Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.

There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

Influencing factors and processes of interprofessional professional education (IPE) implementation.

BACKGROUND: Interprofessional education (IPE) is an instructional approach for equipping health professions students with essential competencies needed to provide collaborative patient-centred care. The implementation and sustainability of IPE are challenging for many institutions. This qualitative study identified barriers and facilitators in the processes of IPE implementation. METHODS: We conducted mixed focus groups (FGs) with faculty members from medicine, dentistry, pharmacy, nutrition and dietetics, nursing, chiropractic, Chinese medicine, and other health sciences programmes; who were involved in the planning of IPE at institutional or programme level, or who participated in IPE activity. Transcripts were analysed using grounded theory. RESULTS: We identified 25 barriers and facilitators, clustered under five major categories of commitment, faculty engagement, IPE design, support, and delivery. CONCLUSIONS: Successful implementation of IPE may hinge on actions in 5 stages; commitment, faculty engagement, IPE design, support, and delivery. The processes will require consistent leadership to break down professional silos and enhance collaborative effort in IPE implementation.

Twelve tips for institutional approach to outcome-based education in health professions programmes.

Outcome-based education (OBE) has brought along a significant development in health professions education in the past decade. The shift from a process-driven to product-driven model of education is valuable for ensuring graduate quality and facilitating global movement of healthcare workers. Such a model can align the expectations of key stakeholders in an era of rapid knowledge expansion and technological advancement. Nevertheless, the experienced benefits of OBE depend on the effectiveness of its implementation. This article therefore provides practical tips and strategies for implementing OBE in order to maximize its potential.

Safety and efficacy of en bloc transurethral resection versus conventional transurethral resection for primary nonmuscle-invasive bladder cancer: a meta-analysis.

BACKGROUND: The purpose of this meta-analysis is to compare the safety and efficacy of en bloc transurethral resection of bladder tumor (EBRT) versus conventional transurethral resection of bladder tumor (CTURBT). METHODS: We performed a meta-analysis of relevant articles through November 2019 using PubMed, Embase, and Cochrane Central Register to compare the safety and efficacy of EBRT versus CTURBT. The main endpoint included the operation time (OT), hospitalization time (HT), catheterization time (AT), perioperative period complications, bladder detrusor muscle found in the specimen, the residual tumor on the base, the ratio of the same site recurrence, and 12/24/36-month recurrence rate. Cochrane Collaboration's Revman software, version 5.3, was used for statistical analysis. RESULTS: A total of 19 studies with 2651 patients were included, 1369 underwent EBRT and 1282 underwent CTURBT. Patients treated with EBRT had a significantly lower AT, HT, obturator nerve reflex, bladder perforation, bladder irritation, postoperative complications, and 24-month recurrence rate than those who underwent CTURBT. While no significant difference was found in terms of OT, the ratio of bladder detrusor muscle found in the specimen, the residual tumor on the base, 12-month recurrence rate, 36-month recurrence rate, and the ratio of the same site recurrence. In mitomycin subgroup, EBRT was superior to CTURBT in terms of 12/24-month recurrence rate. Similarly, in the prospective subgroup and retrospective subgroup, EBRT had a lower 24-month recurrence rate than CTURBT. However, no significant difference was found in the low, intermediate, and high-risk group in the light of 12-36-month recurrence rate. CONCLUSIONS: Based on the included 19 articles, EBRT had a significantly lower AT, HT, intraoperative and postoperative complications, and 24-month recurrence rate than those treated with CTURBT. Well-designed randomized controlled trials were needed to reevaluate these outcomes. TRIAL REGISTRATION: This meta-analysis was reported in agreement with the PRISMA statement and was registered on PROSPERO 2019 CRD42019121673.

Comparison of Two Autoimmune Dysglycemia Syndromes: Insulin Autoimmune Syndrome (IAS) and Type B Insulin Resistance Syndrome (B-IRS).

