The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies

Background: The Framingham Heart Study (FHS) recently obtained initial results from the first genome-wide association scan for renal traits. The study of 70,987 single nucleotide polymorphisms (SNPs) in 1,010 FHS participants provides a list of SNPs showing the strongest associations with renal traits which need to be verified in independent study samples. Methods: Sixteen SNPs were selected for replication based on the most promising associations with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and serum cystatin C in FHS. These SNPs were genotyped in 15,747 participants of the Atherosclerosis in Communities (ARIC) Study and evaluated for association using multivariable adjusted regression analyses. Primary outcomes in ARIC were CKD and eGFR. Secondary prospective analyses were conducted for association with kidney disease progression using multivariable adjusted Cox proportional hazards regression. The definition of the outcomes, all covariates, and the use of an additive genetic model was consistent with the original analyses in FHS. Results: The intronic SNP rs6495446 in the gene MTHFS was significantly associated with CKD among white ARIC participants at visit 4: the odds ratio per each C allele was 1.24 (95% CI 1.09–1.41, p = 0.001). Borderline significant associations of rs6495446 were observed with CKD at study visit 1 (p = 0.024), eGFR at study visits 1 (p = 0.073) and 4 (lower mean eGFR per C allele by 0.6 ml/min/1.73 $\text{m}^2$, p = 0.043) and kidney disease progression (hazard ratio 1.13 per each C allele, 95% CI 1.00–1.26, p = 0.041). Another SNP, rs3779748 in EYA1, was significantly associated with CKD at ARIC visit 1 (odds ratio per each T allele 1.22, p = 0.01), but only with eGFR and cystatin C in FHS. Conclusion: This genome-wide association study provides unbiased information implicating MTHFS as a candidate gene for kidney disease. Our findings highlight the importance of replication to identify common SNPs associated with renal traits

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology

Background: Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries.Methods: We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty.Discussion: This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach.Systematic review registration: PROSPERO CRD42021234119</p

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Tiatsididiureettien käyttö suurentaa luuntiheyttä ja pienentää murtumariskiä:järjestelmällinen kirjallisuuskatsaus ja meta-analyysi

Tiivistelmä Verenpainetaudin hoidossa käytettävät tiatsididiureetit estävät natriumin ja kloridin takaisinimeytymistä munuaisissa, jolloin natriumin, kloridin ja veden eritys virtsaan lisääntyy. Lisäksi tiatsidit vähentävät kalsiumin ja lisäävät kaliumin eritystä. Koska tiatsidit vähentävät kalsiumin eritystä, on pohdittu tiatsididiureettien suotuisaa vaikutusta luuntiheyteen ja murtumariskiin. Teimme järjestelmällisen kirjallisuuskatsauksen tiatsididiureettien vaikutuksesta luuntiheyteen ja murtumariskiin pohjautuen satunnaistettuihin ja kontrolloituihin lääketutkimuksiin. Lisäksi teimme meta-analyysin tiatsididiureettien vaikutuksesta murtumariskiin. Järjestelmällisen kirjallisuuskatsauksen perusteella tiatsididiureettien käyttäjillä luuntiheys on suurentunut verrattuna lähtötilaan tai lume-/kontrollilääkettä käyttäneisiin. Meta-analyysin perusteella tiatsidiryhmän lääkkeet pienensivät suhteellista murtumariskiä 25 prosenttia valtaosin iäkkäistä potilaista koostuneissa tutkimuksissa. Puolessa meta-analyysiin valituista tutkimuksista ei kuitenkaan käytetty Suomessa yleisimmin käytettyä hydroklooritiatsidia. Kirjallisuuskatsauksessa ja meta-analyysissä saatiin tukea oletukselle, että tiatsididiureettien käyttö suurentaa luuntiheyttä ja pienentää murtumariskiä. Verenpainetaudin hoidossa tiatsidit näyttäisivät tuovan iäkkäillä potilailla lisähyötyä murtumariskin pienenemisen muodossa. Tiatsidien tunnetut haittavaikutukset tulee huomioida hoitopäätöstä tehdessä. Koska tiatsidien murtumavaikutuksia selvittävät tutkimukset on tehty pääosin verenpainetautia sairastavilla, ei tiatsideja voida suositella normotensiivisten potilaiden murtumariskin pienentämiseen.Summary Thiazide diuretics increase bone mineral density and lower fracture risk : systematic review and meta-analysis Thiazide diuretics exert their antihypertensive effect by inhibiting the reabsorption of sodium and chloride in kidneys, leading to increases in urinary sodium, chloride and water excretion. In addition, thiazides decrease urinary calcium excretion while increasing that of potassium. Since thiazides reduce the excretion of calcium, it has been hypothesized that thiazides could exert a beneficial effect on bone mineral density and reduce the risk of fractures. We conducted a systematic review of randomized controlled trials to determine if thiazide diuretics have any beneficial effect on bone mineral density and the risk of fractures. We also performed a meta-analysis on the effect of thiazides on the risk of fractures. The systematic literature review demonstrated that the use of thiazides was associated with an increased bone mineral density. A 25% lower risk of fractures was demonstrated in the meta-analysis of the studies with mostly elderly patients. However, hydrochlorothiazide, the most widely used thiazide in Finland, was used only in half of the studies included in the meta-analysis. Thiazide diuretics are useful in the treatment of hypertension, and the lower fracture risk is an additional benefit in older patients. However, one should take into consideration the widely recognized adverse effect of thiazides before starting the treatment. Finally, since the studies reporting on thiazide use and hip fractures were conducted in hypertensive patients, the thiazides cannot be recommended to prevent fractures in normotensive individuals

Climate Change Education : A New Approach for a World of Wicked Problems

Human activity is the most important factor determining our future. The rapid growths of population and materialistic ways of living have given rise to what many geologists now call the era of the Anthropocene. We argue that in order to solve the wicked problems of the Anthropocene—such as climate change—we need education to be organized around sensing and actualizing the full potential of a human being. It is necessary to clarify the goal of education and the ideals of society toward that pursuit. Climate change education supports building societies that are characterized by flexible, creative, adaptable, well-informed and inventive sustainable well-being communities. In this article, we define the special aspects of climate change education and ask: how could we educate people for transformation toward a sustainable future? What kind of holistic change in thinking and action is needed for the construction of hope and of a sustainable future? What kind of pedagogical approaches can promote full humanness?Peer reviewe