patients.
Habitat selection that has fitness consequences has important implications for conservation activities. For example, habitat characteristics that influence nest success in birds can be manipulated to ...improve habitat quality with the goal of ultimately improving reproductive success. We examined habitat selection by the threatened streaked horned lark (Eremophila alpestris strigata) at both the breeding-site (territory) and nest-site scales. Larks were selective at both spatial scales but with contrasting selection. At the territory scale, male larks selected sparsely vegetated grasslands with relatively short vegetation. At the nest-site scale, female larks selected sites within territories with higher vegetation density and more perennial forbs. These nest-site scale choices had reproductive consequences, with greater nest success in areas with higher densities of perennial forbs. We experimentally manipulated lark habitat structure in an attempt to mimic the habitat conditions selected by larks by using late summer prescribed fires. After the burn, changes in vegetation structure were in the direction preferred by larks but habitat effects attenuated by the following year. Our results highlight the importance of evaluating habitat selection at spatial scales appropriate to the species of interest, especially when attempting to improve habitat quality for rare and declining species. They also highlight the importance of conducting restoration activities in a research context. For example, because the sparsely vegetated conditions created by fire attenuate, there may be value in examining more frequent burns or hotter fires as the next management and research action. We hope the design outlined in this study will serve as an integrated research and management example for conserving grassland birds generally.
Conventional chemo-immunotherapy fails to cure the majority of mantle cell lymphoma patients and causes substantial toxicity. Resistant mantle cell lymphoma cells commonly overexpress and are ...dependent on the anti-apoptotic protein, Mcl-1, for survival. In this study, we use potent lipidoid nanoparticles to deliver siRNA to silence Mcl-1 expression. Studies were conducted using two different mantle cell lymphoma cell lines, a normal (JeKo-1) and an aggressive (MAVER-1) line, to assess the ability of lipidoid nanoparticles to be used broadly in the treatment of mantle cell lymphoma. Mcl-1 mRNA silencing and protein knockdown was observed as early as one day after treatment and the lipidoid nanoparticles achieved sustained silencing of Mcl-1 mRNA for at least four days in both JeKo-1 and MAVER-1 cells. Eighty percent silencing was achieved at three days post-transfection in JeKo-1 cells while 50% silencing was achieved in MAVER-1 cells, which are more resistant to transfection. Interestingly, silencing of Mcl-1 induced apoptosis in nearly 30% of both JeKo-1 and MAVER-1 cells three days post-transfection. Additionally, Mcl-1 silencing and the resultant apoptosis in mantle cell lymphoma cells were dose dependent. These data suggest that lipidoid nanoparticles siRNA therapy targeting Mcl-1 has potential as a new treatment modality for mantle cell lymphoma and many other cancers that overexpress Mcl-1. The combination of anti-Mcl-1 lipidoid nanoparticles with other forms of targeted therapy offers hope for reducing or replacing cytotoxic chemotherapy as standard treatment for mantle cell lymphoma.
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