Insulin autoimmune syndrome (IAS) and type B insulin resistance syndrome (B-IRS) are rare autoimmune dysglycemia syndromes, but their treatment and prognosis are different. This study aimed to provide a basis for the clinical differential diagnosis of IAS and B-IRS. This was a retrospective study of the medical records of all patients diagnosed with IAS or B-IRS between January 2006 and March 2018 at the Chinese PLA General Hospital. Demographic, clinical, biochemistry, treatment, and follow-up data were examined. There were several different biochemical parameters between IAS (n=13) and B-IRS (n=6): white blood count (WBC, 7.05±3.06 vs. 2.70±0.73×109/l, p=0.004), platelet (249±56.6 vs. 111±68.0×109/l, p<0.001), serum creatine (59.0±17.8 vs. 43.1±7.05 µmol/l, p=0.013), serum albumin (42.3±5.17 vs. 33.6±3.40 g/l, p=0.002), triglyceride (median, 1.33 (1.01, 1.93) vs. 0.56 (0.50, 0.79) mmol/l, p=0.002), plasma IgG (1183±201 vs. 1832±469 mg/ml, p=0.018), IgA (328±140 vs. 469±150 mg/ml, p=0.018), and C3 (128±23.4 vs. 45.3±13.5 mg/l, p<0.001). Fasting insulin in the IAS and B-IRS patients was high (299-4708 vs. 118-851 mU/l, p=0.106), and there was a difference in 2 h oral glucose tolerance test insulin (4217-8343 mU/l vs. 274-1143 mU/l, p=0.012). Glycated hemoglobin (HbA1c) in the B-IRS patients was higher than in IAS patients (114±14.4. vs. 40.6±8.89 mmol/mol, p<0.001). Serum insulin-like growth factor-1 (IGF-1) was lower in all B-IRS patients (25±0.00 vs. 132±52.7 ng/ml, p<0.001). Although IAS and B-IRS are autoimmune hyperinsulinemic dysglycemic syndromes, several clinical parameters (body mass index, HbA1c, WBC, platelet, albumin, triglyceride, IgG, C3, and IGF-1) are different between these two syndromes.

Phenotypes of AKT3 deletion: a case report and literature review.

AKT3 (v-akt murine thymoma viral oncogene homolog 3) is located at chromosome 1q44 and encodes a 479 amino acid protein, a member of the protein kinase B (PKB) family. This gene is frequently involved in 1q44 deletion syndrome in patients with microcephaly, intellectual disability, and dysmorphic features. Phenotype and genotype studies of patients with 1q44 deletion syndrome have suggested that deletion of the AKT3 gene is responsible for the microcephaly in these patients. However, the phenotype of pure AKT3 deletion has not been studied. We report on a 1q44 deletion involving only AKT3 in a boy and his father. The boy has microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features. His father does not have microcephaly and is of normal intelligence. We also analyzed the available information on the phenotypes of 13 individuals carrying a pure AKT3 gene deletion identified through literature review and database search. To our knowledge, this is the first report of a paternally inherited pure AKT3 deletion with full clinical description. This is also the first report to suggest that (1) AKT3 deletion is associated with microcephaly and intellectual disability with incomplete penetrance; (2) a pure AKT3 deletion is likely to be inherited in contrast to the larger 1q44 deletions, which are mostly de novo and (3) there seems to be no consistent or characteristic dysmorphism associated with pure AKT3 deletion.

Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review.

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.

Nasogastric or nasojejunal feeding in predicted severe acute pancreatitis: a meta-analysis.

INTRODUCTION: Enteral feeding can be given either through the nasogastric or the nasojejunal route. Studies have shown that nasojejunal tube placement is cumbersome and that nasogastric feeding is an effective means of providing enteral nutrition. However, the concern that nasogastric feeding increases the chance of aspiration pneumonitis and exacerbates acute pancreatitis by stimulating pancreatic secretion has prevented it being established as a standard of care. We aimed to evaluate the differences in safety and tolerance between nasogastric and nasojejunal feeding by assessing the impact of the two approaches on the incidence of mortality, tracheal aspiration, diarrhea, exacerbation of pain, and meeting the energy balance in patients with severe acute pancreatitis. METHOD: We searched the electronic databases of the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We included prospective randomized controlled trials comparing nasogastric and nasojejunal feeding in patients with predicted severe acute pancreatitis. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the two reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as Risk Ratio (RR) with 95% confidence intervals (CIs). RESULTS: We included three randomized controlled trials involving a total of 157 patients. The demographics of the patients in the nasogastric and nasojejunal feeding groups were comparable. There were no significant differences in the incidence of mortality (RR=0.69, 95% CI: 0.37 to 1.29, P=0.25); tracheal aspiration (RR=0.46, 95% CI: 0.14 to 1.53, P=0.20); diarrhea (RR=1.43, 95% CI: 0.59 to 3.45, P=0.43); exacerbation of pain (RR=0.94, 95% CI: 0.32 to 2.70, P=0.90); and meeting energy balance (RR=1.00, 95% CI: 0.92 to 1.09, P=0.97) between the two groups. Nasogastric feeding was not inferior to nasojejunal feeding. CONCLUSIONS: Nasogastric feeding is safe and well tolerated compared with nasojejunal feeding. Study limitations included a small total sample size among others. More high-quality large-scale randomized controlled trials are needed to validate the use of nasogastric feeding instead of nasojejunal feeding.

