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Nature's selection of the contemporary nucleobases in RNA and DNA continues to intrigue the origin of life community. While the prebiotic synthesis of the N-glycosyl bond has historically been a central area of investigation, variations in hydrolytic stabilities among the N-glycosyl bonds may have presented an additional selection pressure that contributed to nucleobase and nucleoside evolution. To experimentally probe this hypothesis, a systematic kinetic analysis of the hydrolytic deglycosylation reactions of modified, alternative and native nucleosides was undertaken. Rate constants were measured as a function of temperature (at pH 1) to produce Arrhenius and Eyring plots for extrapolation to 37°C and determination of thermodynamic activation parameters. Rate enhancements based on the differences in reaction rates of deoxyribo- and ribo-glycosidic bonds were found to vary under the same conditions. Rate constants of deoxynucleosides were also measured across the pH range of 1 - 3 (at 50°C), which highlighted how simple changes to the heterocycle alone can lead to significant variation in deglycosylation rates. The contemporary nucleosides exhibited the slowest deglycosylation rates in comparison to the non-native/alternative nucleosides, which we suggest as experimental support for nature's selection of the fittest N-glycosyl bonds.

This series of experiments used rats to compare counterconditioning and extinction of conditioned fear responses (freezing) with respect to the effects of a context shift. In each experiment, a stimulus was paired with shock in context A, extinguished or counterconditioned through pairings with sucrose in context B, and then tested for renewal outside of context B. Counterconditioned fear responses exhibited greater ABA renewal than extinguished fear responses. This result was observed using a between-subjects design (Experiment 1) and a within-subject design in which counterconditioned and extinguished stimuli were equated in all respects other than their signaling of sucrose (Experiment 2). Counterconditioned fear responses also exhibited greater ABC renewal than extinguished fear responses (Experiment 3). This result was observed using a within-subject design in which context C was identical to context B in terms of its associative history, and when counterconditioned and extinguished CSs were tested in compounds matched for their association with both shock and sucrose (Experiment 4). These results are consistent with models which hold that context regulates expression of associations formed in counterconditioning and extinction, and allow the level of regulation to be greater following counterconditioning than extinction, as noted in previous studies.

Four experiments used between- and within-subject designs to examine appetitive-aversive interactions in rats. Experiments 1 and 2 examined the effect of an excitatory appetitive conditioned stimulus (CS) on acquisition and extinction of conditioned fear. In Experiment 1, a CS shocked in a compound with an appetitive excitor (i.e., a stimulus previously paired with sucrose) underwent greater fear conditioning than a CS shocked in a compound with a neutral stimulus. Conversely, in Experiment 2, a CS extinguished in a compound with an appetitive excitor underwent less extinction than a CS extinguished in a compound with a neutral stimulus. Experiments 3 and 4 compared the amount of fear conditioning to an appetitive excitor and a familiar but neutral target CS when the compound of these stimuli was paired with shock. In each experiment, more fear accrued to the appetitive excitor than to the neutral CS. These results show that an appetitive excitor influences acquisition and extinction of conditioned fear to a neutral CS and itself undergoes a greater associative change than the neutral CS across compound conditioning. They are discussed with respect to the role of motivational information in regulating an associative change in appetitive-aversive interactions.

Background: Information on inappropriate dosing of direct oral anticoagulants (DOACs) is scarce in the Australian context. Aim: To describe the prevalence and potential predictors of inappropriate dosing of DOACs. Methods: Patients who received DOACs during admission under a general medical unit over a 2‐year period (from January 2017 to December 2018) were retrospectively studied. Appropriateness of the dosing regimen was verified against the recommendations of the Therapeutic Goods Administration of Australia. Data were obtained from medical records and analysed in univariate and multivariate logistic regression models. The variables associated with under‐ and overdosing were also determined. Results: A total of 203 (mean age 71.6 ± 14.5 years, females 52%) patients were studied. Inappropriate dosing occurred in 44 (22%) patients: underdosing 27 (13%) and overdosing 17 (8%). Age ≥75 years (P < 0.01), lower estimated creatinine clearance (CrCl) (P < 0.01), prescription of DOAC prior to index admission (P < 0.01) and higher Charlson Comorbidity Index (P < 0.01), HAS‐BLED (P < 0.01) and CHA2DS2‐VASc (P < 0.01) scores had a significant univariate association with inappropriate dosing. However, in the multivariate logistic regression only lower CrCl (odds ratio (OR) 1.04, 95% confidence interval (CI): 1.01–1.07, P < 0.01) and prescription of DOAC prior to index admission (OR 2.62, 95% CI: 1.01–6.75, P = 0.047) remained significantly associated with inappropriate dosing. Impaired renal function also had a significant association with underdosing (OR 1.04, 95% CI: 1.01–1.07, P = 0.01) and borderline significance with overdosing (OR 1.03, 95% CI: 1.00–1.07, P = 0.06). Conclusion: Inappropriate dosing of DOACs, especially underdosing, is common in clinical practice. Clinicians should exercise due diligence when prescribing DOACs to patients with renal impairment and in outpatient settings. [ABSTRACT FROM AUTHOR]

In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement of extinguished responding. Augmentation of recovery was not observed if the retrieval and extinction training occurred in different contexts. These results contrast with those reported in earlier papers by Monfils and coworkers in rats and by Schiller and coworkers in humans. We suggest that these contrasting results could depend on the contrasting influences of either: (1) occasion-setting contextual associations vs. direct context-CS associations formed as a consequence of the retrieval trial or (2) discrimination vs. generalization between the circumstances of conditioning and extinction.

ABSTRACT This study assessed the relative clinical sensitivity and specificity, as well as reproducibility, for high-risk HPV types of the Roche cobas HPV test when processed using the Roche cobas 5800 system. The results from this study demonstrate that the cobas HPV test using the cobas 5800 system fulfils the Meijer criteria for use in population-based cervical screening. This clinical validation study also examines the clinical sensitivity and specificity based on partial genotyping, with separate detection of HPV16 and HPV18, compared with the Roche cobas 4800 HPV test, a second-generation standard comparator assay. The cobas HPV test has a relative clinical sensitivity of 1.000, when compared with the cobas 4800 HPV test to detect histologically confirmed CIN2+ lesions in woman aged 30 years or older, with a relative clinical specificity of 0.995. The general intra- and inter-laboratory agreement for the cobas HPV test on the cobas 5800 system for finding a HPV positive result were 99.1% and 99.6%, respectively.IMPORTANCEThis study demonstrates, for the first time, the clinical performance of the Roche cobas HPV test when processed using the new cobas 5800 system [cobas (5800)]. This study shows that the cobas (5800) demonstrates relative clinical sensitivity and specificity, when compared with a standard comparator HPV test, which meets the international HPV test validation requirements. Intra- and inter-laboratory reproducibility also fulfills these criteria. The current study demonstrates that the cobas (5800) can be used for primary HPV-based cervical screening on cervical specimens.

Abstract Introduction Workplace violence affects the dignity and well‐being of healthcare workers and poses threats to the efficiency and success of the healthcare system. Healthcare workers in the emergency department (ED) are known to be vulnerable to workplace violence. This study explored the prevalence of workplace violence in the ED in Hong Kong and factors associated with self‐reported workplace violence. Methods An anonymous, voluntary, self‐administered and web‐based cross‐sectional survey was carried out from 1 June to 30 June 2022 among doctors and nurses in three regional EDs. Multivariable logistic regression analyses were conducted to examine the factors associated with workplace violence. Results A total of 162 healthcare workers including 57 doctors and 105 nurses participated in the study, with an overall response rate of 50.8%. The overall prevalence of workplace violence was 66.7%. Verbal abuse (64.2%) was more common than physical violence (20.4%). Nursing group was significantly correlated with physical violence (aOR 7.27, p = 0.005). Reporting rate of workplace violence remained low (18.2% for physical violence and 12.5% for verbal abuse). More than half of the participants with experience of workplace violence reported that the incident affected their mental well‐being. Conclusions Workplace violence was a significant concern in the local ED and under‐reporting was not uncommon. Impact of workplace violence on healthcare workers and the healthcare system should be well recognised. Workplace violence protocol and prevention strategies are crucial.

Background Music listening has been found to be effective in reducing stress levels with different participant samples. Relatively little evidence has been obtained from people with high neurotic tendency (HNT), whose dispositional psychological characteristics might dampen the effect of music listening. This study therefore tried to examine the immediate effect of music listening in reducing stressful feelings of participants with either high or low neurotic tendency. Participants and procedure Seventy-nine undergraduate participants who were identified as having either HNT or low neurotic tendency (LNT) accomplished a stressful task before listening to a comforting music piece. Negative affect (NA) scores and heart rate were measured at different phases. Results Results in a within-subjects analysis showed that the stressor and music listening could significantly alter the stressful feeling of both participant groups. Although the percentage changes in heart rate were similar between the groups, the changes of NA score which were measured after either the stressful task or the music listening session were consistently lower in the HNT group than the LNT group. Conclusions The divergence revealed a loose connection between the subjective feelings and the bodily changes in the HNT group, which could be important for clinicians and practitioners to take into consideration in psychology when evaluating the stressful feelings for their clients with HNT.

Identifying proteins in cell extracts by shotgun proteomics involves digesting the proteins, sequencing the resulting peptides by data-dependent mass spectrometry (MS/MS), and searching protein databases to identify the proteins from which the peptides are derived. Manual analysis and direct spectral comparison reveal that scores from two commonly used search programs (Sequest and Mascot) validate less than half of potentially identifiable MS/MS spectra (class positive) from shotgun analyses of the human erythroleukemia K562 cell line. Here we demonstrate increased sensitivity and accuracy using a focused search strategy along with a peptide sequence validation script that does not rely exclusively on XCorr or Mowse scores generated by Sequest or Mascot, but uses consensus between the search programs, along with chemical properties and scores describing the nature of the fragmentation spectrum (ion score and RSP). The approach yielded 4.2% false positive and 8% false negative frequencies in peptide assignments. The protein profile is then assembled from peptide assignments using a novel peptide-centric protein nomenclature that more accurately reports protein variants that contain identical peptide sequences. An Isoform Resolver algorithm ensures that the protein count is not inflated by variants in the protein database, eliminating ~25% of redundant proteins. Analysis of soluble proteins from a human K562 cells identified 5130 unique proteins, with ~100 false positive protein assignments.

Abstract Background Scoliosis is widely prevalent among osteogenesis imperfecta (OI) patients, and is progressive with age. However, factors affecting scoliosis in OI are not well known. Methods We retrospectively retrieved longitudinal radiographic and clinical records of consecutive OI patients seeking treatments at our hospital from 2014 to 2022, graded their pre-operative spinal conditions into four outcome groups, estimated their progression rates, and descriptively and inferentially analyzed the genetic and non-genetic factors that may affect the outcomes and progression rates. Results In all, 290 OI patients met the inclusion criteria, where 221 had genetic records. Of these 221, about 2/3 had mutations in COL1A1 or COL1A2, followed by mutations in WNT1 (9.0%), IFITM5 (9.0%) and other OI risk genes. With an average age of 12.0 years (interquartile range [IQR] 6.9–16.1), 70.7% of the cohort had scoliosis (Cobb angle > 10°), including 106 (36.5%) mild (10°–25°), 40 (13.8%) moderate (25°–50°), and 59 (20.3%) severe (> 50°) scoliosis patients. Patients with either COL1A1 and COL1A2 were strongly biased toward having mild or no scoliosis, whereas patients with mutations in IFITM5, WNT1 and other recessive genes were more evenly distributed among the four outcome grades. Lower-limb discrepancy, bone mineral density (BMD) and age of first drug used were all significantly correlated with severity outcomes. Using multivariate logistic regression, we estimated that each year older adds an odds ratio of 1.13 (95% confidence interval [CI] 1.07–1.2) in progression into advanced stages of scoliosis. We estimated a cohort-wide progression rate of 2.7 degrees per year (95% CI 2.4–3.0). Early-onset patients experienced fast progressions during both infantile and adolescent stages. Twenty-five of the 59 (42.8%) patients with severe scoliosis underwent spinal surgeries, enjoying an average Cobb angle reduction of 33° (IQR 23–40) postoperatively. Conclusion The severity and progression of scoliosis in osteogenesis imperfecta were affected by genetic factors including genotypes and mutation types, and non-genetic factors including age and BMD. As compared with COL1A1, mutations in COL1A2 were less damaging while those on IFITM5 and other recessive genes conferred damaging effects. Progression rates were the fastest in the adolescent adult age-group.

Abstract Objectives Providencia is a genus of gram-negative bacteria within the order Enterobacterales, closely related to Proteus and Morganella. While ubiquitous in the environment, some species of Providencia, such as P. rettgeri and P. stuartii, are considered emerging nosocomial pathogens and have been implicated in urinary tract infection, gastrointestinal illness, and travelers’ diarrhea. Given their intrinsic resistance to many commonly used antibiotics, this study aimed to isolate and sequence bacteriophages targeting a clinical P. rettgeri isolate. Data description Here we report the complete genome sequence of three novel Providencia phages, PibeRecoleta, Stilesk and PatoteraRojo, which were isolated against a clinical P. rettgeri strain sourced from a patient in a metropolitan hospital in Victoria, Australia. The three phages contain dsDNA genomes between 60.7 and 60.9 kb in size and are predicted to encode between 72 and 73 proteins. These three new phages, which share high genomic similarity to two other Providencia phages previously isolated on P. stuartii, serve as important resources in our understanding about Providencia bacteriophages and the potential for future phage-based biotherapies.

Recently, the prevalence of macrolide-resistant Moraxella catarrhalis has been reported, especially among Chinese children. The fitness cost of resistance is reported to render the resistant bacteria less virulent. To investigate the correlation between macrolide susceptibility of M. catarrhalis and pathogenicity, the whole genome of 70 M. catarrhalis isolates belonging to four clonal complexes with different macrolide susceptibilities was sequenced. The gene products were annotated with the Gene Ontology terms. Based on 46 extracted essential virulence genes, 19 representative isolates were selected to infect type II alveolar cells (A549 cells). The ability of these isolates to adhere and invade human epithelial cells and to produce cytokines was comparatively analysed. Furthermore, mice were infected with a pair of M. catarrhalis isolates with different pathogenic behaviours and macrolide susceptibilities to examine pulmonary clearance, histological findings, and the production of cytokines. The percentages of annotations for binding, metabolic process, cellular process, and cell were non-significantly different between the macrolide-resistant and macrolide-susceptible groups. The presence of uspA2, uspA2H, pilO, lbpB, lex1, modM, mboIA, and mboIB significantly differed among the four clonal complexes and macrolide susceptibility groups. Furthermore, compared with those in macrolide-susceptible isolates, the adhesion ability was stronger (P = 0.0019) and the invasion ability was weaker (P

Abstract Pandemic fatigue is a growing public health concern of the lingering COVID-19 pandemic. Despite its widespread mass media coverage, systematic empirical investigations are scarce. Under the Hong Kong Jockey Club SMART Family-Link Project, we conducted online and telephone surveys amid the pandemic in February to March 2021 to assess self-reported pandemic fatigue (range 0–10) in Hong Kong adults (N = 4726) and its associations with sociodemographic and psycho-behavioral (high vs low to moderate) variables. Data were weighted by sex, age, and education of the general population. Binary logistic regression models yielded adjusted odds ratios (aORs) for high pandemic fatigue (score ≥ 7) for sociodemographic and psycho-behavioral variables. 43.7% reported high pandemic fatigue. It was less common in older people (55–64 years: aOR 0.56, 95% CI 0.39–0.82; 65 + years: 0.33, 0.21–0.52) versus age group 18–24 years, but more common in those with tertiary education (1.36, 1.15–1.62) versus secondary or below. High pandemic fatigue was positively associated with depressive symptoms (aOR 1.83, 95% CI 1.55–2.17), anxiety symptoms (1.87, 1.58–2.20), loneliness (1.75, 1.32–2.31), personal fear of COVID-19 (2.61, 2.12–3.23), family fear of COVID-19 (2.03, 1.67–2.47), and current alcohol use (1.16, 1.00–1.33), but negatively associated with self-rated health (0.79, 0.68–0.92), personal happiness (0.63, 0.55–0.72), personal adversity coping capability (0.71, 0.63–0.81), family adversity coping capability (0.79, 0.69–0.90), family well-being (0.84, 0.73–0.97), family communication quality (0.86, 0.75–0.98), and frequent home exercise (0.82, 0.69–0.96; versus less frequent). We first used a single-item tool to measure COVID-19 pandemic fatigue, showing that it was common and associated with worse mental health, lower levels of personal and family well-being and alcohol use.

Abstract Background Osteogenesis imperfecta (OI) is a group of rare skeletal dysplasia. Long bone deformity and scoliosis are often associated with progressively deforming types of OI. FKBP65 (encoded by FKBP10, OMIM *607063) plays a crucial role in the processing of type I procollagen. Autosomal recessive variants in FKBP10 result in type XI osteogenesis imperfecta. Methods Patients diagnosed with OI were recruited for a genetic test. RT‐PCR and Sanger sequencing were applied to confirm the splicing defect in FKBP10 mRNA with the splice‐site variant. The bone structure was characterized by Goldner's trichrome staining. Bioinformatic analyses of bulk RNA sequencing data were performed to examine the effect of the FKBP10 variant on gene expression. Results Here we reported three children from a consanguineous family harboured a homozygous splice‐site variant (c.918‐3C > G) in FKBP10 intron and developed long bone deformity and early onset of scoliosis. We also observed frequent long bone fractures and spinal deformity in another 3 OI patients with different FKBP10 variants. The homozygous splicing variant identified in the fifth intron of FKBP10 (c.918‐3C > G) led to abnormal RNA processing and loss of FKBP65 protein and consequently resulted in aberrant collagen alignment and porous bone morphology. Analysis of transcriptomic data indicated that genes involved in protein processing and osteoblast differentiation were significantly affected in the patient‐derived osteoblasts. Conclusion Our study characterized the clinical features of OI patients with FKBP10 variants and revealed the pathogenesis of the c.918‐3C > G variant. The molecular analyses helped to gain insight into the deleterious effects of FKBP10 variants on collagen processing and osteoblast differentiation.

Abstract Background Osteogenesis imperfecta (OI) is a rare congenital disorder of the skeletal system, inflicting debilitating physical and psychological distress on patients and caregivers. Over the decades, much effort has been channeled towards understanding molecular mechanisms and developing new treatments. It has recently become more apparent that patient-reported outcome measurements (PROM) during treatment, healing and rehabilitation are helpful in facilitating smoother communication, refining intervention strategies and achieving higher quality of life. To date, systematic analyses of PROM in OI patients remain scarce. Results Here, utilizing a PROM Information System, we report a cross-sectional and longitudinal study in a southern Chinese cohort of 90 OI patients, covering both the child and adult age-groups. In the child group where both self and parental surveys were obtained, we identified two clusters of comparable sizes showing different outlooks in physical mobility and emotional experiences. One cluster (Cluster 1) is more negative about themselves than the other (Cluster 2). A concordance of 84.7% between self and parental assessments was recorded, suggesting the stability and validity of PROM-based stratification. Clinical subtyping, deformity, leg length discrepancy, and limited joint mobility were significantly associated with this stratification, with Cluster 1 showing higher percentages of severe phenotypes than Cluster 2. Since OI is a genetic disorder, we performed genetic testing on 72 of the 90 patients, but found no obvious association between genotypes and the PROM stratification. Analyses of longitudinal data suggested that patients tended to stay in the same psychological state, in both clusters. Adult patients also showed a continuous spectrum of self-evaluation that matches their clinical manifestations. Conclusion By systematically analyzing patient-reported outcomes, our study demonstrated the link between the sociopsychological wellbeing of OI patients, and their clinical manifestations, which may serve as the basis for evaluating clinical interventions and help achieve better patient-centric medical practices. The lack of genotype-PROM association may be due to the diverse mutational spectrum in OI, which warrants further investigation when a larger sample size is available.

Abstract Background Tumor-draining lymph nodes (TDLNs) are primary sites, where anti-tumor lymphocytes are primed to tumor-specific antigens and play pivotal roles in immune responses against tumors. Although adoptive cell therapy (ACT) using lymphocytes isolated from TDLNs were reported, characterization of immune activity of lymphocytes in TDLNs to tumor cells was not comprehensively performed. Here, we demonstrate TDLNs to have very high potential as cell sources for immunotherapy. Methods Lymphocytes from TDLNs resected during surgical operation were cultured with autologous-tumor cells for 2 weeks and evaluated tumor-reactivity by IFNγ ELISPOT assay. We investigated the commonality of T cell receptor (TCR) clonotypes expanded by the co-culture with tumor cells with those of tumor infiltrating lymphocytes (TILs). Results We found that that TCR clonotypes of PD-1-expressing CD8+ T cells in lymph nodes commonly shared with those of TILs in primary tumors and lymphocytes having tumor-reactivity and TCR clonotypes shared with TILs could be induced from non-metastatic lymph nodes when they were co-cultured with autologous tumor cells. Conclusion Our results imply that tumor-reactive effector T cells were present even in pathologically non-metastatic lymph nodes and could be expanded in vitro in the presence of autologous tumor cells and possibly be applied for ACT.

Abstract Locules are the seed‐bearing structure of fruits. Multiple locules are associated with increased fruit size and seed set, and therefore, control of locule number is an important agronomic trait. Locule number is controlled in part by the CLAVATA‐WUSCHEL pathway. Disruption of either the CLAVATA1 receptor‐like kinase or its ligand CLAVATA3 can cause larger floral meristems and an increased number of locules. In an EMS mutagenized population of Brassica rapa, we identified a mutant allele that raises the number of locules from four to a range of from six to eight. Linkage mapping and genetic analysis support that the mutant phenotype is due to a missense mutation in a CLAVATA 1 (CLV1) homolog. In addition to increased locule number, additional internal gynoecia are formed in brclv1 individuals, suggesting a failure to terminate floral meristem development, which results in decreased seed production.

IntroductionCirculating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we’ve compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol.MethodsPatient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel.ResultsUp to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging.ConclusionLongitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC.

BackgroundWe have reported both perceived benefits and harms of the COVID-19 outbreak and their socioeconomic disparities amid the pandemic in Hong Kong. We further investigated whether such perceptions and disparities had changed after 10 months.MethodsUnder the Hong Kong Jockey Club SMART Family-Link Project, we conducted two cross-sectional surveys online on perceived personal and family benefits and harms of the COVID-19 outbreak in Hong Kong adults in May 2020 (after Wave 2 was under control; N = 4,891) and in February and March 2021 (after Wave 4 was under control; N = 6,013). We collected sociodemographic information, including sex, age, education, household income, and housing. Using multivariate models of analysis of covariance (MANCOVA), we compared perceived benefits and harms and socioeconomic disparities between the two surveys.ResultsAdjusting for sex and age, the prevalence of 17 out of 18 perceived personal and family benefits of COVID-19 outbreak increased (Ps < 0.001). Six of 11 perceived personal and family harms decreased (Ps < 0.001) and 4 increased (Ps < 0.001). The total number of perceived personal and family benefits increased substantially (Ps < 0.001), whereas that of perceived personal harms decreased (P = 0.01) and family harms remained stable (P > 0.05). Socioeconomic disparities, however, persisted—more perceived benefits in those with higher socioeconomic status (Ps < 0.001) and more perceived harms in those with lower (Ps ≤ 0.005).ConclusionWe have first reported that perceived personal and family benefits of the COVID-19 outbreak increased substantially over 10 months amid the pandemic, while perceived personal and family harms were lower and stable, respectively. Socioeconomic disparities of the perceived benefits and harms persisted, which need to be monitored and addressed urgently.

Background: Loss of skeletal muscle mass and function is one of the major musculoskeletal health problems in the aging population. Recent studies have demonstrated differential proteomic profiles at different fetal stages, which might be associated with muscle growth and development. We hypothesized that extract derived from fetal muscle tissues at the stage of hypertrophy could ameliorate the loss of muscle mass and strength in aged mice.Methods: To allow sufficient raw materials for investigation, skeletal muscle extract from fetal sheep at week 16 of gestation and maternal tissue were used in the present study. iTRAQ (isobaric tags for relative and absolute quantitation) and KEGG pathway analyses identified differentially expressed proteins in fetal sheep muscle extract vs. adult sheep muscle extract. Effects of FSME and ASME on human myoblast proliferation were studied. To examine the effect of FSME in vivo, C57BL/6 male mice at 20 months of age were subjected to intramuscular administration of FSME or vehicle control for 8 weeks. A grip strength test and ex vivo muscle force frequency test were conducted. Finally, serum samples were collected for multiplex analysis to determine potential changes in immunological cytokines upon FSME injection.Results: Compared with ASME, 697 and 412 peptides were upregulated and downregulated, respectively, in FSME, as indicated by iTRAQ analysis. These peptides were highly related to muscle development, function, and differentiation from GO enrichment analysis. FSME promoted cell proliferation of myoblast cells (+300%, p < 0.01) without causing significant cytotoxicity at the tested concentration range compared with ASME. After 8 weeks of FSME treatment, the percentage of lean mass (+10%, p < 0.05), grip strength (+50%, p < 0.01), and ability in fatigue resistance were significantly higher than those of the control group. Isometric forces stimulated by different frequencies were higher in the control group. Histologically, the control group showed a larger cross-sectional area (+20%, p < 0.01) than the FSME group. The multiplex assay indicated that FSME treatment did not lead to an elevated circulatory level of inflammatory cytokines. Of note, after FSME treatment, we observed a significant drop in the circulating level of IL-12 (p40) from 90.8 ± 48.3 pg/ml to 82.65 ± 4.4 pg/ml, G-CSF from 23476 ± 8341.9 pg/ml to 28.35 ± 24.2 pg/ml, KC from 97.09 ± 21.2 pg/ml to 29.2 ± 7.2 pg/ml, and RANTES from 325.4 ± 17.3 pg/ml to 49.96 ± 32.1 pg/ml.Conclusion: This is the first study demonstrating the beneficial effect of fetal muscle extract on muscle health in aged mice. Further analysis of the active ingredients of the extract will shed light on the development of a novel treatment for sarcopenia.

Objectives: To examine the comparative stochasticity profile of six commercial SARS-CoV-2 nucleic acid amplification tests (NAATs) and how this may affect retesting paradigms. Methods: Commercial quality control (QC) material was serially diluted in viral transport media to create a panel covering 10–10,000 copies/ml. The panel was tested across six commercial NAATs. A subset of high cycle threshold results was retested on a rapid PCR assay to simulate retesting protocols commonly used to discriminate false positives. Results: Performance beyond the LOD differed among assays, with three types of stochasticity profiles observed. The ability of the rapid PCR assay to reproduce a true weak positive specimen was restricted to its own stochastic performance at the corresponding viral concentration. Conclusion: Stochastic performance of various NAATs overlap across low viral concentrations and affect retesting outcomes. Relying on retesting alone to discriminate false positives risk missing true positives even when a more sensitive assay is deployed for confirmatory testing.

The broad learning system (BLS) framework gives an efficient solution for training flat-structured feedforward networks and flat structured deep neural networks. However, the classical BLS model and other variants focus on the faultless situation only, where enhancement nodes, feature mapped nodes, and output weights of a BLS network are assumed to be realized in a perfect condition. When a trained BLS network suffers from coexistence of weight/node failures, the trained network has a greatly degradation in its performance if a countermeasure is not taken. In order to reduce the effect of weight/node failures on the BLS network’s performance, this paper proposes an objective function for enhancing the fault aware performance of BLS networks. The objective function contains a fault aware regularizer term which handles the weight/node failures. A learning algorithm is then derived based on the objective function. The simulation results show that the performance of the proposed fault aware BLS (FABLS) algorithm is superior to the classical BLS and two state-of-the-arts BLS algorithms, namely correntropy criterion BLS (CBLS) and weighted BLS (WBLS).

Summary: Background: Current microbiological methods lack the resolution to accurately identify multidrug-resistant organism (MDRO) transmission, however, whole genome sequencing can identify highly-related patient isolates providing opportunities for precision infection control interventions. We investigated the feasibility and potential impact of a prospective multi-centre genomics workflow for hospital infection control. Methods: We conducted a prospective genomics implementation study across eight Australian hospitals over 15 months (2017,2018), collecting all clinical and screening isolates from inpatients with vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec), or ESBL Klebsiella pneumoniae (ESBL-Kp). Genomic and epidemiologic data were integrated to assess MDRO transmission. Findings: In total, 2275 isolates were included from 1970 patients, predominantly ESBL-Ec (40·8%) followed by MRSA (35·6%), vanA VRE (15·2%), and ESBL-Kp (8·3%).Overall, hospital and genomic epidemiology showed 607 patients (30·8%) acquired their MDRO in hospital, including the majority of vanA VRE (266 patients, 86·4%), with lower proportions of ESBL-Ec (186 patients, 23·0%), ESBL-Kp (42 patients, 26·3%), and MRSA (113 patients, 16·3%). Complex patient movements meant the majority of MDRO transmissions would remain undetected without genomic data.The genomics implementation had major impacts, identifying unexpected MDRO transmissions prompting new infection control interventions, and contributing to vanA VRE becoming a notifiable condition. We identified barriers to implementation and recommend strategies for mitigation. Interpretation: Implementation of a multi-centre genomics-informed infection control workflow is feasible and identifies many unrecognised MDRO transmissions. This provides critical opportunities for interventions to improve patient safety in hospitals. Funding: Melbourne Genomics Health Alliance (supported by State Government of Victoria, Australia), and National Health and Medical Research Council (Australia).

As the use of next‐generation sequencing (NGS) for plasma cell‐free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)‐related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH‐related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan‐Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH‐related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH‐related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH‐related mutation in plasma cfDNA. These CH‐related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor‐derived from CH‐related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients.

Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 187 Chinese OI patients, majority of whom are of southern Chinese origin. By targeted sequencing, 63 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 8 novel COL1A1 and 7 novel COL1A2 variants. We validated a novel splicing mutation in COL1A1. A diverse mutational and phenotypic spectrum was observed, coupling with the heterogeneity observed in the transcriptomic data derived from osteoblasts of six patients from our cohort. Missense mutations were significantly associated (χ2p = 0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate treatment during the juvenile stage (10–15 years old). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective bisphosphonate treatment in an age-specific manner may help to improve OI patient management.

ABSTRACT Introduction: Cardiothoracic surgery (CTS) has seen a decline in interest and application rates in recent years. As a relatively small speciality, teaching and placements in CTS are often not included during undergraduate study and postgraduate training. We aim to evaluate the exposure to CTS during both undergraduate study and postgraduate training. Methods: A ten-question online survey was designed and delivered to Foundation Year Two (FY2) doctors who graduated in 2017 and completed their two-year postgraduate foundation training in 2019. Medical schools with no graduates in 2017 and 2018 were excluded from our study. IBM® SPSS Statistics, version 25, and Microsoft Excel 365® were used for Student’s t-test statistical analysis. Results: Three hundred and six FY2 doctors across 16 medical schools completed the survey, none of which included compulsory CTS attachments as their undergraduate curriculum. Thirty-two respondents (10.5%) underwent CTS attachments lasting between one to three weeks. Only 14 (43.8%) had worked in a cardiothoracic unit during their two-year Foundation Programme; 10 of which (71.2%) subsequently made an application for cardiothoracic speciality training. Most of the participants with previous exposure to CTS, during either undergraduate study or postgraduate Foundation Programme training or both, were significantly more likely to make an application to CTS training (P

In prolonged intense exercise training, the training load of athletes may be reduced once their hemoglobin concentrations ([Hb]s) are decreased dramatically. We previously reported that intermittent hypoxia exposure (IHE) could be used to alleviate the decrease of [Hb] and help to maintain the training load in rats. To further explore the feasibility of applying IHE intervention to athletes during prolonged intense exercise training, 6 trained swimmers were recruited to conduct a 4-week IHE intervention at the intervals after their [Hb] dropped for 10% or more during their training season. IHE intervention lasted 1 h and took place once a day and five times a week. Hematological and hormonal parameters, including [Hb], red blood cells (RBC), hematocrit (Hct), reticulocytes, serum erythropoietin (EPO), testosterone (T) and cortisol (C) were examined. After the IHE intervention was launched, [Hb], RBC and Hct of the subjects were increased progressively with their maximum levels (P < 0.01) showing at the third or fourth week, respectively. An increase in reticulocyte count (P < 0.01) suggests that IHE intervention promotes erythropoiesis to increase [Hb]. Besides, serum level of EPO, the hormone known to stimulate erythropoiesis, was overall higher than that before the IHE intervention, although it was statistically insignificant. Furthermore, the serum level of T, another hormone known to stimulate erythropoiesis, was increased progressively with the maximum level showing at the fourth week. Collectively, this study further confirms that IHE intervention may be used as a new strategy to prevent intense exercise training-induced reductions in [Hb].

