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The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis of complex traits. However, performing GWASs on millions of samples often leads to trade-offs between computational efficiency and statistical power, reducing the benefits of large-scale data collection efforts. We developed Quickdraws, a method that increases association power in quantitative and binary traits without sacrificing computational efficiency, leveraging a spike-and-slab prior on variant effects, stochastic variational inference and graphics processing unit acceleration. We applied Quickdraws to 79 quantitative and 50 binary traits in 405,088 UK Biobank samples, identifying 4.97% and 3.25% more associations than REGENIE and 22.71% and 7.07% more than FastGWA. Quickdraws had costs comparable to REGENIE, FastGWA and SAIGE on the UK Biobank Research Analysis Platform service, while being substantially faster than BOLT-LMM. These results highlight the promise of leveraging machine learning techniques for scalable GWASs without sacrificing power or robustness. Quickdraws is a mixed-model association tool with a noninfinitesimal prior for analyzing binary and quantitative traits, using a scalable variational inference that allows analysis of biobank-scale cohorts.

Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of analyses. We develop FastSMC, an IBD detection algorithm that combines a fast heuristic search with accurate coalescent-based likelihood calculations. FastSMC enables biobank-scale detection and dating of IBD segments within several thousands of years in the past. We apply FastSMC to 487,409 UK Biobank samples and detect ~214 billion IBD segments transmitted by shared ancestors within the past 1500 years, obtaining a fine-grained picture of genetic relatedness in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the use of genomic data to localize a sample’s birth coordinates with a median error of 45 km. We seek evidence of recent positive selection by identifying loci with unusually strong shared ancestry and detect 12 genome-wide significant signals. We devise an IBD-based test for association between phenotype and ultra-rare loss-of-function variation, identifying 29 association signals in 7 blood-related traits. Accurately measuring genetic relatedness by Identical-By-Descent (IBD) segments is challenging in biobank-level genome data. The authors present IBD method FastSMC, which when applied to the UK Biobank gives a detailed picture of genetic relatedness and evolutionary history in the UK over the past 2000 years.

Fine particulate matter that have a diameter of <2.5 μm (PM2.5) are an important factor of anthropogenic pollution since they are associated with the development of acute respiratory illnesses. The aim of this prospective study is to examine the correlation between PM2.5 levels in the semi-urban city of Volos and Emergency Department (ED) visits for respiratory causes. ED visits from patients with asthma, pneumonia and upper respiratory infection (URI) were recorded during a one-year period. The 24 h PM2.5 pollution data were collected in a prospective manner by using twelve fully automated air quality monitoring stations. PM2.5 levels exceeded the daily limit during 48.6% of the study period, with the mean PM2.5 concentration being 30.03 ± 17.47 μg/m3. PM2.5 levels were significantly higher during winter. When PM2.5 levels were beyond the daily limit, there was a statistically significant increase in respiratory-related ED visits (1.77 vs. 2.22 visits per day; p: 0.018). PM2.5 levels were also statistically significantly related to the number of URI-related ED visits (0.71 vs. 0.99 visits/day; p = 0.01). The temperature was negatively correlated with ED visits (r: −0.21; p < 0.001) and age was found to be positively correlated with ED visits (r: 0.69; p < 0.001), while no statistically significant correlation was found concerning humidity (r: 0.03; p = 0.58). In conclusion, PM2.5 levels had a significant effect on ED visits for respiratory causes in the city of Volos.