The Multiple Mini-Interview (MMI) for student selection in health professions training - a systematic review.

BACKGROUND: The Multiple Mini-Interview (MMI) has been used increasingly for selection of students to health professions programmes. OBJECTIVES: This paper reports on the evidence base for the feasibility, acceptability, reliability and validity of the MMI. DATA SOURCES: CINAHL and MEDLINE STUDY ELIGIBILITY CRITERIA: All studies testing the MMI on applicants to health professions training. STUDY APPRAISAL AND SYNTHESIS METHODS: Each paper was appraised by two reviewers. Narrative summary findings on feasibility, acceptability, reliability and validity are presented. RESULTS: Of the 64 citations identified, 30 were selected for review. The modal MMI consisted of 10 stations, each lasting eight minutes and assessed by one interviewer. The MMI was feasible, i.e. did not require more examiners, did not cost more, and interviews were completed over a short period of time. It was acceptable, i.e. fair, transparent, free from gender, cultural and socio-economic bias, and did not favour applicants with previous coaching. Its reliability was reported to be moderate to high, with Cronbach's alpha = 0.69-0.98 and G = 0.55-0.72. MMI scores did not correlate to traditional admission tools scores, were not associated with pre-entry academic qualifications, were the best predictor for OSCE performance and statistically predictive of subsequent performance at medical council examinations. CONCLUSIONS: The MMI is reliable, acceptable and feasible. The evidence base for its validity against future medical council exams is growing with reports from longitudinal investigations. However, further research is needed for its acceptability in different cultural context and validity against future clinical behaviours.

[Roles of targeting Ras/Raf/MEK/ERK signaling pathways in the treatment of esophageal carcinoma].

Ras is best known for its ability to regulate cell growth, proliferation and differentiation. Mutations in Ras are associated with the abnormal cell proliferation which can result in incidence of all human cancers. Extracellular signal-regulated kinase (ERK) is a downstream effector of Ras and plays important roles in prognosis of tumors. Recently, evidence has gradually accumulated to demonstrate that there are other effectors between Ras and ERK, these proteins interact each other and constitute the thorough Ras/Raf/MEK/ERK signaling pathway. The pathway has profound effects on incidence of esophageal carcinoma and clinical applications of some chemotherapeutic drugs targeting the pathway. Further understanding of the relevant molecular mechanisms of Ras/Raf/MEK/ERK signaling pathway can be helpful for the development of efficient targeting therapeutic approaches which contribute to the treatment of esophageal cancer. In this article, roles of Ras/Raf/MEK/ERK signaling pathway in esophageal carcinoma as well as pharmacological targeting point in the pathway are reviewed.

Epilepsy with cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

The clinical significance of chromosomal microdeletions and microduplications was predicted based on their gene content, de novo or familial inheritance and accumulated knowledge recorded on public databases. A patient group comprised of 247 cases with epilepsy and its common co-morbidities of developmental delay, intellectual disability, autism spectrum disorders, and congenital abnormalities was reviewed prospectively in a diagnostic setting using a standardized oligo-array CGH platform. Seventy-three (29.6%) had copy number variations (CNVs) and of these 73 cases, 27 (37.0%) had CNVs that were likely causative. These 27 cases comprised 10.9% of the 247 cases reviewed. The range of pathogenic CNVs associated with seizures was consistent with the existence of many genetic determinants for epilepsy.

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

The cGAS-STING pathway-related gene signature can predict patient prognosis and immunotherapy responses in prostate adenocarcinoma.

The cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway is essential in inflammation-driven tumor occurrence and progression. However, the prognostic roles and immune functions of cGAS-STING pathway-related genes in patients with prostate adenocarcinoma (PRAD) remain unclear. cGAS-STING pathway-related genes were obtained from the gene set enrichment analysis (GSEA) website. Univariate Cox regression analysis was performed to screen the prognosis-related hub genes in the cancer genome atlas (TCGA) and GSE116918 datasets. Unsupervised clustering analysis was performed to identify different clusters. The least absolute shrinkage and selection operator and multivariate Cox regression analyses were applied to develop a prognostic risk model. The prognostic values and predictive performance of risk signature were assessed by the Kaplan-Meier curve and receiver operating characteristic curve. The IMvigor210 cohort was used to investigate the potential values of the risk score in immunotherapeutic responses. Two clusters were identified based on the expression matrix of 12 prognosis-related genes. Specifically, better overall survival was observed in cluster 2 than cluster 1 in both datasets. Inflammation-related pathway enrichment and immune cell infiltration levels were altered between 2 clusters. Moreover, 6 genes (CASP8, GRK6, IL3RA, PLCB1, TBKBP1, and TNFSF10) were identified to generate a cGAS-STING pathway-related signature (CPRS). Survival analysis showed that patients in the high-risk group showed a more dismal survival than those in the low-risk group in TCGA and GSE116918 datasets. Notably, the CPRS can differentiate responsive patients from non-responsive individuals treated with PD-L1 blockades in an independent cohort. In addition, higher CPRS was associated with a more favorable prognosis. The proposed risk model was developed based on 6 cGAS-STING pathway related-genes, which can be used as a promising predictor for patient survival and immunotherapeutic responses in PRAD, contributing to treatment strategy-related decision-making.

BAP1 Tumour Predisposition Syndrome Due to Whole BAP1 Gene Deletion.

BRCA-1-associated protein-1 (BAP1) tumour predisposition syndrome (BAP1-TPDS) is a dominant hereditary cancer syndrome. The full spectrum of associated malignancies is yet to be fully characterised. We detail the phenotypic features of the first reported family with a whole BAP1 gene deletion. This report also adds to the emerging evidence that the rhabdoid subtype of meningioma is a part of the clinical spectrum of this tumour predisposition syndrome.

Malic enzyme 2 promotes the progression of hepatocellular carcinoma via increasing triglyceride production.

The incidence and mortality of hepatocellular carcinoma (HCC) are gradually increasing during the past years. Recently, some studies have reported that malic enzyme (ME) plays an important role in cancer development, while the involvement of ME2 in HCC remains still undetermined. Here, we demonstrated that ME2 played an oncogenic role in HCC. ME2 was overexpressed in HCC tissues. TCGA database showed that the ME2 transcript level was inversely associated with the survival of HCC patients. Loss-of-function and gain-of-function assays showed that ME2 promoted HCC cell growth and migration. Furthermore, the xenografted tumorigenesis of MHCC97H cells was retarded by ME2 knockdown. ME2 silencing also suppressed the cell cycle process and induced apoptosis. Mechanistically, ME2 potentiated triglyceride synthesis, inhibition of which suppressed the proliferation and migration. We propose that ME2 promotes HCC progression by increasing triglyceride production.

Detection of microchromosomal aberrations in refractory epilepsy: a pilot study.

Seizures often occur in patients with microchromosomal aberrations responsible for moderate to severe intellectual disability. We hypothesised that epilepsy alone could be caused by microdeletions or microduplications, which might also relate to epilepsy refractory to medication. Chromosomes from 20 subjects with epilepsy and repeated failure of antiepileptic medication were examined using molecular methods. Firstly, the 41 subtelomeric regions were scanned using fluorescence in situ hybridization and multiplex ligation-dependent probe amplification. Secondly, a genome-wide scan was carried out using oligonucleotide-array comparative genome hybridisation on two platforms: Nimblegen and Agilent. Two aberrations (2/20) were identified: a recurrent microdeletion at 15q13.3 previously characterised in patients with seizures that generally respond to medication, and a novel 1.15 Mb microchromosomal duplication at 10q21.2 also present in the unaffected mother. We conclude that gene content of microchromosomal aberrations is not a major cause of refractory seizures, but that microchromosomal anomalies are found in an appreciable fraction of such cases.