Burnout, anxiety and depression in healthcare workers during the early COVID-19 period in Singapore

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The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile

<p>Abstract</p> <p>Background</p> <p>Overall gastric cancer survival remains poor mainly because there are no reliable methods for identifying highly curable early stage disease. Multi-protein profiling of gastric fluids, obtained from the anatomic site of pathology, could reveal diagnostic proteomic fingerprints.</p> <p>Methods</p> <p>Protein profiles were generated from gastric fluid samples of 19 gastric cancer and 36 benign gastritides patients undergoing elective, clinically-indicated gastroscopy using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry on multiple ProteinChip arrays. Proteomic features were compared by significance analysis of microarray algorithm and two-way hierarchical clustering. A second blinded sample set (24 gastric cancers and 29 clinically benign gastritides) was used for validation.</p> <p>Results</p> <p>By significance analysyis of microarray, 60 proteomic features were up-regulated and 46 were down-regulated in gastric cancer samples (<it>p </it>< 0.01). Multimarker clustering showed two distinctive proteomic profiles independent of age and ethnicity. Eighteen of 19 cancer samples clustered together (sensitivity 95%) while 27/36 of non-cancer samples clustered in a second group. Nine non-cancer samples that clustered with cancer samples included 5 pre-malignant lesions (1 adenomatous polyp and 4 intestinal metaplasia). Validation using a second sample set showed the sensitivity and specificity to be 88% and 93%, respectively. Positive predictive value of the combined data was 0.80. Selected peptide sequencing identified pepsinogen C and pepsin A activation peptide as significantly down-regulated and alpha-defensin as significantly up-regulated.</p> <p>Conclusion</p> <p>This simple and reproducible multimarker proteomic assay could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy for gastric cancer and pre-malignant lesions.</p

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Infigratinib mediates vascular normalization, impairs metastasis and improves chemotherapy in hepatocellular carcinoma.

The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGFR expression in 17.7% (11 of 62) of HCC models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and Sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug Vinorelbine to promote apoptosis, suppress tumor growth and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 via gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion Treatments with Infigratinib alone or in combination with Vinorelbine may be effective in a subset of HCC patients with FGFR-driven tumors

Pediatric out-of-hospital cardiac arrest in Korea: A nationwide population-based study

Study objectives: Our objective was to describe the incidence and demographics of pediatric out-of-hospital cardiac arrest (OHCA) in Korea. Methods: We identified non-traumatic OHCA patients aged less than 20 years from a Korean nationwide OHCA registry (2006-2007). Data from emergency medical service (EMS) run-sheets and hospital records were reviewed. We excluded cases with unknown hospital outcomes. Patient characteristics, treatment by EMS, and outcomes were compared by age groups: infant (< 1 year), children (1-11 years), and adolescents (12-19 years). Results: A total of 971 patients including infants (n = 299, 30.8%), children (n = 305, 31.4%), and adolescents (n = 367, 37.8%) met inclusion criteria. The incidence of pediatric OHCA was 4.2 per 100,000 person-years (67.1 in infants, 2.5 in children, and 3.5 in adolescents). The rate of cardiopulmonary resuscitation administered was 82.1% (infants 80.6%, children 82.0%, and adolescent 83.4%). The rate of applying automated external defibrillators and advanced airway management (endotracheal intubation or laryngeal mask airway), was only 4.1% and 2.5%, respectively. 7.4% showed ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in the initial ECG. Survival to hospital discharge for all pediatric OHCA was 4.9% (2.9% for infants, 4.7% for children, and 7.2% of adolescents). For EMS-treated pediatric OHCA or patients with VF or pulseless VT, the rate was 5.0% and 31.6%, respectively. Conclusion: Incidence and hospital outcomes in pediatric OHCA in Korea were comparable to other population-based nationwide reports. (c) 2009 Elsevier Ireland Ltd. All rights reserved.This study was financially supported by the Korea Center for Disease Control and Prevention (2007–2008).Atkins DL, 2009, CIRCULATION, V119, P1484, DOI 10.1161/CIRCULATIONAHA.108.802678Herlitz J, 2007, AM J EMERG MED, V25, P1025, DOI 10.1016/j.ajem.2007.03.008Gerein RB, 2006, ACAD EMERG MED, V13, P653, DOI 10.1197/j.aem.2005.12.025Donoghue AJ, 2005, ANN EMERG MED, V46, P512, DOI 10.1016/j.annemergmed.2005.05.028Young KD, 2004, PEDIATRICS, V114, P157Engdahl J, 2003, RESUSCITATION, V58, P131, DOI 10.1016/S0300-9572(03)00108-4Broides A, 2000, ISRAEL MED ASSOC J, V2, P672Sirbaugh PE, 1999, ANN EMERG MED, V33, P174KUISMA M, 1995, RESUSCITATION, V30, P141MOGAYZEL C, 1995, ANN EMERG MED, V25, P484RONCO R, 1995, ARCH PEDIAT ADOL MED, V149, P210THOMPSON JE, 1990, PEDIATRICS, V86, P302EISENBERG M, 1983, ANN EMERG MED, V12, P672

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer1, 2, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer3, 4, 5. Additionally, although many people with cachexia show hypermetabolism3, 6, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell–based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid–induced oxidative stress could be targeted to prevent cancer-induced cachexia.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore