Identification of a rare de novo three-way complex t(5;20;8)(q31;p11.2;p21) with microdeletions on 5q31.2, 5q31.3, and 8p23.2 in a patient with hearing loss and global developmental delay: case report

<p>Abstract</p> <p>Background</p> <p>Complex chromosome rearrangements (CCRs), which involve more than two breakpoints on two or more chromosomes, are uncommon occurrences. Although most CCRs appear balanced at the level of the light microscope, many demonstrate cryptic, submicroscopic imbalances at the translocation breakpoints.</p> <p>Results</p> <p>We report a female with hearing loss and global developmental delay with a complex three-way unbalanced translocation (5;20;8)(q31;p11.2;p21) resulting in microdeletions on 5q31.2, 5q31.3, and 8p23.2 identified by karyotyping, microarray analysis and fluorescence in situ hybridization.</p> <p>Discussion</p> <p>The microdeletion of bands 8p23.2 may be associated with the hearing impairment. Furthermore, the characterization of this patient's chromosomal abnormalities demonstrates the importance of integrated technologies within contemporary cytogenetics laboratories.</p

Long-term trends in human body size track regional variation in subsistence transitions and growth acceleration linked to dairying

Evidence for a reduction in stature between Mesolithic foragers and Neolithic farmers has been interpreted as reflective of declines in health, however, our current understanding of this trend fails to account for the complexity of cultural and dietary transitions or the possible causes of phenotypic change. The agricultural transition was extended in primary centers of domestication and abrupt in regions characterized by demic diffusion. In regions such as Northern Europe where foreign domesticates were difficult to establish, there is strong evidence for natural selection for lactase persistence in relation to dairying. We employ broad-scale analyses of diachronic variation in stature and body mass in the Levant, Europe, the Nile Valley, South Asia, and China, to test three hypotheses about the timing of subsistence shifts and human body size, that: 1) the adoption of agriculture led to a decrease in stature, 2) there were different trajectories in regions of in situ domestication or cultural diffusion of agriculture; and 3) increases in stature and body mass are observed in regions with evidence for selection for lactase persistence. Our results demonstrate that 1) decreases in stature preceded the origins of agriculture in some regions; 2) the Levant and China, regions of in situ domestication of species and an extended period of mixed foraging and agricultural subsistence, had stable stature and body mass over time; and 3) stature and body mass increases in Central and Northern Europe coincide with the timing of selective sweeps for lactase persistence, providing support for the "Lactase Growth Hypothesis.

Meteorological, impact and climate perspectives of the 29 June 2017 heavy precipitation event in the Berlin metropolitan area

Extreme precipitation is a weather phenomenon with tremendous damaging potential for property and human life. As the intensity and frequency of such events is projected to increase in a warming climate, there is an urgent need to advance the existing knowledge on extreme precipitation processes, statistics and impacts across scales. To this end, a working group within the Germany-based project, ClimXtreme, has been established to carry out multidisciplinary analyses of high-impact events. In this work, we provide a comprehensive assessment of the 29 June 2017 heavy precipitation event (HPE) affecting the Berlin metropolitan region (Germany), from the meteorological, impacts and climate perspectives, including climate change attribution. Our analysis showed that this event occurred under the influence of a mid-tropospheric trough over western Europe and two shortwave surface lows over Britain and Poland (Rasmund and Rasmund II), inducing relevant low-level wind convergence along the German–Polish border. Over 11 000 convective cells were triggered, starting early morning 29 June, displacing northwards slowly under the influence of a weak tropospheric flow (10 m s−1 at 500 hPa). The quasi-stationary situation led to totals up to 196 mm d−1, making this event the 29 June most severe in the 1951–2021 climatology, ranked by means of a precipitation-based index. Regarding impacts, it incurred the largest insured losses in the period 2002 to 2017 (EUR 60 million) in the greater Berlin area. We provide further insights on flood attributes (inundation, depth, duration) based on a unique household-level survey data set. The major moisture source for this event was the Alpine–Slovenian region (63 % of identified sources) due to recycling of precipitation falling over that region 1 d earlier. Implementing three different generalised extreme value (GEV) models, we quantified the return periods for this case to be above 100 years for daily aggregated precipitation, and up to 100 and 10 years for 8 and 1 h aggregations, respectively. The conditional attribution demonstrated that warming since the pre-industrial era caused a small but significant increase of 4 % in total precipitation and 10 % for extreme intensities. The possibility that not just greenhouse-gas-induced warming, but also anthropogenic aerosols affected the intensity of precipitation is investigated through aerosol sensitivity experiments. Our multi-disciplinary approach allowed us to relate interconnected aspects of extreme precipitation. For instance, the link between the unique meteorological conditions of this case and its very large return periods, or the extent to which it is attributable to already-observed anthropogenic climate change.</p

Meteorological, impact and climate perspectives of the 29 June 2017 heavy precipitation event in the Berlin metropolitan area

Extreme precipitation is a weather phenomenon with tremendous damaging potential for property and human life. As the intensity and frequency of such events is projected to increase in a warming climate, there is an urgent need to advance the existing knowledge on extreme precipitation processes, statistics and impacts across scales. To this end, a working group within the Germany-based project, ClimXtreme, has been established to carry out multidisciplinary analyses of high-impact events. In this work, we provide a comprehensive assessment of the 29 June 2017 heavy precipitation event (HPE) affecting the Berlin metropolitan region (Germany), from the meteorological, impacts and climate perspectives, including climate change attribution. Our analysis showed that this event occurred under the influence of a mid-tropospheric trough over western Europe and two shortwave surface lows over Britain and Poland (Rasmund and Rasmund II), inducing relevant low-level wind convergence along the German–Polish border. Over 11 000 convective cells were triggered, starting early morning 29 June, displacing northwards slowly under the influence of a weak tropospheric flow (10 m s$^{−1}$ at 500 hPa). The quasi-stationary situation led to totals up to 196 mm d$^{−1}$, making this event the 29 June most severe in the 1951–2021 climatology, ranked by means of a precipitation-based index. Regarding impacts, it incurred the largest insured losses in the period 2002 to 2017 (EUR 60 million) in the greater Berlin area. We provide further insights on flood attributes (inundation, depth, duration) based on a unique household-level survey data set. The major moisture source for this event was the Alpine–Slovenian region (63 % of identified sources) due to recycling of precipitation falling over that region 1 d earlier. Implementing three different generalised extreme value (GEV) models, we quantified the return periods for this case to be above 100 years for daily aggregated precipitation, and up to 100 and 10 years for 8 and 1 h aggregations, respectively. The conditional attribution demonstrated that warming since the pre-industrial era caused a small but significant increase of 4 % in total precipitation and 10 % for extreme intensities. The possibility that not just greenhouse-gas-induced warming, but also anthropogenic aerosols affected the intensity of precipitation is investigated through aerosol sensitivity experiments. Our multi-disciplinary approach allowed us to relate interconnected aspects of extreme precipitation. For instance, the link between the unique meteorological conditions of this case and its very large return periods, or the extent to which it is attributable to already-observed anthropogenic climate change

A pilot study for augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder

<p>Abstract</p> <p>Background</p> <p>This study examined augmenting atomoxetine with extended-release methylphenidate in children whose attention-deficit/hyperactivity disorder (ADHD) previously failed to respond adequately to stimulant medication.</p> <p>Methods</p> <p>Children with ADHD and prior stimulant treatment (<it>N </it>= 25) received atomoxetine (1.2 mg/kg/day) plus placebo. After 4 weeks, patients who were responders (<it>n </it>= 4) were continued on atomoxetine/placebo while remaining patients were randomly assigned to either methylphenidate (ATX/MPH) (1.1 mg/kg/day) or placebo augmentation (ATX/PB) for another 6 weeks. Patients and sites were blind to timing of active augmentation. Safety measures included vital signs, weight, and adverse events. Efficacy was assessed by ADHD rating scales.</p> <p>Results</p> <p>Categorical increases in vital signs occurred for 5 patients (3 patients in ATX/MPH, 2 patients in ATX/PBO). Sixteen percent discontinued the study due to AE, but no difference between augmentation groups. Atomoxetine treatment was efficacious on outcome measures (<it>P </it>≤ .001), but methylphenidate did not enhance response.</p> <p>Conclusion</p> <p>Methylphenidate appears to be safely combined with atomoxetine, but conclusions limited by small sample. With atomoxetine treatment, 43% of patients achieved normalization on ADHD ratings.</p

Character pathology and neuropsychological test performance in remitted opiate dependence

<p>Abstract</p> <p>Background</p> <p>Cognitive deficits and personality pathology are prevalent in opiate dependence, even during periods of remission, and likely contribute to relapse. Understanding the relationship between the two in vulnerable, opiate-addicted patients may contribute to the design of better treatment and relapse prevention strategies.</p> <p>Methods</p> <p>The Millon Multiaxial Clinical Inventory (MCMI) and a series of neuropsychological tests were administered to three subject groups: 29 subjects receiving methadone maintenance treatment (MM), 27 subjects in protracted abstinence from methadone maintenance treatment (PA), and 29 healthy non-dependent comparison subjects. Relationships between MCMI scores, neuropsychological test results, and measures of substance use and treatment were examined using bivariate correlation and regression analysis.</p> <p>Results</p> <p>MCMI scores were greater in subjects with a history of opiate dependence than in comparison subjects. A significant negative correlation between MCMI scores and neuropsychological test performance was identified in all subjects. MCMI scores were stronger predictors of neuropsychological test performance than measures of drug use.</p> <p>Conclusion</p> <p>Formerly methadone-treated opiate dependent individuals in protracted opiate abstinence demonstrate a strong relationship between personality pathology and cognitive deficits. The cause of these deficits is unclear and most likely multi-factorial. This finding may be important in understanding and interpreting neuropsychological testing deficiencies in opiate-dependent subjects.</p

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury:Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis

Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI