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Colonoscopy with endoscopic resection of detected colonic adenomas interrupts the adenoma-carcinoma sequence and reduces the incidence of colorectal cancer and cancer-related mortality. In the past decade, there have been significant developments in instruments and techniques for endoscopic polypectomy. Guidelines have been formulated by various professional bodies in Europe, Japan and the United States, but some of the recommendations differ between the various bodies. An expert professional workgroup under the auspices of the Academy of Medicine, Singapore, was set up to provide guidance on the endoscopic management of colonic polyps in Singapore. A total of 23 recommendations addressed the following issues: accurate description and diagnostic evaluation of detected polyps; techniques to reduce the risk of post-polypectomy bleeding and delayed perforation; the role of specific endoscopic resection techniques; the histopathological criteria for defining endoscopic cure; and the role of surveillance colonoscopy following curative resection.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.

Objective: Self-Care of Heart Failure Index (SCHFI) v6.2 Chinese is an instrument used to assess the ability of self-care behaviour among heart failure patients. It has been validated in Taiwan, however, it is yet to be validated in Malaysia. As a multi-ethnic country, Chinese language has been one of the major languages in Malaysia. Therefore, this study was conducted to examine the reliability of Self-Care of Heart Failure Index (SCHFI) v6.2 Chinese among Malaysian population. Design: A successive independent sample design was used throughout a 4-months data collection period. Setting: Eighty heart failure patients from University of Malaya Medical Centre and National Heart Institute were recruited through purposive sampling. The two hospitals were chosen because they have specialized heart clinics that eased the data collection. The out-patients were screened by the cardiologists for their eligibility to participate in this study. Measures: The samples were administered with SCHFI v6.2 Chinese. The item endorsement index, internal consistency and item-total correlation of SCHFI v6.2 Chinese were examined. Results: The maintenance subscale of SCHFI showed a low internal consistency (Cronbach α = .52) while the management and confidence subscales showed an acceptable internal consistency (Cronbach α = .67 and .90 respectively). Conclusion: SCHFI v6.2 Chinese is a reliable instrument to be used among the Malaysian population.

Objective This research was performed to investigate the correlation between acute kidney injury (AKI) and systemic immune-inflammation index (SII) in severe acute pancreatitis (SAP) patients. Methods The study included 218 SAP patients from Chongqing Jiangjin Center Hospital during January 2016 to October 2020. The SII was defined as platelet × neutrophil/lymphocyte ratio. After univariate analysis, logistic regression analysis was used for analyzing independent risk factors of AKI in SAP patients. Receiver operating characteristic (ROC) curve was used for analyzing the prognostic value of the SII. Results AKI occurred in 74 cases and its incidence rate was 33.9%. The median SII value of AKI patients was higher than that of patients without AKI. After multivariate analysis, SII, age, triglyceride (TG), neutrophil ratio (NEU-R), C-reactive protein (CRP), aspartate aminotransferase (AST), and serum albumin (ALB) were independent predictors of AKI. Serum ALB was an independent protective factor. The optimum threshold truncation value of SII was 2880.1*10^9/L. Compared with other inflammatory factors, SII had a better prediction efficiency. Conclusion The SII, TG, NEU-R, CRP, and ALB were significant independent predictors of AKI in SAP patients. Serum TG, NEU-R, CRP, and SII were risk factors. Serum ALB was a protective factor. The SII may be a novel, simple, and strong marker for the accurate early prediction of AKI in SAP patients.

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Purpose ClinGen provides gene-specific guidance for interpretation of sequence variants in MYH7. We assessed laboratory and clinical impact of reclassification by the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) and ClinGen recommendations in 43 MYH7 variants reported by a diagnostic laboratory between 2013 and 2017. Methods Fifty-two proband reports containing MYH7 variants were reinterpreted by original ACMG-AMP and ClinGen guidelines. Evidence items were compared across schemes and reasons for classification differences recorded. Laboratory impact was assessed by number of recommended report reissues, and reclassifications coded as clinically "actionable" or "equivalent." Available pedigrees were reviewed to describe projected cascade impact. Results ClinGen produced a higher proportion of diagnostic classifications (65% of variants) compared with ACMG-AMP (54%) and fewer variants of uncertain significance (30% versus 42%). ClinGen classification resulted in actionable changes in 18% of variants with equal upgrades and downgrades from original report. ClinGen's revisions to PM1 and PS4 contributed to classification differences in 21% and 19% of variants respectively. Each classification change per proband report impacted, on average, 3.1 cascade reports with a further 6.3 first- and second-degree relatives potentially available for genotyping per family. Conclusion ClinGen's gene-specific criteria provide expert-informed guidance for interpretation of MYH7 sequence variants. Periodic re-evaluation improves diagnostic confidence and should be considered by clinical and laboratory teams.

The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long-read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of complex I subunits, providing evidence of isolated complex I deficiency. Through multi-omic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene-disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.