Background: School-based green space activities have been found to be beneficial to the physical activity level and lifestyle habits of adolescent students. However, their effects on green space use and satisfaction, mental health, and dietary behaviors required further investigation. This study aimed to investigate the effects of school-based hydroponic planting integrated with health promotion activities in improving green space use, competence and satisfaction, healthy lifestyle, mental health, and health-related quality of life (QoL) among early adolescent students in secondary schools.Methods: This study adopted a three-group comparison design (one control and two intervention groups). Secondary school students (N = 553) of grades 7–9 participated in either (1) hydroponic planting (two times per week for 8 months) integrated with health promotion activities; (2) only health promotion activities (one time per week for 6 weeks); or (3) control group. Outcomes assessed by questionnaire included green space use and satisfaction, life happiness, lifestyle, depressive symptoms, and health-related QoL.Results: After adjusting for sex and school grade, the scores in “green space distance and use” and “green space activity and competence” were significantly better in the intervention groups than in the control group. Hydroponic planting integrated with health promotion activities was also associated with better scores in dietary habits and resistance to substance use. Intervention groups had a higher score in “Green space sense and satisfaction” and life happiness when compared with the control group.Conclusions: Our study shows that the school-based hydroponic planting integrated with health promotion activities were feasible and, to a certain extent, useful to improve green space use and competence, dietary habits, and resistance to substance use among early adolescent students in secondary schools in urban areas. Future studies should address the limitations identified, for example, designing a randomized controlled trial that could fit school schedules to generate new evidence for physical and mental health in adolescent communities.

Abstract Objective: To examine the current literature behind the evolution of mitral valve surgery techniques and their impact on patient outcomes. Methods: An electronic literature search among major databases was performed (PubMed, Embase, Scopus, Cochrane, and Google scholar). All the relevant articles were screened and identified to be included in this narrative review. The main outcomes were postoperative morbidity, length of in-hospital stay, and long-term mortality. Results: Minimally invasive and robot-assisted approach to mitral valve repair and replacements has shown great potential in improving surgical outcomes when compared against traditional midline sternotomy. Selected patients can benefit from percutaneous mitral valve surgery; however, more evidence is required to ascertain its long-term outcomes. Conclusion: Current evidence suggests that robotic and minimal invasive mitral valve surgeries are increasing in practice with satisfactory perioperative and mortality rates. However, long-term data is yet to be published to support current practice.

There are two important issues in the construction of a radial basis function (RBF) neural network. The first one is to select suitable RBF centers. The second one is that the resultant RBF network should be with good fault tolerance. This paper proposes an algorithm that is able to select RBF centers and to train fault tolerant RBF networks simultaneously. The proposed algorithm borrows the concept from sparse approximation. In our formulation, we first define a fault tolerant objective function based on all input vectors from the training samples. We then introduce the minimax concave penalty (MCP) function, which is an approximation of ℓ0-norm, into the objective function. The MCP term is able to force some unimportant RBF weights to zero. Hence the RBF node selection process can be achieved during training. As the MCP function is nondifferentiable and nonconvex, traditional gradient descent based algorithms are still unable to minimize the modified objective function. Based on the alternating direction method of multipliers (ADMM) framework, we develop an algorithm, called ADMM-MCP, to minimize the modified objective function. The convergent proof of the proposed ADMM-MCP algorithm is also presented. Simulation results show that the proposed ADMM-MCP algorithm is superior to many existing center selection algorithms under the concurrent fault situation.

Abstract Cancer pharmacogenomics is the science concerned with understanding genetic alterations and its effects on the pharmacokinetics and pharmacodynamics of anti-cancer drugs, with the aim to provide cancer patients with the precise medication that will achieve a good response and cause low/no incidence of adverse events. Advances in biotechnology and bioinformatics have enabled genomic research to evolve from the evaluation of alterations at the single-gene level to studies on the whole-genome scale using large-scale genotyping and next generation sequencing techniques. International collaborative efforts have resulted in the construction of databases to curate the identified genetic alterations that are clinically significant, and these are currently utilized in clinical sequencing and liquid biopsy screening/monitoring. Furthermore, countless clinical studies have accumulated sufficient evidence to match cancer patients to therapies by utilizing the information of clinical-relevant alterations. In this review we summarize the importance of germline alterations that act as predictive biomarkers for drug-induced toxicity and drug response as well as somatic mutations in cancer cells that function as drug targets. The integration of genomics into the medical field has transformed the era of cancer therapy from one-size-fits-all to cancer precision medicine.