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Background Five to ten percent of the global population have unruptured intracranial aneurysms, and ruptured brain aneurysms cause approximately 500,000 deaths a year. Flow-diverting stent treatment is a less invasive intracranial aneurysm treatment that induces aneurysm thrombosis. The imaging characteristics of a novel primarily bioresorbable flow-diverting stent (BFDS) are assessed in comparison to the leading metal stent using fluoroscopy, CT, and MRI. Methods X-ray/fluoroscopic images of stents were taken using a human cadaveric skull model. CT and MRI were acquired using silicone flow models of residual aneurysms. Images were analyzed with Likert scales in anonymous surveys by neurointerventionalists. Quantitative measurements of radiographic density (CT) and artifact boundary size (CT & MRI) were also obtained. Results Visibility of the BFDS on X-ray was less than the metal stent but deemed adequate for deployment and intraprocedural assessment. The metal stent was more radiopaque than the BFDS on CT, but qualitative assessment was not significantly different for the two stents. MRI imaging was significantly better using the BFDS in terms of overall artifact and intraluminal assessment. Conclusions The BFDS has adequate visualization on X-ray/fluoroscopy and should be clinically acceptable for fluoroscopic deployment. On MRI, there is less quantitative artifact as well as overall improved qualitative assessment that will allow for more detailed non-invasive imaging follow-up of treated aneurysms, potentially reducing the need for digital subtraction catheter angiography.

Data on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes associated with molnupiravir or nirmatrelvir-ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.We analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir-ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir-ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], intensive care unit [ICU] admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.We identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91-23·45]) versus matched controls (38·07 events [33·85-42·67]; HR 0·48 [95% CI 0·40-0·59], p0·0001) and in nirmatrelvir-ritonavir recipients (10·28 events [7·03-14·51]) versus matched controls (26·47 events [21·34-32·46]; HR 0·34 [0·23-0·50], p0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52-0·69], p0·0001; nirmatrelvir-ritonavir 0·57 [0·45-0·72], p0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57-0·83], p=0·0001; nirmatrelvir-ritonavir 0·73 [0·54-0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15-1·64], p=0·0005; nirmatrelvir-ritonavir 1·38 [1·07-1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.During a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.Health and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).For the Chinese translation of the abstract see Supplementary Materials section.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and cigarette smoke is the main risk factor. Detecting its earliest stages and preventing a decline in lung function are key goals. The pathogenesis of COPD is complex but has some similarities to cystic fibrosis (CF), a disease caused by mutations in the cftr gene. CF leads to chronic inflammation, abnormal mucus, and cycles of infection. Cigarette smoke exposure also causes CFTR dysfunction, and it is probably not a coincidence that inflammation, mucus obstruction, and infections are also characteristics of COPD, although the exacerbations can be quite different. We review here the acute effects of cigarette smoke on CFTR function and its potential role in COPD. Understanding CFTR regulation by cigarette smoke may identify novel drug targets and facilitate the development of therapeutics that reduce the progression and severity of COPD.

To review the current literature regarding the health disparities in the prevalence, diagnosis, and management of pediatric food allergy and discuss possible interventions.Literature search of PubMed and Google Scholar databases regarding pediatric food allergy and health disparities.Original research articles, reviews, and guidelines on health disparities in pediatric food allergy were included in this review.The overall prevalence of food allergy appears to be increasing and disproportionately affecting minority groups. Racial and socioeconomic disparities are evident across all aspects of food allergy care: diagnosis, prevention, acute management (eg, access to epinephrine autoinjectors, visits to emergency department), and long-term management (eg, oral immunotherapy). Children of minority populations and those of low socioeconomic status are at a greater risk of food insecurity, which is further exacerbated by the high cost of allergen-free foods and limited support from food assistance programs.Racial, ethnic, and socioeconomic disparities in food allergy among children in the United States are evident and negatively affect the outcomes of children with food allergies. Active efforts to decrease racial and socioeconomic disparities, through education, research, and advocacy, will be important to help improve health outcomes in food allergy for all children, regardless of their race, ethnicity, or socioeconomic status.

A 33-year-old, 8 weeks pregnant, presented with severe upper abdominal pain with vomiting on a background of a previous laparoscopic Nissen fundoplication for reflux disease. An urgent MRI had shown herniation of the fundoplication wrap through the diaphragmatic hiatus. The cause of her symptoms was attributed to hyperemesis gravidarum. The plan was to manage this patient conservatively until the conclusion of her pregnancy. This plan was revised when she presented for the second time and developed worsening pain and haematemesis. An emergency gastroscopy showed ischaemic changes in most of the stomach requiring the patient to undergo an emergency laparotomy. In pregnant patients, presenting with abdominal pain, vomiting as well as haematemesis, having had previous antireflux surgery, incarceration of the stomach must be considered as a differential. Prompt assessment and early senior decision-making is extremely important in avoiding a potentially catastrophic outcome for such patients.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new potential therapeutic targets(1–5). However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers (SEs) are highly and specifically hypermutated in 92% of DLBCL samples, display signatures of activation-induced cytidine deaminase (AID) activity, and are linked to genes encoding B-cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated SEs linked to the BCL6, BCL2, and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (BCL6) and the steroid-receptor NR3C1 (BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA-binding, downregulated target gene expression, and led to the counter-selection of cells harboring corrected alleles, indicating oncogenic dependency on the SE mutations. This pervasive SE mutational mechanism reveals a novel major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.

Isometric strength training has been reported to benefit various sport-related dynamic performances. However, it is still unknown whether performing isometric strength training at single or multiple joint angles would elicit greater benefit. Purpose: To compare the effects of isometric bench press performed at single (SIBP) and multiple (MIBP) joint angles on dynamic strength and overhead throwing performance. Methods: Sixteen male softball and baseball athletes performed overhead throwing, 1-repetition-maximum (1RM) bench press, and ballistic push-up during pretest and posttest. They were then randomly assigned to either SIBP or MIBP to undergo 12 strength training sessions. During the training, isometric bench press was performed at only 90° elbow angle for SIBP but at 60°, 90°, and 120° elbow angles for MIBP. Results: A significant main time effect was observed for bench press 1RM (P = .003) and relative 1RM (P P = .037). There was no significant change in overhead throwing velocity in either group. There was also no significant difference in change in all measures between groups. However, a moderate effect in favor of MIBP was observed for change in ballistic push-up peak power (P = .180, g = 0.67). Conclusions: Based on the current findings, the inclusion of both SIBP and MIBP were equally beneficial to maximal strength development. However, performing MIBP had a greater effect on power development.

Aims Concern about the cardiovascular safety of coronavirus disease 2019 (COVID-19) vaccines among individuals with cardiovascular disease (CVD) may lead to vaccine hesitancy. We sought to assess the association between two COVID-19 vaccines, BNT162b2 and CoronaVac, and the risk of major adverse cardiovascular events (MACE) in individuals with established CVD. Methods and results We identified individuals with a history of CVD before 23 February 2021 and a diagnosis of MACE between 23 February 2021 and 31 January 2022 in Hong Kong. MACE was defined as a composite of myocardial infarction, stroke, revascularization, and cardiovascular death. Electronic health records from the Hong Kong Hospital Authority were linked to vaccination records from the Department of Health. A self-controlled case-series method was used to evaluate the risk of MACE for 0–13 and 14–27 days after two doses of COVID-19 vaccine. We estimated incidence rate ratios (IRRs) to compare the risk of MACE between each risk period and the baseline period. A total of 229 235 individuals with CVD were identified, of which 1764 were vaccinated and had a diagnosis of MACE during the observation period (BNT162b2 = 662; CoronaVac = 1102). For BNT162b2, IRRs were 0.48 [95% confidence interval (CI) 0.23–1.02] for the first dose and 0.87 (95% CI 0.50–1.52) for the second dose during the 0–13 days risk period, 0.40 (95% CI 0.18–0.93) for the first dose and 1.13 (95% CI 0.70–1.84) for the second dose during the 14–27 days risk period. For CoronaVac, the IRRs were 0.43 (95% CI 0.24–0.75) for the first dose and, 0.73 (95% CI 0.46–1.16) for the second dose during the 0–13 days risk period, 0.54 (95% CI 0.33–0.90) for the first dose and 0.83 (95% CI 0.54–1.29) for the second dose during the 14–27 days risk period. Consistent results were found in subgroup analyses for different sexes, age groups and different underlying cardiovascular conditions. Conclusion Our findings showed no evidence of an increased risk of MACE after vaccination with BNT162b2 or CoronaVac in patients with CVD. Future research is required to monitor the risk after the third dose of each vaccine.

Background Little is known whether patients with lower health literacy could retain the practice and knowledge of home blood pressure monitoring (HBPM) after an educational programme. Methods A cluster randomised controlled trial in five primary care clinics recruited participants with uncontrolled hypertension. Clinics were randomised either to a HBPM group education (Risk Assessment and Management Programme (RAMP-group), or individual counselling of self-management (RAMP-individual). Health literacy was assessed by the Chinese Health Literacy Scale for Chronic Care. Practice and knowledge of HBPM were surveyed by a 10-item HBPM knowledge checklist and patient record review 6 months after interventions. Predictors for regular HBPM and good HBPM knowledge were assessed by multivariate logistic regression models. Results 287 participants (RAMP-group: 151; RAMP-individual: 136) were follow-up for 6 months. 272 participants completed the knowledge questionnaires (response rate 94.8%). 67.8% of the participants performed HBPM regularly, and there was no statistical difference between both interventions. Age more than 65 (adjusted odds ratios (aOR) 2.58, 95% CI 1.37 to 4.86, p=0.003), not working (aOR 2.34, 95% CI 1.10 to 4.97, p=0.027)and adequate health literacy (aOR 2.25, 95% CI 1.28 to 3.95, p=0.005) predicted regular HBPM. Participants in RAMP-group demonstrated a significant lower body weight than those in RAMP-individual (−0.3±2.0 kg vs +0.7 ±1.7 kg, p Conclusion Patients could retain HBPM knowledge better after RAMP-group than RAMP-individual. Older, retired and patients with adequate health literacy were more likely to continue weekly HBPM 6 months after education. Trial registration number NCT02551393.

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8(+) T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Background Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. Methods Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. Results Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. Conclusions Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.

Whether 5-aminosalicylic acid (ASA) can be stopped in patients with stable ulcerative colitis (UC) remains unclear. We aimed to examine whether 5-ASA can be safely withdrawn in UC patients who have been in corticosteroid-free clinical remission for ≥ 1 year.This is a retrospective cohort study using territory-wide healthcare database in Hong Kong. Primary outcome was development of UC flare, defined as new corticosteroid use or UC-related hospitalizations within 5 years. UC patients on oral 5-ASA ≥ 2 g daily for ≥ 1 year with C-reactive protein (CRP) 10 mg/dL and no 5-ASA dosage escalation, UC-related hospitalization or corticosteroid use in the past year were included. Patients on biological agents were excluded. Patients were classified as "stopping" if 5-ASA was withdrawn for ≥ 90 days within follow-up period. We performed multivariable Cox regression models adjusting for demographics, blood parameters and immunosuppressants used. Adjusted hazard ratio (aHR) with 95% confidence interval (CI) was reported comparing stopping and continuous-use groups.A total of 1408 patients were included with a median follow-up duration of 41.8 months (interquartile range [IQR]: 17.2-60.0 months). Stopping 5-ASA was not associated with an increased risk of UC flare (aHR 0.91; 95% CI 0.64-1.31; P = 0.620). A higher CRP levels at the time of stopping 5-ASA (aHR 1.15; 95% CI: 1.01-1.30; P = 0.037) were associated with increased risk of flare.Stopping 5-ASA in UC patients in corticosteroid-free remission for ≥ 1 year was not associated with increased risk of flare. Future prospective trials should evaluate the role of stopping 5-ASA in stable UC patients.

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

Children with autism commonly suffer from comorbid functional gastrointestinal disorders (FGID) and anxiety. The raised prevalence of both conditions in autism suggests complex reciprocal relationships, which are seldom explored in non-treatment-seeking FGID. The relationships between subtypes of FGID and anxiety are also unclear. This study recruited boys with autism and age-matched typically developing (TD) boys, aged 4-11 years, who were not actively seeking help for gastrointestinal problems. Their parents completed the Rome IV Diagnostic Questionnaires for Pediatric FGID. Four groups of children with and without autism/FGID were identified and compared on their anxiety level using the Spence children's anxiety scale. In 69 boys with autism and 69 age-matched TD boys, FGID were identified in 22 and 16 boys, respectively. ANCOVA demonstrated a significant interaction effect of autism and FGID on anxiety (F[1, 129] = 5.43, p = 0.021), while conditional logistic regression identified an interaction effect of autism and anxiety on the odds of FGID (OR 1.038, 95% CI 1.002-1.075, p = 0.038). Explorative post hoc analysis showed higher anxiety in functional nausea and vomiting disorder (p = 0.033) and functional abdominal pain disorder (p = 0.029) among boys with autism than TD boys with the same respective subtypes of FGID. In summary, among prepubertal boys with autism, the presence of FGID that are non-treatment-seeking in nature, has a significantly stronger association with higher levels of anxiety than TD boys. The strength of association may be more prominent in subtypes of FGID. Possible pathomechanisms including the underlying microbiota spectra and inflammatory paths should be explored in future studies. LAY SUMMARY: Anxiety and gastrointestinal problems are common symptoms in autism. Given that gut health could be linked to emotions, their association in young boys with autism was studied. The presence of nausea vomiting, or abdominal pain were associated with raised anxiety among boys with autism, yet this was not observed in typically developing boys. This suggests that anxiety among autistic children could be partly explained by the presence of FGID.