Aims To establish if COVID-19 has worsened outcomes in patients with AO 31 A or B type hip fractures. Methods Retrospective analysis of prospectively collected data was performed for a five-week period from 20 March 2020 and the same time period in 2019. The primary outcome was mortality at 30 days. Secondary outcomes were COVID-19 infection, perioperative pulmonary complications, time to theatre, type of anaesthesia, operation, grade of surgeon, fracture type, postoperative intensive care admission, venous thromboembolism, dislocation, infection rates, and length of stay. Results In all, 76 patients with hip fractures were identified in each group. All patients had 30-day follow-up. There was no difference in age, sex, American Society of Anesthesiologists (ASA) classification or residence at time of injury. However, three in each group were not fit for surgery. No significant difference was found in 30-day mortality; ten patients (13%) in 2019 and 11 patients (14%) in 2020 (p = 0.341). In the 2020 cohort, ten patients tested positive for COVID-19, two (20%) of whom died. There was no significant increase in postoperative pulmonary complications. Median time to theatre was 20 hours (interquartile range (IQR) 16 to 25) in 2019 versus 23 hours (IQR 18 to 30) in 2020 (p = 0.130). Regional anaesthesia increased from 24 (33%) cases in 2019 to 46 (63%) cases in 2020, but ten (14%) required conversion to general anaesthesia. In both groups, 53 (70%) operations were done by trainees. Hemiarthroplasty for 31 B type fractures was the most common operation. No significant difference was found for intensive care admission or 30-day venous thromboembolism, dislocation or infection, or length of stay. Conclusion Little information exists on mortality and complications after hip fracture during the COVID-19 pandemic. At the time of writing, no other study of outcomes in the UK has been published. Cite this article: Bone Joint Open 2020;1-7:415–419.

We report a patient diagnosed with PGM1‐CDG at 11 years of age after two biallelic likely pathogenic variants in PGM1 were found on research genomic sequencing. To our knowledge, he is the first patient with PGM1‐CDG to be reported with a restrictive cardiomyopathy. Other clinical manifestations included cleft palate, asymptomatic elevated transaminases, intellectual disability and myopathy resulting in exercise intolerance. He was trialed on oral galactose therapy in increasing doses for 18 weeks to assess if there was any biochemical and clinical benefit. His galactose was continued for a further 9 months beyond the initial galactose treatment period due to improvements in exercise tolerance and myopathy. Treatment with galactose demonstrated an improvement in liver function and myopathy with improved exercise tolerance. Treatment with galactose for 15 months did not change heart function and exercise stress test results were stable.

Pathogenic variants in methyl-CpG protein 2 (MECP2; OMIM 300005) result in an X-linked, severe, and progressive epigenetic disorder, Rett syndrome (RTT, OMIM: 312750), that predominantly affects females (Rett, 1966). Using Neul's revised diagnostic criteria, affected individuals can be clinically classified as classic or atypical RTT (Neul et al., 2010). After 6–18 months of apparently normal development, girls with the classic form of RTT gradually start losing their previously acquired skills including spoken language and other communication, coordination, and social interaction. Along with acquired microcephaly, affected girls lose purposeful use of their hands and develop midline stereotypic hand movements, breathing irregularities, seizures, scoliosis, and disturbed sleeping patterns. The partial/complete loss of spoken language is one of the core diagnostic criteria which is essential to be present for an affected individual to be classified as an individual with classic RTT. However, it is not necessarily a required criterion when classifying individuals with atypical RTT (Neul et al., 2010; Schonewolf-Greulich et al., 2019). As per the definitions adopted in the article by Neul et al. (2010) “… an individual who had learned to babble but then loses this ability is considered to have a loss of acquired language …” Owing to the broad variability of the phenotype in individuals with RTT, a proportion of them satisfy some, but not all, of the necessary revised diagnostic criteria and are classified as atypical RTT. Furthermore, individuals may be classified as RTT-like, exhibiting some clinical features associated with RTT, but not enough to be classified as either classic or atypical RTT (Ip et al., 2018). Approximately 97% of individuals with classic RTT and 86% of individuals with atypical RTT have pathogenic variants in MECP2 (Neul et al., 2014). A small proportion of individuals with clinical features overlapping with RTT have been reported with pathogenic variants in cyclin-dependent kinase-like 5 (CDKL5, OMIM: 300203) and forkhead box G1 (FOXG1, OMIM: 164874); however, a significant proportion of individuals clinically classified as RTT remain without a definite genetic diagnosis (Armani et al., 2012).

Parkinson’s disease (PD) decreases the quality of life of the affected individuals. The incidence of PD is expected to increase given the growing aging population. Motor symptoms associated with PD render the patients unable to self-care and function properly. Given that several drugs have been developed to control motor symptoms, highly sensitive scales for clinical evaluation of drug efficacy are needed. Among such scales, the objective and continuous evaluation of wearable devices is increasingly utilized by clinicians and patients. Several electronic technologies have revolutionized the clinical monitoring of PD development, especially its motor symptoms. Here, we review and discuss the recent advances in the development of wearable devices for bradykinesia, tremor, gait, and myotonia. Our aim is to capture the experiences of patients and clinicians, as well as expand our understanding on the application of wearable technology. In so-doing, we lay the foundation for further research into the use of wearable technology in the management of PD.

Background Male infertility is a major issue in human reproduction health, yet known genetic factors are only responsible for a small fraction of cases. TSGA10 is a testis-specific protein that is highly conserved among different species. A previous study has reported a homozygous mutation in TSGA10 in a male infertile patient; however, function analysis of Tsga10 genes in knockout mice has not yet been undertaken. Objectives The aim of the present work was to analyse the function of TSGA10 protein in the spermatogenesis of Tsga10+/- mice. Materials and methods Tsga10+/- mice were generated by CRISPR/Cas9 technology, in vitro fertilization (IVF), western blot, co-immunoprecipitation and other methods were used to the function analysis. Results Heterozygous Tsga10 male mice created by CRISPR/Cas9 were infertile and presented significantly reduced sperm motility because of disordered mitochondrial sheath formation. Furthermore, TSGA10 can interact with GRP78 and NSUN2, which are associated with peri-implantation lethality and the gonadotropin-releasing hormone (GnRH) network. Discussion and conclusion We demonstrate that deficiency of Tsga10 gene can lead to male infertility in mice. TSGA10 is involved in the correct arrangement of mitochondrial sheath in spermatozoa. Future studies on TSGA10 include an in-depth exploration of the underlying mechanisms of TSGA10 in spermatogenesis, early embryonic development and GnRH network.

yeyachun and danshen exist as Chinese patent medicine, Xuemai Tong, and are clearly effective at alleviating liver fibrosis (LF). Previous studies have indicated that triterpenoids from yeyachun (EFT), and phenolic acids from danshen (SMP) are effective in the treatment of LF. The regulation of intestinal flora is an effective method for treating LF. The aim of this study was to investigate the effect of a mixture of EFT and SMP on carbon tetrachloride (CCl4) induced LF. Our results showed the mixture significantly decreased liver damage and fibrosis index, and maintained liver tissue composition, compared to the model group. Moreover, the imbalance of symptoms of intestinal flora was improved. The mixture also caused changes to metabolites of gut flora. Furthermore, the expression of CD68 in liver tissues from the treated groups was significantly decreased when compared to the model group. However, no significant difference was observed from microstructure of gut tissues and LPS concentrations in the serum between mixture treated mice and model mice. This study suggests that the mixture of EFT and SMP had a significant effect on CCl4 induced LF, and the mechanism of this action, at least in part, involved the regulation of intestinal flora and their metabolites.

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.

Objectives To establish a modified strategy of the feeding artery ablation (FAA) procedure as an add-on to percutaneous radiofrequency ablation (RFA) for patients with hypervascular hepatocellular carcinoma (HCC), and to evaluate the outcomes. Materials and methods For this prospective, single-arm study, from June 2014 to August 2016, twenty-five patients with hypervascular HCC, 2–5 cm in diameter were treated by contrast-enhanced ultrasound (CEUS)-guided FAA before conventional RFA. Technical success of FAA and subsequent perfusion change of the tumor were evaluated by CEUS. Technical efficacy and ablation sizes were evaluated by CT/MRI at 1 month. Therapeutic outcomes, including local tumor progression (LTP), overall survival (OS), and recurrence-free survival (RFS) were evaluated using the Kaplan–Meier method. Results One or two target feeding arteries were visible on CEUS for 52.6% (61/116) of the hypervascular HCCs 2–5 cm in diameter. The technical success rate of the FAA was 100%; 13/25 (52.0%) target tumors were evaluated as complete perfusion response, while 12/25 (48.0%) were evaluated as partial perfusion response. The ablation volume was 41.9 ± 17.5 cm3 (14.9–78.2 cm3) and the ablative safety margin was 8.2 ± 1.9 mm (4–12 mm) at the 1-month evaluation. These parameters did not differ significantly between the complete and partial subgroups. The cumulative rates of LTP at 1-, 2-, and 3-year follow-ups were 0.0%, 4.2% and 4.2%, respectively. The 3-year OS and RFS were 70.3% vs. 59.8%, respectively. There were no treatment-related deaths. Major complications occurred in one patient (4.0%). Conclusion As an add-on to conventional percutaneous RFA, tailored CEUS-guided FAA can reduce tumor perfusion and provide good local control of HCC.

Osteomyelitis had been treated and managed in an organized manner since past decade, and yet, still creates a substantial burden to entire healthcare system as a whole as its complications are exasperating. Although rare, squamous cell carcinoma could be one of the complications of chronic osteomyelitis. The aim of the work was to outline the presentation of illness and depict the carcinomatous transformation of chronic wound, based on literature review and patients operated on in the authors’ department. In this case report, we would like to present a case of moderately differentiated squamous cell carcinoma in a 67 years old gentleman with 20 years history of chronic osteomyelitis. For our patient, option of amputation was chosen and no complications had been observed with the patient being fully satisfied and daily function restored after prosthesis fitting.

Air pollution is a reversible cause of significant global mortality and morbidity. Epidemiological evidence suggests associations between air pollution exposure and impaired cognition and increased risk for major depressive disorders. However, the neural bases of these associations have been unclear. Here, in healthy human subjects exposed to relatively high air pollution and controlling for socioeconomic, genomic, and other confounders, we examine across multiple levels of brain network function the extent to which particulate matter (PM(2.5)) exposure influences putative genetic risk mechanisms associated with depression. Increased ambient PM(2.5) exposure was associated with poorer reasoning and problem solving and higher-trait anxiety/depression. Working memory and stress-related information transfer (effective connectivity) across cortical and subcortical brain networks were influenced by PM(2.5) exposure to differing extents depending on the polygenic risk for depression in gene-by-environment interactions. Effective connectivity patterns from individuals with higher polygenic risk for depression and higher exposures with PM(2.5), but not from those with lower genetic risk or lower exposures, correlated spatially with the coexpression of depression-associated genes across corresponding brain regions in the Allen Brain Atlas. These converging data suggest that PM(2.5) exposure affects brain network functions implicated in the genetic mechanisms of depression.

Purpose To discuss the possible reasons why percutaneous intratumoral ethanol injection (PEI) combined with radiofrequency ablation (RFA) to treat hepatocellular carcinoma (HCC) reduced the recurrence and metastasis compared with RFA alone. Materials and methods Forty VX2 tumor-bearing rabbits were randomly divided into four groups (n = 10): the PEI, RFA, PEI-RFA, and control groups. Five rabbits from each group were sacrificed on the 3rd and 7th days after ablation. The number of metastatic tumors in the lung was counted. The ablation volume was measured, and residual tumor specimens were prepared for hematoxylin and eosin staining and caspase-3, Ki-67, and VEGF immunohistochemical staining. Results The volume of ablation in the PEI-RFA group was significantly larger than that in the RFA and PEI groups (p 0.05). The number of microthrombi in the PEI-RFA group was greater than that in the control and RFA groups (p

We have read with interest the paper by Abrahami et al on the risk of colorectal cancer (CRC) with long-term proton pump inhibitor (PPI) usage with a new user and active comparator design (PPI users n=1 293 749 and histamine-2 receptor antagonist (H2RA) users n=292 387, from 1 January 1990 to 30 April 2018 with 1-year follow-up).1 The authors found that overall use of PPI did not increase the risk of CRC (HR 1.02, 95% CI 0.92 to 1.14). However, the HR increased by 2–4 years (HR 1.45, 95% CI 1.28 to 1.60) and more than 4 years (HR 1.60, 95% CI 1.42 to 1.80) with cumulative duration of PPI usage. Similar patterns were …

Human T-cell leukemia virus type 1 (HTLV-1) mainly infects CD4+T-cells and induces chronic, persistent infection in infected individuals with some progressing to develop adult T-cell leukemia/lymphoma (ATL). Whilst HTLV-1 alters cellular differentiation, activation and survival, it is unknown whether and how these changes contribute to malignant transformation of infected T-cells. In this study, we used single-cell RNA-Seq and TCR-Seq to investigate T-cell differentiation and HTLV-1-mediated transformation processes. We analyzed 87,742 single cells from peripheral blood of 12 infected and 3 uninfected individuals. Using multiple independent bioinformatic methods, we demonstrated that naïve T-cells dynamically change into activated T-cells including infected cells, which seamlessly transitioned into ATL cells characterized by clonally expanded, highly-activated T-cells. Notably, the more activated ATL cells are, the more they acquire Treg signatures. Intriguingly, HLA class II genes were uniquely induced in infected cells, further upregulated in ATL cells and was induced by viral protein Tax. Functional assays revealed that by upregulating HLA class II, HTLV-1-infected cells can act as tolerogenic antigen presenting cells (APCs) to induce anergy of antigen specific T-cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at single-cell level.Graphical Abstract

Photodynamic therapy (PDT) represents an effective treatment to cure cancer. The targeting ability of the photosensitizer is of utmost importance. Photosensitizers that discriminate cancer cells can avoid the killing of normal cells and improve PDT efficacy. However, the design and synthesis of photosensitizers conjugated with a recognition unit of cancer cell markers is complex and may not effectively target cancer. Considering that the total RNA content in cancer cells is commonly higher than in normal cells, this study has developed the photosensitizer QICY with RNA-targeting abilities for the discrimination of cancer cells. QICY was specifically located in cancer cells rather than normal cells due to their stronger electrostatic interactions with RNA, thereby further improving the PDT effects on the cancer cells. After intravenous injection into mice bearing a xenograft tumor, QICY accumulated into the tumor location through the enhanced permeability and retention effect, automatically targeted cancer cells under the control of RNA, and inhibited tumor growth under 630 nm laser irradiation without obvious side effects. This intelligent photosensitizer with RNA-targeting ability not only simplifies the design and synthesis of cancer-cell-targeting photosensitizers but also paves the way for the further development of highly efficient PDTs.

Objectives To explore the risk factors of preoperative hypoalbuminemia and its’ effects on complications in the elderly with primary hip arthroplasty. Methods A total of 211 elderly inpatients who underwent hip arthroplasty were collected. All patients were divided into the control group (preoperative serum albumin ≥35 g/L) and case group (preoperative serum albumin Results Compared to controls, hypoalbuminemia patients were older (P = 0.026), had lower BMI (P = 0.045), higher cardiac function score (P < 0.0001), higher ASA scores (P = 0.023), and longer hospital stay (P < 0.001). The intraoperative albumin loss in the case group was significantly higher than that of in control group (P < 0.001), but there was no significant difference in operation time and intraoperative blood loss between the two groups (P >0.05). Compared to controls, hypoalbuminemia patients had a higher risk for any complication (P = 0.014), such as delayed wound healing, pleural effusion, and pneumonia. The risk of postoperative complications increased by 6.9% with every 1 year old is increasing (age > 60). The risk of postoperative complications in the case group was 1.89 times higher than that in the control group. Conclusion Patients with older age, poor nutritional status, and more than 2 concomitant diseases are more likely to develop preoperative hypoalbuminemia. Preoperative hypoalbuminemia is related to the increased incidence of postoperative complications. Perioperative albumin loss is not only due to perioperative blood loss, but also related to vascular permeability and abnormal albumin metabolism.

Exome sequencing and Drosophila modeling revealed variants in SMARCA5 as a novel cause of a neurodevelopmental disorder., Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

BACKGROUND As a kind of benign tumor, pituitary adenomas have attracted increasing attention from researchers. The plasmacytoma variant translocation 1 (PVT1) is a molecule in the lncRNA family protein that has been proven to play critical roles in many cancers; however, no study has explored the special biological roles of PVT1 in pituitary adenoma. MATERIAL AND METHODS The qRT-PCR assay was conducted to evaluate PVT1 expressions in various cell lines and tissues. Loss of function assays were carried out to detect the influence of silenced PVT1 on the proliferation, migration, and epithelial-mesenchymal transition (EMT) of pituitary adenoma cells. Western blotting was used to identify correlation between ß-catenin and PVT1. RESULTS The PVT1 expressions were significantly enhanced in tissues of pituitary adenoma and cancer cells. Cell migration and proliferation were inhibited when the PVT1 gene was knocked down. Knockdown of PVT1 repressed the migration and EMT of pituitary adenoma cells. The PVT1 downregulation obviously blocked Wnt/ß-catenin signaling pathway activity. PVT1 aggravated progression of pituitary adenoma through initiating the Wnt/ß-catenin signaling pathway. CONCLUSIONS PVT1 exerts an oncogenic role through activating Wnt/ß-catenin signaling in pituitary adenoma cells. The present results may provide a potential therapeutic target or approach for treating pituitary adenomas.

Introduction Endoscopic submucosal dissection (ESD) in the colon and rectum has been developed with good reported outcomes. The main advantage of ESD is the ability to perform en bloc resection, which has implications for complete excision and pathological analysis. Locally, the use of ESD in colonic lesions has seen recent traction. Our study aimed to review the outcomes of the first 50 cases of endoscopic excision of advanced colonic lesions using ESD at our institution. Methods This was a retrospective study of all patients who underwent ESD at our institution from September 2010 to October 2016. Data collected included patient demographics, resection technique, conversion rate and morbidity. Results 51 patients underwent ESD during the study period. All patients were of American Society of Anesthesiologists (ASA) class 1-3. Their median age was 60.0 years and the majority (n = 36) were male. The mean procedure time was 80.9 minutes. 36 (76.6%) of cases underwent en bloc resection. 4 (7.8%) cases required conversion to surgery, mainly due to difficulty in raising the colonic lesions. 3 (5.9%) patients had malignancy as the final histology. 2 (4.3%) patients had recurrence during surveillance scope. No cases of early mortality were reported. Conclusion Our results suggest that ESD for advanced colonic lesions can be safely performed. Expertise needs to be developed to achieve satisfactory en bloc resection rates.

Objectives: To investigate the effects of low-dose aminolevulinic acid photodynamic therapy (ALA-PDT) on photoaging in human dermal fibroblasts (HDFs) and to explore the mechanism of Nuclear factor erythroid 2-related factor 2(Nrf2)-mediated photorejuvenation in vitro. Methods: A photoaging model was established through repeated exposure of HDFs to UVA. Total superoxide dismutase (SOD) expression was detected by a SOD activity assay. Nrf2 was knocked down through adenovirus infection, and successful knockdown was confirmed by Western blot analysis and quantitative polymerase chain reaction. Results: Sustained exposure to UVA induced photoaging in HDFs. Total SOD activity was significantly increased by low-dose aminolevulinic acid (ALA)-PDT. Upon application of low doses of ALA-PDT to photoaging HDFs, Nrf2 was translocated to the nucleus; in addition, the expression of Nrf2, transforming growth factor-β1 (TGF-β1), type I and III collagen (COL1 and COL3), heme oxygenase 1 (HO-1), and p-ERK was increased, while the expression of matrix metalloproteinase 9 (MMP-9) was decreased. However, after Nrf2 was knocked down in HDFs, the expression of TGF-β1, COL1, COL3, and HO-1 was significantly decreased, while the expression of MMP-9 was increased. Conclusion: This study revealed that low-dose ALA-PDT decreases UVA-mediated photoaging through an Nrf2-mediated antioxidant effect.

Background Tumor mutations and tumor microenvironment are associated with resistance to cancer immunotherapies. However, peripheral T cell in effective anti-programmed death 1 (PD-1) antibody treatment is poorly understood. Methods Mass spectrometry and conventional flow cytometry were used to investigate peripheral blood cells isolated from patients. Furthermore, melanoma mouse model was performed to assess the role of CXCR3 signaling in anti-PD-1 antibody treatment. Findings We revealed a marked increase in the percentage of CXCR3+ T cells in the blood of cancer patients after the first pembrolizumab infusion. This percentage decreased after the second infusion in responsive patients, whereas a sustained high percentage of CXCR3+ T cells was observed in patients with progressive disease. A low percentage of CXCR3+ T cells presented in patients with stable disease or a partial response was confirmed by conventional flow cytometry. Intriguingly, blockade of CXCR3 signaling exacerbated tumor growth in mice. Intratumoral injection with recombinant CXCL9/10 plus intraperitoneal injection of anti-PD1 antibody inhibited the tumor growth in mice. Interpretation The dynamic changes in CXCR3+ T cells in blood may be a prognostic factor in anti-PD-1 immunotherapy, and promotion of CXCR3-mediated signaling may be beneficial to the anti-PD-1 therapy. Fund This work was supported by the National Natural Science Foundation of China (Nos. 81722047, 81871944, 81670553, 81874317, 81572389, 81730100) and Jiangsu province key medical talents (Nos. ZDRCA2016026), The “Deng Feng” Distinguished Scholars Program, National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (Number: 2018ZX09201002), and the Fundamental Research Funds for the Central Universities (020814380117)., Highlights • The first infusion of anti-PD-1 antibody rapidly increases CXCR3+ T cells in blood in melanoma and head and neck cancer patients. • Retention of CXCR3+ T cells in blood is associated with the resistance to anti-PD-1 therapy. • CXCR3-dependent T cell tumor accumulation is required for effective anti-PD-1 immunotherapy. • Intratumoural injection with recombinant CXCL9/10 improved the anti-PD-1 antibody treatment

There are increasing reports of a type of lung cancer that manifests as solitary cystic airspaces. The purpose of this case series was to identify the CT features and possible mechanisms of solitary cystic lung cancer, on the basis of CT observations and pathologic characteristics. The clinical, imaging, and pathologic data of 106 patients with solitary cystic lung cancer were collected and analyzed between January 2011 and December 2017. CT images were reviewed independently by three radiologists who were blinded to pathologic findings. Demographic data and clinical and smoking status were extracted from the medical records. The mean age was 58.8 years 6 10.6 (standard deviation) (range, 30–82 years). CT features in the 106 patients included nonuniform cystic walls in 96 (90.6%) patients, cyst septations in 62 (58.5%) patients, nodular walls in 58 (54.7%) patients, ground-glass opacity around the cyst in 53 patients (50.0%), and irregular margins in 42 (39.6%) patients. At histologic examination, the majority of cases (81 [87.1%] of 93) were adenocarcinoma.

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non–structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression in vitro. Small homologous RNA–mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death in vitro. HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors in vivo. Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.—Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.

Major abdominal surgery in the elderly is challenging and complex. Frailty as a clinical entity in the elderly is increasingly recognized as a useful assessment tool to identify at-risk patients. We aim to review recent literature on frailty in surgical preoperative evaluation and postoperative recovery and determine its applications in emergency surgery. Frailty has been established as an independent predictor of morbidity and mortality in elderly surgical patients. Individualized treatment goals and tailor-made interventions to optimize clinical conditions in frail patients before and after surgery improve outcomes. Sarcopenia is increasingly recognized as a predictor of poor surgical outcome in elderly; its use in emergency surgery is promising. More research into this area is needed. Frailty is a useful tool to identify at-risk patients for optimization and targeted intervention before major surgery. To meet the complex needs of these patients, an integrated transdisciplinary approach is recommended.

The lipid phosphatase gene FIG4 is responsible for Yunis-Varon syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence.

Accumulating evidence has indicated that long noncoding RNA NEAT1 exerts critical roles in cancers. So far, the detailed biological role and mechanisms of NEAT1, which are responsible for human gastric cancer (GC), are still largely unknown. Here, we observed that NEAT1 and STAT3 expressions were significantly upregulated in human GC cells including BGC823, SGC-7901, AGS, MGC803, and MKN28 cells compared with normal gastric epithelial cells GES-1, while miR-506 was downregulated. We inhibited NEAT1 and observed that NEAT1 inhibition was able to repress the growth, migration, and invasion of GC cells. Conversely, overexpression of NEAT1 exhibited an increased ability of GC progression in BGC823 and SGC-7901 cells. Bioinformatics analysis, dual luciferase reporter assays, RIP assays, and RNA pull-down tests validated the negative binding correlation between NEAT1 and miR-506. In addition, it was found that miR-506 can modulate the expression of NEAT1 in vitro. STAT3 was predicted as a messenger RNA (mRNA) target of miR-506, and miR-506 mimics can suppress STAT3 mRNA expression. Subsequently, it was observed that downregulation of NEAT1 can restrain GC development by decreasing STAT3, which can be reversed by miR-506 inhibitors. Therefore, it was hypothesized in our study that NEAT1 can be recognized as a competing endogenous RNA to modulate STAT3 by sponging miR-506 in GC. In conclusion, we implied that NEAT1 can serve as an important biomarker in GC diagnosis and treatment.

Background ICU patients may require renal replacement therapy (RRT). Sharing RRT equipment carries a risk of BBV transmission, which mainly relates to Hepatitis B (HBV), Hepatitis C (HCV) and HIV. Since 2012, all Glasgow Royal Infirmary ICU patients undergo routine BBV screening, with RRT machines allocated for patients with specific BBV statuses. Routine BBV testing is beneficial to both the individual and society. This study aims to determine if routine BBV testing in the ICU contributes to the discovery of undiagnosed BBV infections. Methods This single-centre retrospective observational study examined prospectively collected clinical data from 1069 ICU admissions. Proportions were compared using a two-proportion z-test and a logistic regression model was carried out to determine if deprivation quintile was independently associated with the seroprevalence of BBVs. Results The BBV seroprevalence in the cohort studied: 0.45% (HBV), 11.7% (HCV), and 0.91% (HIV). The seroprevalence of HBV in the cohort studied was similar to that of Scotland (p = 0.11), but the seroprevalence of HCV (p Conclusion This study shows that routine BBV testing in the ICU is useful in discovering new BBV infections. This is the first observational study focusing on the value of routine BBV testing in an ICU setting to our knowledge.

Background Coinfection with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) diminishes the value of the CD4+ T-cell count in diagnosing AIDS, and increases the rate of HTLV-1–associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such characteristics. We investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and clonal expansion. Methods We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected, and 12 HIV-1 and 13 HTLV-1 monoinfected individuals. Proviral loads (PVL) were quantified using real-time polymerase chain reaction (PCR). Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing. Results PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in monoinfected individuals. The degree of oligoclonality of both HIV-1– and HTLV-1–infected cells in coinfected individuals was also greater than in monoinfected subjects. ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 monoinfected individuals. Conclusions HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and clonality of virus-infected cells and thus may alter the risks of both HTLV-1– and HIV-1–associated disease.

SummaryAlthough defective synaptic transmission was suggested to play a role in neurodegenerative diseases, the dynamics and vesicle pools of synaptic vesicles during neurodegeneration remain elusive. Here, we performed real-time three-dimensional tracking of single synaptic vesicles in cortical neurons from a mouse model of Huntington’s disease (HD). Vesicles in HD neurons had a larger net displacement and radius of gyration compared with wild-type neurons. Vesicles with a high release probability (Pr) were interspersed with low-Pr vesicles in HD neurons, whereas high-Pr and low-Pr vesicle pools were spatially separated in wild-type neurons. Non-releasing vesicles in HD neurons had an abnormally high prevalence of irregular oscillatory motion. These abnormal dynamics and vesicle pools were rescued by overexpressing Rab11, and the abnormal irregular motion was rescued by jasplakinolide. These results suggest the abnormal dynamics and vesicle pools of synaptic vesicles in the early stages of HD, suggesting a possible pathogenic mechanism of neurodegenerative diseases.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as “GENE-related phenotype descriptor” (e.g., “CFTR-related cystic fibrosis”). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Introduction. Stroke recurrence accounts for a great percentage of catastrophic complications, yet no comprehensive study has analyzed the factors associated with stroke recurrence in Cameroon. We carried out this case-control study to better understand the factors associated with the stroke recurrence in Cameroon. Methods. We collected sociodemographic, clinical, neuroimaging, laboratory, and therapeutic data of eligible patients who consulted the neurology and cardiology department of the Yaounde Central Hospital in Cameroon. We included all patients at least five years removed from their first stroke event who consulted the authors’ institution as of January 15, 2019. Wilcoxon signed-rank and Fisher’s exact tests were used. Also, a Cox regression model was used to identify confounders.Results. We recruited 100 patients; seven out of ten patients had hypertension, while six out of 10 had a sedentary lifestyle. Half of the patients consumed alcohol regularly, while one patient out of five had diabetes. Most patients presented with their first stroke event, and a quarter had a stroke recurrence. Stroke recurrence was associated with right handedness (OR = 0.23, 95% CI = 0.16–0.33), congestive heart failure (OR = 3.45, 95% CI = 1.16–10.28), gout (OR = 4.34, 95% CI = 1.09–18.09), dysarthria (OR = 4.34, 95% CI = 1.30–14.54), and facial palsy (OR = 3.96, 95% CII = 1.49 – 10.51), as well as modifiable factors such as elevated abdominal circumference (P

Chronic Kidney Disease (CKD) is a serious threat to human health. In addition, kidney fibrosis is a key pathogenic intermediate for the progression of CDK. Moreover, excessive activation of fibroblasts is key to the development of kidney fibrosis and this process is difficult to control. Notably, fraxinellone is a natural compound isolated from Dictamnus dasycarpus and has a variety of pharmacological activities, including hepatoprotective, anti-inflammatory and anti-cancer effects. However, the effect of fraxinellone on kidney fibrosis is largely unknown. The present study showed that fraxinellone could alleviate folic acid-induced kidney fibrosis in mice in a dose dependent manner. Additionally, the results revealed that fraxinellone could effectively down-regulate the expression of CUGBP1, which was highly up-regulated in human and murine fibrotic renal tissues. Furthermore, expression of CUGBP1 was selectively induced by the Transforming Growth Factor-beta (TGF-β) through p38 and JNK signaling in kidney fibroblasts. On the other hand, downregulating the expression of CUGBP1 significantly inhibited the activation of kidney fibroblasts. In conclusion, these findings demonstrated that fraxinellone might be a new drug candidate and CUGBP1 could be a promising target for the treatment of kidney fibrosis.

Background Venous thromboembolism (VTE) is a serious complication that may occur after total knee arthroplasty (TKA), leading to the recommendation of routine chemoprophylaxis by international guidelines. This study aims to determine if short-duration chemoprophylaxis after TKA reduces the incidence of VTE in an Asian population. Methods A retrospective study of 316 patients who underwent unilateral primary TKA between 1 January 2011 and 31 December 2013 was conducted. All patients received mechanical prophylaxis. One hundred seventeen patients (37%) received additional chemoprophylaxis, whereas 199 patients (63%) did not. A Doppler ultrasound (DUS) of both lower limbs was conducted for all patients within 6 days after surgery (median = 3 days) to assess for both proximal and distal DVT. Chemoprophylaxis in the form of enoxaparin (low molecular weight heparin; LMWH), aspirin, or heparin was administered until patients had a normal DUS, for a median duration of 4 days. Patients were followed up clinically for a minimum of 6 months to monitor for delayed or recurrent VTE and at least 2 years for patient-reported outcome measures. Results Overall, 24 patients (7.59%) developed deep vein thrombosis (DVT): three proximal and 21 distal DVTs. Twenty-three of the 24 patients were asymptomatic. Twenty of 199 patients (10.05%) with only mechanical prophylaxis developed DVT, whereas four of 117 patients (3.42%) with additional chemoprophylaxis developed DVT. Multivariate analysis showed that chemoprophylaxis use was associated with reduced incidence of DVT (odds ratio = 0.19, p value = 0.011). Other factors associated with increased DVT incidence include female gender (odds ratio = 5.45, p value = 0.034), positive history of cancer (odds ratio = 5.14, p value = 0.044), and increased length of stay in hospital (odds ratio = 1.19, p value Conclusions Our study has shown that despite the low incidence of DVT in Asian patients undergoing TKA, short-duration chemoprophylaxis might be effective in reducing the incidence of DVT. However, most DVTs observed in our study were distal and may be of limited clinical significance. Further studies are needed to investigate the impact of chemoprophylaxis use on the incidence of PE and overall mortality rates among Asian patients.

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations inSMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals withde novoor dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5DrosophilaorthologIswiled to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function.Iswiloss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate thatSMARCA5pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

BackgroundConceptualizations of delusion formation implicate, in part, deficits at feed-forward information transfer across posterior to prefrontal cortices, resulting in dysfunctional integration of new information in favor of over-familiar prior beliefs. Here, we used functional MRI and machine learning models to examine feedforward parietal-prefrontal information transfer in schizophrenia patients in relation to delusional thinking, and polygenic risk for schizophrenia.MethodsWe studied 66 schizophrenia patients and 143 healthy controls as they performed context updating during working memory (WM). Dynamic causal models of effective connectivity were focused on prefrontal and parietal cortex, where we examined parietal-prefrontal connectivity in relation to delusions in patients. We further tested for an effect of polygenic risk for schizophrenia on connectivity in healthy individuals. We then leveraged support vector regression models to define optimal normalized target connectivity tailored for each patient, and tested the extent to which deviation from this target predicted individual variation in delusion severity.ResultsIn schizophrenia patients, updating and manipulating context information was disproportionately less accurate than was WM maintenance, with a task accuracy-by-diagnosis interaction. Also, patients with delusions tended to have relatively reduced feedforward effective connectivity during context updating in WM manipulation. The same parietal-prefrontal feedforward prefrontal effective connectivity was adversely influenced by polygenic risk for schizophrenia in healthy subjects. Individual patients’ deviation from predicted ‘normal’ feedforward connectivity based on the support vector models correlated with delusional severity.ConclusionsThese computationally-derived observations support a role for feed-forward parietal-prefrontal information processing deficits in delusional psychopathology, and in genetic risk for schizophrenia.

The diagnosis of mitochondrial disorders remains a challenging and often unmet need. We sought to investigate a sibling pair with suspected mitochondrial disease and a clinical presentation notable for global developmental delay, poor growth, sensorineural hearing loss, and brain MRI abnormalities, both with early death. Following uninformative exome and genome sequencing of the family quartet, RNA sequencing was pursued as an orthogonal testing strategy. RNA sequencing of fibroblasts from the older sibling identified the presence of a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. NDUFB10 encodes a subunit of mitochondrial OXPHOS complex I. Differential expression analysis relative to control samples suggested significantly decreased expression. The cryptic exon was found to contain a rare intronic variant, NM_004548.3:c.131-442G>C, that was homozygous in both affected siblings and absent from population allele frequency databases. Immunoblot and quantitative proteomic analysis of fibroblasts from the older sibling revealed decreased abundance of complex I subunits associated with NDUFB10, providing evidence of isolated complex I deficiency. Biallelic variants in NDUFB10 have previously been reported in a single individual with infantile-onset mitochondrial disease. We present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two further individuals. This variant results in loss of expression and overall destabilization of mitochondrial OXPHOS complex I and highlights the importance of RNA sequencing as a complementary diagnostic tool in patients undergoing genome-wide diagnostic evaluation.

Cerebral ischemia is a common refractory brain disease, resulting from a reduction in the blood flow to the brain. Mitochondrial dysfunction leads to ischemic stroke and brain injury. Cordyceps sinensis (CS) is an important traditional Chinese medicine, which has been linked to neuroprotection in recent studies. In this study, we investigated the role of the mitochondrial respiratory chain and the mitochondrial apoptotic pathway on the protective effect of Cordyceps sinensis extract (CSE) against cerebral ischemia injury both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) model, administration of CSE relieved neuronal morphological damage and attenuated the neuronal apoptosis. CSE also reduced neurobehavioral scores and oxygen free radical (OFR), while improving the levels of ATP, cytochrome c oxidase (COX), and mitochondrial complexes I-IV. Furthermore, the mRNA expression of Bax, cytochrome c (Cyt c) and caspase-3 were down-regulated. In brain microvascular endothelial cells (BMECs) exposed to oxygen and glucose deprivation (OGD), CSE prevented OGD-induced cellular apoptosis, and recovered the reduction of mitochondrial membrane potential (MMP). Moreover, CSE treatment induced an increase of Bcl-2 protein expression and a decrease of Bax, Cyt c and caspase-3 protein expression. Meanwhile, the caspase-3, -8, and -9 activities were also inhibited. The results indicate that CSE can relieve cerebral ischemia injury and exhibit protective effects via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway.

An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

The aging population is an increasing healthcare concern in developing countries. In Singapore, 25% of the local population are expected to be older than 65 years old by 2030. Colorectal cancer (CRC) is ranked third most diagnosed cancers worldwide with up to 1.8 million new cases diagnosed in 2018. 60% of newly diagnosed CRC are among patients who are 70 years or older and hence majority of these patients will invariably face challenges with frailty and multiple comorbidities that require appropriate assessment and stratification. The standard of care in patients with stage I or II CRC is surgery with curative intent. For patients with stage III CRC, upfront surgical resection of tumor along with adjuvant chemotherapy is the internationally recommended treatment approach. As for those patients with metastatic disease, they are usually managed within a multidisciplinary team and considered for surgical resection if deemed feasible. Elderly patients are mostly burdened with frailty, functional dependency and existing co-morbidities, all of which are predictors of early postoperative mortality and morbidity in patients with CRC. This article thus aims to review existing evidence to discuss the intricate decision-making process for the surgical management of elderly patient with CRC.

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.