Effects of eight neuropsychiatric copy number variants on human brain structure

peer reviewedMany copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions. © 2021, The Author(s)

Overprinting orogenic events, ductile extrusion and strain partitioning during Caledonian transpression, NW Mainland Shetland

A 3.6 km thick stack of mid-crustal deformed Precambrian rocks is associated with the North Roe Nappe (NRN) and Walls Boundary Fault in the northernmost Scottish Caledonides on NW Mainland Shetland. The greenschist- to amphibolite-facies rocks display unusually complex and heterogeneous combinations of coaxial and non-coaxial transpressional deformation. Previously published isotopic dating, together with new detailed field mapping and microstructural characterisation show that the NRN preserves a record of Neoarchaean, Neoproterozoic (Knoydartian) and Ordovician-Silurian (Caledonian) overprinting deformation and metamorphism. Neoarchaean events in the Uyea Gneiss Complex located in its footwall are reworked by younger events in the overlying nappe pile. The main ductile fabrics were formed during Caledonian top-to-the W/NW thrusting and top-to-the N sinistral shearing, with subordinate regions of top- to-the E extensional and NNE-SSW dextral shearing. In lower parts of the NRN, these different kinematic domains are texturally indistinguishable and overprinting relationships are absent. At higher levels, top-to-the-W/NW thrust-related fabrics are consistently overprinted by top-to-the-N/NE sinistral shearing. The highly partitioned transpressional deformation shows similarities with equivalent rocks of the Moine Nappe in NW Scotland

Current issues on safety of prokinetics in critically ill patients with feed intolerance

Feed intolerance in the setting of critical illness should be treated promptly given its adverse impact on morbidity and mortality. The technical difficulty of postpyloric feeding tube placement and the morbidities associated with parenteral nutrition prevent these approaches being considered as first-line nutrition. Prokinetic agents are currently the mainstay of therapy for feed intolerance in the critically ill. Current information is limited but suggests that erythromycin or metoclopramide (alone or in combination) are effective in the management of feed intolerance in the critically ill and not associated with significant cardiac, haemodynamic or neurological adverse effects. However, diarrhoea is a very common gastrointestinal side effect, and can occur in up to 49% of patients who receive both erythromycin and metoclopramide. Fortunately, the diarrhoea associated with prokinetic treatments has not been linked to Clostridium difficile infection and settles soon after the drugs are ceased. Therefore, prolonged or prophylactic use of prokinetics should be avoided. If diarrhoea occurs, the drugs should be stopped immediately. To minimize avoidable adverse effects the ongoing need for prokinetic drugs in these patient should be reviewed daily.Nam Q. Nguyen and Swee Lin Chen Yi Me

Lymph node evaluation and survival after curative-intent resection of duodenal adenocarcinoma: A matched cohort study

Lymph node (LN) metastasis in patients with duodenal adenocarcinoma is associated with poor prognosis; however, the optimal extent of LN assessment and the interaction between LN assessment and adjuvant systemic therapy is poorly understood. Resected non-metastatic duodenal adenocarcinoma patients (n = 1743) were identified in the National Cancer Database (1998–2011). Logistic regression analysis identified covariates associated with LN metastasis. The influence of increasing LN cut-off points on overall survival (OS) was analysed using the log-rank test and Cox proportional hazards modelling. Adjuvant chemotherapy (AC) and surgery alone cohorts were matched (1:1) by propensity scores based on the likelihood of nodal metastasis or survival hazard on Cox modelling. OS in the matched cohort was compared by Kaplan–Meier estimates. LN metastases were present in 865 (49.6%) patients. Increasing LN assessment was associated with an increased likelihood of nodal involvement (P = 0.008). In node-negative patients, increasing LN assessment was associated with a decreased risk of death, with the largest actuarial survival differences observed for ≥15 LN (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48–0.82, P = 0.001). In the propensity score-matched cohort of node-negative patients, AC was associated with non-significant improvements in 5-year actuarial (66.1% versus 58.7%, HR 0.79, 95% CI 0.53–1.18, P = 0.249), and did not vary by adequacy of LN counts (<15 LNs: HR 0.79, 95% CI 0.51–1.24, P = 0.305; ≥15 LNs: HR 0.90, 95% CI 0.35–2.30, P = 0.900). The extent of LN identification has prognostic significance in resected node-negative duodenal adenocarcinoma, but cannot be implicated in the selection of node-negative patients for AC. By analysis of the United States National Cancer Database:•Duodenal adenocarcinoma is a rare gastrointestinal malignancy.•Prognostically relevant lymph node cut-points are associated with survival variations in resected patients.•Adjuvant systemic therapy does not provide a survival advantage for node-negative patients with ‘inadequate’ lymph node staging