Study objective We aimed to evaluate and characterize the scale and relationships of emergency department (ED) visits and excess mortality associated with the early phase of the COVID-19 pandemic in the territory of Hong Kong. Methods We conducted a territory-wide, retrospective cohort study to compare ED visits and the related impact of the COVID-19 pandemic on mortality. All ED visits at 18 public acute hospitals in Hong Kong between January 1 and August 31 of 2019 (n=1,426,259) and 2020 (n=1,035,562) were included. The primary outcome was all-cause mortality in the 28 days following an ED visit. The secondary outcomes were weekly number of ED visits and diagnosis-specific mortality. Results ED visits decreased by 27.4%, from 1,426,259 in 2019 to 1,035,562 in 2020. Overall period mortality increased from 28,686 (2.0%) in 2019 to 29,737 (2.9%) in 2020. The adjusted odds ratio for 28-day, all-cause mortality in the pandemic period of 2020 relative to 2019 was 1.26 (95% confidence interval 1.24 to 1.28). Both sexes, age more than 45 years, all triage categories, all social classes, all ED visit periods, epilepsy (odds ratio 1.58, 95% confidence interval 1.20 to 2.07), lower respiratory tract infection, and airway disease had higher adjusted ORs for all-cause mortality. Conclusion A significant reduction in ED visits in the first 8 months of the COVID-19 pandemic was associated with an increase in deaths certified in the ED. The government must make provisions to encourage patients with alarming symptoms, mental health conditions, and comorbidities to seek timely emergency care, regardless of the pandemic.

Conventional magnetic resonance imaging (MRI) often acquires no signal in anterior cruciate ligament (ACL) due to the short apparent transverse relaxation time of ACL. Ultrashort echo time (UTE) MRI is capable of imaging ACL with high signal which enables quantitative ACL assessment. This study aimed to investigate the correlations of the mechanical and microstructural properties of human ACL specimens with quantitative three-dimensional UTE Cones (3D-UTE-Cones) MRI measures. ACL specimens were harvested from cadaveric knee joints of thirteen (50.9±21.1 years old, 11 males and 2 female) donors. Specimens were scanned using a series of quantitative 3D-UTE-Cones T(2)* (UTE-T(2)*), T(1) (UTE-T(1)), Adiabatic T(1ρ) (UTE-Adiab-T(1ρ)), and magnetization transfer (UTE-MT) sequences in a wrist coil on a clinical 3T scanner. ACL elastic modulus was measured using a uniaxial tensile mechanical test. Histomorphometry analysis was performed to measure the average fascicle specific surface, fascicle size, and number of cells per unit area. Spearman’s rank correlations of UTE-MRI biomarkers with mechanical and histomorphometry measures were investigated. The elastic modulus of ACL showed significant moderate correlations with UTE-Adiab-T(1ρ) (R=−0.59, P=0.01), macromolecular fraction (MMF) from MT modeling (R=0.54, P=0.01), magnetization transfer ratio (MTR) (R=0.53, P=0.01), UTE-T2* (R=−0.53, P=0.01), and average fascicle specific surface (R=0.54, P=0.01). UTE-MRI showed non-significant correlations with histomorphometry measures. UTE-MRI biomarkers may be useful non-invasive tools for the ACL mechanical assessment.

According to the International Diabetes Federation, the number of adults (age of 20-79) being diagnosed with Diabetes Mellitus (DM) have increased from 285 million in year 2009 to 463 million in year 2019 which comprises of 95% Type 2 DM patient (T2DM). Research have claimed that genetic predisposition could be one of the factors causing T2DM complications. In addition, T2DMcomplications cause an incremental risk to mortality. Therefore, this article aims to discuss some complications of T2DM in and their genetic association. The complications that are discussed in this article are diabetic nephropathy, diabetes induced cardiovascular disease, diabetic neuropathy, Diabetic Foot Ulcer (DFU) and Alzheimer's disease. According to the information obtained, genes associated with diabetic nephropathy (DN) are gene GABRR1 and ELMO1 that cause injury to glomerular. Replication of genes FRMD3, CARS and MYO16/IRS2 shown to have link with DN. The increase of gene THBS2, NGAL, PIP, TRAF6 polymorphism, ICAM-1 encoded for rs5498 polymorphism and C667T increase susceptibility towards DN in T2DM patient. Genes associated with cardiovascular diseases are Adiponectin gene (ACRP30) and Apolipoprotein E (APOE) polymorphism gene with ξ2 allele. Haptoglobin (Hp) 1-1 genotype and Mitochondria Superoxide Dismutase 2 (SOD2) plays a role in cardiovascular events. As for genes related to diabetic neuropathy, Janus Kinase (JAK), mutation of SCN9A and TRPA1 gene and destruction of miRNA contribute to pathogenesis of diabetic neuropathy among T2DM patients. Expression of cytokine IL-6, IL-10, miR-146a are found to cause diabetic neuropathy. Besides, A1a16Va1 gene polymorphism, an oxidative stress influence was found as one of the gene factors. Diabetic retinopathy (DR) is believed to have association with Monocyte Chemoattractant Protein-1 (MCP-1) and Insulin-like Growth Factor 1 (IGF1). Over-expression of gene ENPP1, IL-6 pro-inflammatory cytokine, ARHGAP22's protein rs3844492 polymorphism and TLR4 heterozygous genotype are contributing to significant pathophysiological process causing DR, while research found increases level of UCP1 gene protects retina cells from oxidative stress. Diabetic Foot Ulcer (DFU) is manifested by slowing in reepithelialisation of keratinocyte, persistence wound inflammation and healing impairment. Reepithelialisation disturbance was caused by E2F3 gene, reduction of Tacl gene encoded substance P causing persistence inflammation while expression of MMp-9 polymorphism contributes to healing impairment. A decrease in HIF-1a gene expression leads to increased risk of pathogenesis, while downregulation of TLR2 increases severity of wound in DFU patients. SNPs alleles has been shown to have significant association between the genetic dispositions of T2DM and Alzheimer's disease (AD). The progression of AD can be due to the change in DNA methylation of CLOCK gene, followed with worsening of AD by APOE4 gene due to dyslipidaemia condition in T2DM patients. Insulin resistance is also a factor that contributes to pathogenesis of AD.

Background Gut microbiota dysbiosis and sarcopenia commonly occur in the elderly. Although the concept of the gut–muscle axis has been raised, the casual relationship is still unclear. This systematic review analyses the current evidence of gut microbiota effects on muscle/sarcopenia. Methods A systematic review was performed in PubMed, Embase, Web of Science, and The Cochrane Library databases using the keywords (microbiota* OR microbiome*) AND (sarcopen* OR muscle). Studies reporting the alterations of gut microbiota and muscle/physical performance were analysed. Results A total of 26 pre‐clinical and 10 clinical studies were included. For animal studies, three revealed age‐related changes and relationships between gut microbiota and muscle. Three studies focused on muscle characteristics of germ‐free mice. Seventy‐five per cent of eight faecal microbiota transplantation studies showed that the recipient mice successfully replicated the muscle phenotype of donors. There were positive effects on muscle from seven probiotics, two prebiotics, and short‐chain fatty acids (SCFAs). Ten studies investigated on other dietary supplements, antibiotics, exercise, and food withdrawal that affected both muscle and gut microbiota. Twelve studies explored the potential mechanisms of the gut–muscle axis. For clinical studies, 6 studies recruited 676 elderly people (72.8 ± 5.6 years, 57.8% female), while 4 studies focused on 244 young adults (29.7 ± 7.8 years, 55.4% female). The associations of gut microbiota and muscle had been shown in four observational studies. Probiotics, prebiotics, synbiotics, fermented milk, caloric restriction, and exercise in six studies displayed inconsistent effects on muscle mass, function, and gut microbiota. Conclusions Altering the gut microbiota through bacteria depletion, faecal transplantation, and various supplements was shown to directly affect muscle phenotypes. Probiotics, prebiotics, SCFAs, and bacterial products are potential novel therapies to enhance muscle mass and physical performance. Lactobacillus and Bifidobacterium strains restored age‐related muscle loss. Potential mechanisms of microbiome modulating muscle mainly include protein, energy, lipid, and glucose metabolism, inflammation level, neuromuscular junction, and mitochondrial function. The role of the gut microbiota in the development of muscle loss during aging is a crucial area that requires further studies for translation to patients.

Introduction With mobile technologies becoming more advanced and accessible, mobile health (mHealth) has been incorporated in delivering timely and convenient breastfeeding support. However, its feasibility and potential efficacy remain to be examined. Therefore, the primary objective of this study is to assess the feasibility and acceptability of an online instant messaging peer support group for breastfeeding. The secondary objective is to evaluate the effect of the intervention on breastfeeding outcomes. Methods A pilot randomized controlled trial was conducted. A total of 33 primiparous women were recruited in the antenatal clinic at a public hospital in Hong Kong between March and April 2021. They were randomized to receive either standard care (n = 18) or standard care and receive peer-group support in an online instant messaging app (n = 15). Participants received telephone follow-up for up to six months postpartum or until they stopped breastfeeding. After completing the study, six participants in the intervention group were interviewed to understand their perceptions of the intervention. Results This pilot study shows that online messaging peer support group is feasible and acceptable to women. In total, 54.4% of the eligible women agreed to participate, and 97.0% completed the follow-up. Participants perceived that providing peer support through instant messaging app is appropriate. It serves as a channel for the participants to ask questions and obtain information. Furthermore, meetings of the peer supporters and group members can be held to enhance the effectiveness of the intervention. In addition, no significant differences were found in any and exclusive breastfeeding rates, breastfeeding attitude, and breastfeeding self-efficacy between the two groups. Conclusions This study shows that online messaging peer support group is feasible and acceptable. A full-scale study should be conducted to understand the effect of the online instant messaging peer support group on breastfeeding outcomes. Trial Registration: The study protocol is registered on Clinicaltrial.gov (NCT04826796) on 1 April 2021

Purpose: To determine mortality and outcomes of patients diagnosed with fracture-related infections (FRIs). Methods: FRI patients treated at a trauma centre between 2001 and 2020 were analysed. The primary outcome was 1-year mortality; mortality associations with FRI organism, depth of involvement, and temporality were investigated with multivariable survival analysis. Healthcare-associated and serological outcomes were reported as secondary outcomes. Results: 311 FRIs with mean age of 67.0 and median Charlson comorbidity index of 0 were analysed. Methicillin-sensitive Staphylococcus aureus (MSSA) (29.9%) was the most frequently implicated organism. The majority of FRIs were deep infections (62.7%). FRIs were diagnosed at a median of 40 (IQR 15–200) days post index surgery. The mean follow-up was 5.9 years. One-year mortality amounted to 17.7%. MSSA FRIs were associated with better survival (adj HR 0.34, 95%CI 0.15–0.76, p = 0.008). There was no difference in survivorship between deep or superficial FRI (adj HR 0.86, 95%CI 0.62–1.19, p = 0.353) or in relation to onset time (adj HR 1.0, 95%CI 0.99–1.00, p = 0.943). Implant removal or debridement alone was performed in 61.7% and 17% respectively. Antibiotics was prescribed for 53 (IQR 23–110) days, and patients were hospitalised for 39 (IQR 19–78) days. CRP and ESR normalised in 70.3% (median 46 days) and 53.8% (median 86 days) patients respectively. Conclusion: Fracture-related infections are associated with significant mortality and morbidity regardless of depth and temporality. Non-MSSA FRIs are associated with inferior survival.

Two dual stimuli-activated photosensitizers were developed, in which two or three glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS)-substituted zinc(II) phthalocyanine units were connected via one or two cathepsin B-cleavable Gly-Phe-Leu-Gly peptide linker(s). These dimeric and trimeric phthalocyanines were fully quenched in the native form due to the photoinduced electron transfer to the DNBS substituents and the self-quenching of the phthalocyanine units. In the presence of GSH and cathepsin B, or upon internalization into A549 and HepG2 cancer cells, these probes were activated through the release of free phthalocyanine units. The intracellular fluorescence intensity was increased upon post-incubation with GSH ester or reduced upon pre-treatment with a cathepsin B inhibitor. Upon light irradiation, these photosensitizers became highly cytotoxic with IC50 values of 0.21-0.39 μM. The photocytotoxicity was also dependent on the intracellular GSH and cathepsin B levels. The results showed that these conjugates could serve as smart photosensitizers for targeted photodynamic therapy.

Aim High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown. Methods Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC. Results Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells. Conclusions Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.

Introduction This study developed and piloted the first online training package to support implementation and delivery of brief smoking cessation interventions for therapeutic radiographers in four radiotherapy departments in England. Methods A previously reported systematic literature review and data analysis from the previously reported pre-focus group questionnaire and focus groups enabled the development of an online training package. The questionnaire was repeated by the participating therapeutic radiographers following completion of the training resource (n = 31). The results of the comparative questions from the pre and post questionnaires were analysed using the Statistical Package for Social Sciences (SPSS Version 24). Results In total, 43 therapeutic radiographer participants completed the pre-questionnaire and 31 participants continued to complete the post questionnaire, having completed the online training package. The previously conducted focus groups identified several barriers to the delivery of smoking cessation, that were addressed through the development of an online training package. Following the completion of the training; therapeutic radiographers had increased knowledge and confidence regarding smoking cessation, the number of therapeutic radiographers who believe that smoking cessation is part of their role increased and therapeutic radiographers more routinely have conversations about smoking cessation. Conclusion The training resource improved therapeutic radiographers’ knowledge and confidence and increased awareness of the role of the therapeutic radiographer in the provision of smoking cessation interventions. Challenges remain that continue to prevent some therapeutic radiographers from delivering smoking cessation interventions and strong leadership and implementation of strategy and guidance is essential to ensure wider implementation. Recording and measuring impact of interventions remains an area to be addressed, alongside cultural changes and reassurance around the therapeutic relationship. Implications for practice This training tool has proven to be effective in the sample within this study and should be disseminated and evaluated more widely across radiotherapy provision within the United Kingdom.

Cellular circulating biomarkers from the primary tumor such as circulating tumor cells (CTCs) and circulating hybrid cells (CHCs) have been described to harbor tumor-like phenotype and genotype. CHCs are present in higher numbers than CTCs supporting their translational potential. Methods for isolation of CHCs do not exist and are restricted to low-throughput, time consuming, and biased methodologies. We report the development of a label-free dielectrophoretic microfluidic platform facilitating enrichment of CHCs in a high-throughput and rapid fashion by depleting healthy peripheral blood mononuclear cells (PBMCs). We demonstrated up to 96.5% depletion of PBMCs resulting in 18.6-fold enrichment of cancer cells. In PBMCs from pancreatic adenocarcinoma patients, the platform enriched neoplastic cells identified by their KRAS mutant status using droplet digital PCR with one hour of processing. Enrichment was achieved in 75% of the clinical samples analyzed, establishing this approach as a promising way to non-invasively analyze tumor cells from patients., Montoya Mira & Sapre et al. design a microfluidic device utilizing dielectrophoresis for the enrichment of circulating neoplastic cells that possess both epithelial and immune-like characteristics. They optimized the device using in vitro models and then applied it to clinical samples for clinically relevant mutation analyses.

Background The extent of thyroid surgery remains controversial for differentiated thyroid cancers (DTCs) that measure more than 1 cm but are not considered high risk. This study aimed to compare survival outcomes between hemithyroidectomy (HT) and total thyroidectomy (TT) in non-high-risk DTCs. Methods A population-based retrospective cohort of patients with non-high-risk DTCs more than 1 cm undergoing HT or TT between 1997 and 2017 in a territory with 41 public hospitals and clinics serving a population of 7 million was analysed. Multivariable Cox proportional hazards regression models adjusted for patient demographics and clinical parameters were used to compare the overall, disease-specific, and recurrence-free survival between TT and HT. Risks of postoperative complications were compared between the two groups. Results A total of 4771 patients (HT, 1368; TT, 3403) underwent thyroid surgery as a primary treatment. Median (range) follow-up was 117 (range: 72–179) months. Patients in the TT and HT groups had comparable risks of overall survival (HR 0.87; 95 per cent c.i. 0.73 to 1.04; P = 0.119) and disease-specific survival (HR 0.85; 95 per cent c.i. 0.52 to 1.40; P = 0.518). The TT group had better recurrence-free survival (HR 0.37; 95 per cent c.i. 0.26 to 0.52; P < 0.001) than the HT group. The temporary and permanent hypoparathyroidism rates in TT group were 14.96 per cent and 7.49 per cent respectively; none were reported in the HT group. Conclusions Despite the comparable overall and disease-specific survivals, TT was associated with better recurrence-free survival than HT in a 10-year follow-up. This was at the expense of higher surgical morbidity rate in TT.

Background Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

Cell-free DNA (cfDNA) fragmentation patterns contain important molecular information linked to tissues of origin. We explored the possibility of using fragmentation patterns to predict cytosine-phosphate-guanine (CpG) methylation of cfDNA, obviating the use of bisulfite treatment and associated risks of DNA degradation. This study investigated the cfDNA cleavage profile surrounding a CpG (i.e., within an 11-nucleotide [nt] window) to analyze cfDNA methylation. The cfDNA cleavage proportion across positions within the window appeared nonrandom and exhibited correlation with methylation status. The mean cleavage proportion was ∼twofold higher at the cytosine of methylated CpGs than unmethylated ones in healthy controls. In contrast, the mean cleavage proportion rapidly decreased at the 1-nt position immediately preceding methylated CpGs. Such differential cleavages resulted in a characteristic change in relative presentations of CGN and NCG motifs at 5′ ends, where N represented any nucleotide. CGN/NCG motif ratios were correlated with methylation levels at tissue-specific methylated CpGs (e.g., placenta or liver) (Pearson’s absolute r > 0.86). cfDNA cleavage profiles were thus informative for cfDNA methylation and tissue-of-origin analyses. Using CG-containing end motifs, we achieved an area under a receiver operating characteristic curve (AUC) of 0.98 in differentiating patients with and without hepatocellular carcinoma and enhanced the positive predictive value of nasopharyngeal carcinoma screening (from 19.6 to 26.8%). Furthermore, we elucidated the feasibility of using cfDNA cleavage patterns to deduce CpG methylation at single CpG resolution using a deep learning algorithm and achieved an AUC of 0.93. FRAGmentomics-based Methylation Analysis (FRAGMA) presents many possibilities for noninvasive prenatal, cancer, and organ transplantation assessment.

This study was performed to examine the effects of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on neutropenic toxicity, chemotherapy delivery, and hospitalisation among Chinese patients with breast cancer in Hong Kong.This retrospective study included patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy from November 2007 to October 2013 at Princess Margaret Hospital. Data were collected regarding the usage of G-CSF prophylaxis; incidences of grade 3 or 4 neutropenia, febrile neutropenia, non-neutropenic fever, and infection; hospital admissions, and chemotherapy dose delivery. Patients who began to receive G-CSF prophylaxis during the first cycle of chemotherapy and continued such prophylaxis in subsequent cycles were regarded as the primary G-CSF prophylaxis group.In total, 231 female Chinese patients with breast cancer were included in the analysis. Overall, 193 (83.5%) patients received primary G-CSF prophylaxis. The demographics and tumour characteristics were comparable between patients with and without primary G-CSF prophylaxis. Primary G-CSF prophylaxis significantly reduced febrile neutropenia incidence from 31.6% to 14.5% (relative risk=0.45, 95% confidence interval=0.25-0.81). Primary G-CSF prophylaxis also significantly reduced the incidence of grade 3 or 4 neutropenia from 57.9% to 24.7% (relative risk=0.43, 95% confidence interval=0.30-0.62) and the incidence of febrile neutropenia-related hospital admission from 31.6% to 12.4% (P=0.025). Finally, it enabled more patients to receive adequate chemotherapy dose delivery.Primary G-CSF prophylaxis effectively reduced the incidences of grade 3 or 4 neutropenia and febrile neutropenia, while enabling adequate chemotherapy dose delivery and reducing hospital admissions among Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy.

ObjectiveWe aim to systematically assess the clinical characteristics of ocular myasthenia gravis (OMG) and report on the proportion of patients who develop secondary generalised myasthenia gravis (SGMG).IntroductionOMG is an autoimmune neuromuscular junction disorder resulting in ptosis and diplopia. A proportion of patients with OMG develop weakness in their limbs, respiratory or bulbar muscles, that is, convert to SGMG. The proportion of patients converting to SGMG reported in the literature have been varied. We therefore aim to systematically assess the clinical characteristics of OMG and outcomes of SGMG reported in the literature to date.Inclusion criteriaStudies describing a population of adults with OMG, that is, MG with ocular symptoms and signs only, seen consecutively through a clinical service, reporting on patient characteristics and the outcome of SGMG. Studies on paediatric and congenital myasthenia gravis will be excluded.MethodsWe will conduct an electronic database search for randomised controlled trials, prospective non-randomised studies, observational studies and retrospective studies in MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science. Exploratory database search was conducted on 1 December 2021. Eligibility criteria will include quantitative and qualitative articles written in any language and containing data on OMG. Additional studies will be identified by reviewing bibliographies of retrieved articles. Two independent reviewers will screen titles and abstracts and extract data from full texts, reporting outcomes according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological quality will be assessed using the Joanna Briggs Institute critical appraisal forms.Ethics and disseminationEthical approval is not required for this review, as it will only include published data. Findings will be published in a peer-reviewed journal and disseminated across ophthalmic networks.PROSPERO registration numberCRD42021285257.

The purpose of this study was to correct refractive error-associated bias in optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters.OCT and OCTA imaging were obtained from participants in the Hong Kong FAMILY cohort. The Avanti/AngioVue OCT/OCTA system was used to measure the peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), macular ganglion cell complex thickness (GCCT), and macular superficial vascular complex vascular density (SVC-VD). Healthy eyes, including ones with axial ametropia, were enrolled for analysis.A total of 1346 eyes from 792 participants were divided into 4 subgroups: high myopia (-6D), low myopia (-6D to -1D), emmetropia (-1D to 1D), and hyperopia (1D). After accounting for age, sex, and signal strength, multivariable regression showed strong dependence in most models for NFLT, GCCT, and NFLP-CD on axial eye length (AL), spherical equivalent (SE) refraction, and apparent optic disc diameter (DD). Optical analysis indicated that AL-related transverse optical magnification variations predominated over anatomic variations and were responsible for these trends. Compared to the emmetropic group, the false positive rates were significantly (Chi-square test P0.003) elevated in both myopia groups for NFLT, NFLP-CD, and GCCT. Regression-based adjustment of these diagnostic parameters with AL or SE significantly (McNemar test P0.03) reduced the elevated false positive rates.Myopic eyes are biased to have lower NFLT, GCCT, and NFLP-CD measurements. AL- and SE-based adjustments were effective in mitigating this bias.Adoption of these adjustments into commercial OCT systems may reduce false positive rates related to refractive error.

Background Evidence is lacking about any additional benefits of introducing remdesivir on top of dexamethasone, and the optimal timing of initiation. Methods In a territory-wide cohort of 10 445 coronavirus disease 2019 (COVID-19) patients from Hong Kong who were hospitalized between 21 January 2020 and 31 January 2021, 1544 had received dexamethasone during hospitalization. The exposure group consisted of patients who had initiated remdesivir prior to dexamethasone (n = 93) or co-initiated the 2 drugs simultaneously (n = 373), whereas the nonexposure group included patients who were given remdesivir after dexamethasone (n = 149) or those without remdesivir use (n = 929). Multiple imputation and inverse probability of treatment weighting for propensity score were applied and hazard ratios (HRs) of event outcomes were estimated using Cox regression models. Results Time to clinical improvement (HR = 1.23; 95% CI, 1.02–1.49; P = .032) and positive IgG antibody (HR = 1.22; 95% CI, 1.02–1.46; P = .029) were significantly shorter in the exposure group than that of nonexposure. The exposure group had a shorter hospital length of stay by 2.65 days among survivors, lower WHO clinical progression scale scores from 5 days of follow-up onwards, and lower risks of in-hospital death (HR = .59; 95% CI, .36–.98; P = .042) and composite outcomes; and without experiencing an increased risk of acute respiratory distress syndrome. Differences in the cumulative direct medical costs between groups were no longer significant from 17 days of follow-up onwards. Conclusions Initiation of remdesivir prior to or simultaneously with dexamethasone was associated with significantly shorter time to clinical improvement and positive IgG antibody, lower risk of in-hospital death, in addition to shorter length of hospital stay in patients with moderate COVID-19.

The glutamatergic cycle is essential in modulating memory processing by the hippocampal circuitry. Our combined proton magnetic resonance spectroscopy (1 H-MRS) and task-based functional magnetic resonance imaging (fMRI) study (using face-name paired-associates encoding and retrieval task) of a cognitively normal cohort of 67 healthy adults (18 ApoE4 carriers and 49 non-ApoE4 carriers) found altered patterns of relationships between glutamatergic-modulated synaptic signalling and neuronal activity or functional hyperaemia in the ApoE4 isoforms. Our study highlighted the asymmetric left-right hippocampal glutamatergic system in modulating neuronal activities in ApoE4 carriers versus non-carriers. Such brain differentiation might be developmental cognitive advantages or compensatory due to impaired synaptic integrity and plasticity in ApoE4 carriers. As there was no difference in myoinositol levels measured by MRS between the ApoE4 and non-ApoE4 subgroups, the mechanism is unlikely to be a response to neuroinflammation.

BACKGROUND & AIMS: Processed meat and high sodium intake are common in Western diet. The objective was to examine their independent effects on the risk of colorectal cancer (CRC).METHODS: We performed both observational analysis with UK Biobank and genetic analysis with Mendelian randomization (MR). The 24-h urinary sodium (UNa) and reported intake of processed meat were fitted on incident CRC by multivariable Cox proportional hazard model, adjusted for covariates, such as age, gender, family history, etc. Different sodium measures were used for sensitivity analyses. Two-sample MR analyses were performed using summary data from genome-wide association studies of UNa and CRC. Multivariable MR was adjusted for body mass index.RESULTS: We included 415 524 eligible participants from UK Biobank. During a median follow-up of 11.1 years, 2663 participants were diagnosed with CRC. High intake of processed meat independently increased risk of CRC by 23% (HR 1.23; 95% CI: 1.03 to 1.46), but 24-h UNa was not significantly associated with CRC (HR 0.96; 95% CI: 0.87 to 1.06). Furthermore, MR also showed little evidence for the effect of UNa on CRC (OR 1.02; 95% CI: 0.11 to 9.42). Sensitivity analyses showed consistent results across different measurements of sodium intake.CONCLUSIONS: Intake of processed meat had an independent effect on the risk of CRC, but the risk was not associated with sodium level. Reduction of processed meat intake may be an effective strategy for CRC prevention, while sodium reduction should still be recommended to achieve other health benefits.

Objectives: To estimate the hospital costs among persons with obesity undergoing bariatric surgery compared with those without bariatric surgery. Methods: We analysed the UK Biobank Cohort study linked to Hospital Episode Statistics, for all adults with obesity undergoing bariatric surgery at National Health Service hospitals in England, Scotland, or Wales from 2006 to 2017. Surgery patients were matched with controls who did not have bariatric surgery using propensity scores approach with a ratio of up to 1-to-5 by year. Inverse probability of censoring weighting was used to correct for potential informative censoring. Annual and cumulative hospital costs were assessed for the surgery and control groups. Results: We identified 348 surgical patients (198 gastric bypass, 73 sleeve gastrectomy, 77 gastric banding) during the study period. In total, 324 surgical patients and 1506 matched control participants were included after propensity score matching. Mean 5-year cumulative hospital costs were €11,659 for 348 surgical patients. Compared with controls, surgical patients (n = 324) had significantly higher inpatient expenditures in the surgery year (€7289 vs. €2635, P Conclusions: Bariatric surgery significantly increased the inpatient costs in the surgery year, but was associated with decreased costs in the subsequent 4 years. However, any cost savings made up to 4 years were not enough to compensate for the initial surgical expenditure.

Purpose To study the effect of phacoemulsification on intraocular pressure (IOP) control in patients with preexisting glaucoma drainage implants (GDIs). Design Retrospective, observational case series. Participants A total of 45 patients (51 eyes) with previously placed GDIs who underwent phacoemulsification between January 2013 and March 2018. Methods The list of patients was obtained from billing records. Clinical data were retrieved from the corresponding electronic medical records. Main Outcome Measures Intraocular pressure, number of glaucoma medications before and after phacoemulsification (postoperative day 1, week 1, months 1, 3, 6, 12, 18, and 24), rate of failure (failure defined as IOP >18 mmHg and IOP increase >20% at 2 consecutive visits after month 1, need for additional glaucoma surgery, or loss of light perception vision), and postoperative complications. Results Mean follow-up was 23.0 ± 11.1 months. The average interval between GDI surgery and phacoemulsification was 9.4 ± 6.7 months. An Ahmed glaucoma valve (AGV; New World Medical) was implanted in 12 eyes, a Baerveldt glaucoma implant (BGI; Johnson & Johnson Surgical Vision) was implanted in 36 eyes, and a Molteno (Molteno Ophthalmic Limited) glaucoma implant was implanted in 3 eyes. Before phacoemulsification, the mean IOP was 14.4 ± 4.4 mmHg on 2.1 ± 1.3 glaucoma medications. At postoperative month 24, the mean IOP was 12.6 ± 4.4 mmHg (n = 29, P = 0.519) on 2.0 ± 1.6 (P = 0.457) glaucoma medications. The reduction in IOP was significant only at postoperative week 1 (P = 0.031). The cumulative failure rate was 3.9% at 1 year and 11.8% at 2 years. The AGV group had a significantly higher mean IOP before phacoemulsification than the BGI group (P = 0.016). Analysis of covariance, taking the baseline IOP as a covariate, revealed no differences in postoperative IOP and number of glaucoma medications between groups, except for month 18 (1 patient in the BGI group had uncontrolled IOP requiring surgery). Postoperative complications included cystoid macular edema (10%), corneal decompensation (6%), and choroidal effusion (4%). Conclusions Phacoemulsification after GDI surgery resulted in a transient reduction in IOP at postoperative week 1. Patients with previously placed AGVs had similar postoperative outcomes compared with those with BGIs.

Objective Unique challenges can present in the treatment of small to mid-sized meningiomas that arise from the region of the anterior most aspect of the falx cerebri including its junction with the anterior skull base, what we call the far frontal region. Although this region of the anterior skull base is considered in the surgical approach of olfactory groove meningiomas invading this space, important differences exist between these tumors and those of the far frontal region. Methods Toward refining surgical selection, our cadaveric study details a minimally invasive keyhole superior interhemispheric approach to the far frontal region and 2 illustrative cases show the feasibility of this approach. Results Our cadaveric study defines 5 steps of the approach from the incision, craniectomy, dural opening, approaching the skull base and ipsilateral exposure, and finally falcine resection and bilateral skull base exposure. Two illustrative cases with the approach confirmed visualization of the full extent of tumor and gross total resection with preservation of the unaffected olfactory bulb. Conclusions To the best of our knowledge, our anatomic study is distinctively unique in quantifying the working distance of the keyhole superior interhemispheric exposure and refining visualization of the far frontal region. We discuss these benefits and limitations (i.e., substantial involvement of tumor beyond midline) and differences with large meningiomas of the olfactory groove and far frontal region with significant posterior or lateral extension for which conventional exposures are appropriate.

SUMMARY STATEMENT As the field of healthcare simulation matures, formal accreditation for simulation fellowships and training programs has become increasingly available and touted as a solution to standardize the education of those specializing in healthcare simulation. Some simulation experts hold opposing views regarding the potential value of simulation fellowship program accreditation. We report on the proceedings of a spirited debate at the 20th International Meeting on Simulation in Healthcare in January 2020. Pro arguments view accreditation as the logical evolution of a maturing profession: improving training quality through standard setting, providing external validation for individual programs, and enhancing the program's return on investment. Con arguments view accreditation as an incompletely formulated construct; burdensome to the "financially strapped" fellowship director, misaligned with simulation fellows' needs and expectations, and confusing to administrators mistakenly equating accreditation with credentialing. In addition, opponents of accreditation postulate that incorporating curricular standards, practice guidelines, and strategies derived and implemented without rigor, supporting evidence and universal consensus is premature. This narrative review of our debate compares and contrasts contemporary perspectives on simulation fellowship program accreditation, concluding with formal recommendations for learners, administrators, sponsors, and accrediting bodies.

IntroductionPitch variation, which refers to one's ability to vary fundamental frequency (F0) within or between syllables when speaking, has not been investigated in children with childhood apraxia of speech (CAS). However, pitch variation plays an important role in tone languages, as varying F0 patterns communicate different lexical meanings. This study investigated pitch variation abilities in individuals with CAS via the tone-sequencing tasks (TSTs), focusing on task performance and the effects of syllable structure, lexical status, and tones.MethodThree Cantonese-speaking children with CAS (aged 3;7–5;8 [years;months]) and six children without CAS participated in the study. Children without CAS were divided into two control groups, comprising those with speech and/or language impairment or typical development. TSTs consisted of 56 sets of five repetitions of stimuli. The stimuli varied in syllable structure, lexical status, and tones. Percentage of tones correct (PTC), consistency scores, F0 values, and acoustic repetition duration were measured.ResultsThe CAS group performed more poorly than the control groups on the TST with respect to tone accuracy, consistency, and repetition duration. No interaction effects between group and syllable structure or group and lexical status were found. No significant difference was found on F0 values across time between Tone 1 and Tone 2 syllables in the CAS group. However, interaction effects between group and time points of F0 values on Tone 2 syllables were found.DiscussionThe results suggest that children with CAS have difficulty with pitch variation, which was revealed on the TST with respect to tone accuracy, consistency, and repetition duration. Moreover, children with CAS have difficulty in varying F0 values to produce high-rising tones and tend to use high-level tones to substitute. Clinically, the TST may be useful to assist in the diagnosis of CAS. Isolated vowel stimuli may be useful to test young children or children with severe impairment. Future investigations and development of a normed tool for children with CAS are suggested.