Synaptic plasticity underlies many aspect of learning memory and development. The properties of synaptic plasticity can change as a function of previous plasticity and previous activation of synapses, a phenomenon called metaplasticity. Synaptic plasticity not only changes the functional connectivity between neurons but in some cases produces a structural change in synaptic spines; a change thought to form a basis for this observed plasticity. Here we examine to what extent structural plasticity of spines can be a cause for metaplasticity. This study is motivated by the observation that structural changes in spines are likely to affect the calcium dynamics in spines. Since calcium dynamics determine the sign and magnitude of synaptic plasticity, it is likely that structural plasticity will alter the properties of synaptic plasticity. In this study we address the question how spine geometry and alterations of N-methyl-D-aspartic acid (NMDA) receptors conductance may affect plasticity. Based on a simplified model of the spine in combination with a calcium-dependent plasticity rule, we demonstrated that after the induction phase of plasticity a shift of the long term potentiation (LTP) or long term depression (LTD) threshold takes place. This induces a refractory period for further LTP induction and promotes depotentiation as observed experimentally. That resembles the BCM metaplasticity rule but specific for the individual synapse. In the second phase, alteration of the NMDA response may bring the synapse to a state such that further synaptic weight alterations are feasible. We show that if the enhancement of the NMDA response is proportional to the area of the post synaptic density (PSD) the plasticity curves most likely return to the initial state. Using simulations of calcium dynamics in synaptic spines, coupled with a biophysically motivated calcium-dependent plasticity rule, we find under what conditions structural plasticity can form the basis of synapse specific metaplasticity.

The impetus behind our study was to establish a quantitative comparison between the IRIS collimator and the InCise multileaf collimator (MLC) (Accuray Inc. Synnyvale, CA) for prostate stereotactic body radiation therapy (SBRT). Treatment plans for ten prostate cancer patients were performed on MultiPlan™ 5.1.2 treatment planning system utilizing MLC and IRIS for 36.25 Gy in five fractions. To reduce the magnitude of variations between cases, the planning tumor volume (PTV) was defined and outlined for treating prostate gland only, assuming no seminal vesicle or ex-capsule involvement. Evaluation indices of each plan include PTV coverage, conformity index (CI), Paddick's new CI, homogeneity index, and gradient index. Organ at risk (OAR) dose sparing was analyzed by the bladder wall Dmaxand V37Gy, rectum Dmaxand V36Gy. The radiobiological response was evaluated by tumor control probability and normal tissue complication probability based on equivalent uniform dose. The dose delivery efficiency was evaluated on the basis of planned monitor units (MUs) and the reported treatment time per fraction. Statistical significance was tested using the Wilcoxon signed rank test. The studies indicated that CyberKnife M6™ IRIS and InCise™ MLC produce equivalent SBRT prostate treatment plans in terms of dosimetry, radiobiology, and OAR sparing, except that the MLC plans offer improvement of the dose fall-off gradient by 29% over IRIS. The main advantage of replacing the IRIS collimator with MLC is the improved efficiency, determined from the reduction of MUs by 42%, and a 36% faster delivery time.

A rare case of Sphingomonas paucimobilis endophthalmitis secondary to a penetrating globe injury with a retained intraocular foreign body is presented. A 30-year-old man presented with severe pain following a penetrating left eye injury. Visual acuity (VA) was 6/120. Slit-lamp examination revealed perforation of the temporal cornea and iris, hypopyon, and a fibrinous membrane covering the pupil. Ultrasonography showed dense vitreous infiltration and an orbital CT-scan confirmed the presence of a metallic foreign body in the vitreous cavity. Topical and systemic therapy were initiated. Pars-plana vitrectomy combined with phacoemulsification was performed in order to remove the foreign body; vitreous samples were acquired and Sphingomonas paucimobilis, sensitive to ceftazidime, was identified. To the best of our knowledge, this is the first report of Sphingomonas paucimobilis endophthalmitis following penetrating ocular injury. In this case, Sphingomonas paucimobilis was not resistant to antibiotics. This allowed for a good healing response following vitrectomy despite the fact that long-term retinal complications resulted in low VA.

Ambient air pollution accounts for an estimated 4.2 million deaths worldwide. Particulate matter (PM)2.5 particles are believed to be the most harmful, as when inhaled they can penetrate deep into the lungs. The aim of this study was to examine the relationship between PM2.5 daily air concentrations and pediatric emergency department (ED) visits for respiratory diseases in a Greek suburban area. All pediatric ED visits for asthma-, pneumonia- and upper respiratory infection (URI)-related complaints were recorded during the one-year period. The 24-h PM2.5 air pollution data were prospectively collected from twelve fully automated air quality monitoring stations. The mean annual concentration of PM2.5 was 30.03 μg/m3 (World Health Organization (WHO) Air Quality Guidelines (AQG) Annual mean concentration: 10 μg/m3). PM2.5 levels rose above the WHO Air Quality Guidelines (AQG) 24-h concentrations (25 μg/m3)), 178 times (48.6% of the study period). When PM2.5 levels were above the daily limit, an increase of 32.44% (p < 0.001) was observed in daily pediatric ED visits for respiratory diseases and the increase was much higher during spring (21.19%, p = 0.018). A 32% (p < 0.001) increase was observed in URI-related visits, when PM2.5 levels were ≥25 μg/m3, compared to the mean daily visits when PM2.5 levels were <25 μg/m3. Air pollution levels were associated with increased pediatric ED visits for respiratory-related diseases.

South Asians develop type 2 diabetes (T2D) early in life and often with normal body mass index (BMI). However, reasons for this are poorly understood because genetic research is largely focused on European ancestry groups. We used recently derived multi-ancestry partitioned polygenic scores (pPSs) to elucidate underlying etiological pathways British Pakistani and British Bangladeshi individuals with T2D ( n  = 11,678) and gestational diabetes mellitus (GDM) ( n  = 1,965) in the Genes & Health study ( n = 50,556). Beta cell 2 (insulin deficiency) and Lipodystrophy 1 (unfavorable fat distribution) pPSs were most strongly associated with T2D, GDM and younger age at T2D diagnosis. Individuals at high genetic risk of both insulin deficiency and lipodystrophy were diagnosed with T2D 8.2 years earlier with BMI 3 kg m − 2 lower compared to those at low genetic risk. The insulin deficiency pPS was associated with poorer HbA1c response to SGLT2 inhibitors. Insulin deficiency and lipodystrophy pPSs were associated with faster progression to insulin dependence and microvascular complications. South Asians had a greater genetic burden from both of these pPSs than white Europeans in the UK Biobank. In conclusion, genetic predisposition to insulin deficiency and lipodystrophy in British Pakistani and British Bangladeshi individuals is associated with earlier onset of T2D, faster progression to complications, insulin dependence and poorer response to medication. In a cohort of 50,556 South Asian individuals, partitioned polygenic scores helped identify genetic susceptibility to insulin deficiency and unfavorable fat distribution as key drivers of young-onset T2D diagnosis and faster progression to diabetes-related complications.

Ambient air pollution accounts for an estimated 4.2 million deaths worldwide. Particulate matter (PM)[sub.2.5] particles are believed to be the most harmful, as when inhaled they can penetrate deep into the lungs. The aim of this study was to examine the relationship between PM[sub.2.5] daily air concentrations and pediatric emergency department (ED) visits for respiratory diseases in a Greek suburban area. All pediatric ED visits for asthma-, pneumonia- and upper respiratory infection (URI)-related complaints were recorded during the one-year period. The 24-h PM[sub.2.5] air pollution data were prospectively collected from twelve fully automated air quality monitoring stations. The mean annual concentration of PM[sub.2.5] was 30.03 μg/m[sup.3] (World Health Organization (WHO) Air Quality Guidelines (AQG) Annual mean concentration: 10 μg/m[sup.3]). PM[sub.2.5] levels rose above the WHO Air Quality Guidelines (AQG) 24-h concentrations (25 μg/m[sup.3])), 178 times (48.6% of the study period). When PM[sub.2.5] levels were above the daily limit, an increase of 32.44% (p < 0.001) was observed in daily pediatric ED visits for respiratory diseases and the increase was much higher during spring (21.19%, p = 0.018). A 32% (p < 0.001) increase was observed in URI-related visits, when PM[sub.2.5] levels were ≥25 μg/m[sup.3], compared to the mean daily visits when PM[sub.2.5] levels were <25 μg/m[sup.3]. Air pollution levels were associated with increased pediatric ED visits for respiratory-related diseases.

Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses ( n  = 6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria. Genome-wide analyses identify variants associated with infertility and reproductive hormone levels but find limited polygenic overlap between reproductive hormone levels and infertility at the population level.