Resected colorectal liver metastases (CRLM) frequently recur intrahepatically. Selection criteria for repeat hepatectomy of recurrent CRLM are ill-defined.We performed an institutional review of patients with recurrent CRLM undergoing repeat hepatectomy from 2003 to 19. Post-recurrence overall (rOS) and recurrence-free survival (RFS) were analyzed with Cox proportional hazards modeling.n = 147 experienced recurrent CRLM; 11% (n = 38) received repeat hepatectomy of which there was one Clavien-Dindo IIIa complication. Median rOS was 41 months; median RFS was 9 months. Improved rOS and RFS were independently associated with additional post-operative chemotherapy after repeat hepatectomy (HR 0.35 and 0.34, respectively); poor rOS with recurrent CRLM3 cm (HR 4.4) and12 months from first hepatectomy to recurrence (HR 4.8); poor RFS with ≥3 recurrence liver metastases (HR 2.8) (All P 0.05).Repeat hepatectomy for recurrent CRLM can be performed safely. Worse survival following repeat hepatectomy is independently associated with3 cm and ≥3 liver lesions at recurrence, and12 months to recurrence. Additional post-operative chemotherapy after repeat hepatectomy is associated with improved outcomes.

Patients suffering from end-stage heart failure also suffer from multiple cardiovascular comorbidities such as abdominal aortic aneurysm (AAA). Mechanical support with left ventricular assist device with open repair of AAA repair has rarely been reported in literature. The authors describe a 60-year-old male with end-stage heart failure and a symptomatic AAA with sequential left ventricular assist device insertion and open AAA repair with aortic cross-clamping.

Background Apolipoprotein E ɛ4 allele (ApoE4) is the most common gene polymorphism related to Alzheimer's disease (AD). Impaired synaptic dysfunction occurs in ApoE4 carriers before any clinical symptoms. It remains unknown whether ApoE4 status affects the hippocampal neuromodulation, which further influences brain network topology. Purpose To study the relationship of regional and global network properties by using graph theory analysis and glutamatergic (Glx) neuromodulation in the ApoE isoforms. Study Type Prospective. Subjects Eighty‐four cognitively normal adults (26 ApoE4 and 58 non‐ApoE4 carriers). Field Strength/Sequence Gradient‐echo echo‐planar and point resolved spectroscopy sequence at 3 T. Assessment Glx concentration in bilateral hippocampi were processed with jMRUI (4.0), and graph theory metrics (global: γ, λ, small‐worldness in whole brain; regional: nodal clustering coefficient (C i) and nodal characteristic path length (L i)) in top 20% highly connected hubs of subgroups (low‐risk: non‐ApoE4; high‐risk: APOE4) were calculated and compared. Statistical Tests Two‐sample t test was used to compare metrics between subgroups. Correlations between regional properties and Glx by Pearson's partial correlation with false discovery rate correction. Results Significant differences (P

Aim First use of opioids often happens in adolescence and an increasing number of opioid overdoses are being reported among youth. The purpose of this narrative review was to present the treatment approaches for youth with high-risk opioid use, determine whether the literature supports the use of opioid agonist treatment among youth and identify evidence for better treatment outcomes in the younger population. Methods A search of the literature on PubMed using MeSH terms specific to youth, opioid use and treatment approaches generated 1436 references. Following a screening process, 137 papers were found to be relevant to the treatment of high-risk opioid use among youth. After full-text review, 19 eligible studies were included: four randomized controlled trials, nine observational studies and six reviews. Results Research for the different treatment options among youth is limited. The available evidence shows better outcomes in terms of retention in care and cost-effectiveness for opioid agonist treatment than abstinence-based comparisons. Integrating psychosocial interventions into the continuum of care for youth can be an effective way of addressing comorbid psychiatric conditions and emotional drivers of substance use, leading to improved treatment trajectories. Conclusions From the limited findings, there is no evidence to deny youth with high-risk opioid use the same treatment options available to adults. A combination of pharmacological and youth-specific psychosocial interventions is required to maximize retention and survival. There is an urgent need for more research to inform clinical strategies toward appropriate treatment goals for such vulnerable individuals.

The multifactorial pathophysiology of pelvic floor disorder accounts for the coexistence of several pelvic floor disorders in many women. Up to 54% of women with pelvic organ prolapse (POP) report concurrent stress urinary incontinence (SUI). While POP is a risk factor for coexistent SUI, apical and anterior prolapse can also conceal SUI symptoms that are unmasked by POP repair, resulting in de novo SUI postoperatively. It is important for pelvic reconstructive surgeons to consider the relationship between POP and urinary incontinence in presurgical planning and to discuss with patients the risks and advantages of concurrent versus staged anti-incontinence procedures.

Human serum albumin (HSA) is a broadly used biomarker for the diagnosis of various diseases such as chronic kidney disease. Here, a fluorescent probe TC426 with aggregation-induced emission (AIE) characteristics is reported as a sensitive and specific probe for HSA. This probe is non-emissive in aqueous solution, meanwhile it shows bright fluorescence upon interacting with HSA, which makes it applicable in detecting HSA with a high signal to noise ratio. Besides, the fluorescence of TC426 exhibits a high linear correlation with the concentration of albumin in the range of microalbumin (20-200 mg/L), which has a significant importance for the early diagnosis of glomerulus related diseases. Compared with previously reported HSA probes TPE-4TA and BSPOTPE, TC426 shows comparable anti-interference ability towards creatinine and other major components in urine but is excited by a longer excitation wavelength at the visible light range. Finally, with the established assay, TC426 shows excellent performance in detecting HSA in real human urine, indicating its great potential in practical urinalysis.

Background: There is a knowledge gap in systematic reviews on the impact of opioid agonist treatments on mental health.Objectives: We compared mental health outcomes between different opioid agonis...

The health care sector has made radical changes to hospital operations and care delivery in response to the coronavirus disease (COVID-19) pandemic. This article examines pragmatic applications of simulation and human factors to support the Quadruple Aim of health system performance during the COVID-19 era. First, patient safety is enhanced through development and testing of new technologies, equipment, and protocols using laboratory-based and in situ simulation. Second, population health is strengthened through virtual platforms that deliver telehealth and remote simulation that ensure readiness for personnel to deploy to new clinical units. Third, prevention of lost revenue occurs through usability testing of equipment and computer-based simulations to predict system performance and resilience. Finally, simulation supports health worker wellness and satisfaction by identifying optimal work conditions that maximize productivity while protecting staff through preparedness training. Leveraging simulation and human factors will support a resilient and sustainable response to the pandemic in a transformed health care landscape.