Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Synthesis and evaluation of etoposide and podophyllotoxin analogs against topoisomerase IIα and HCT-116 cells.

Etoposide is a widely-used anticancer agent that targets human type II topoisomerases. Evidence suggests that metabolism of etoposide in myeloid progenitor cells is associated with translocations involved in leukemia development. Previous studies suggest halogenation at the C-2' position of etoposide reduces metabolism. Halogens were introduced into the C-2' position by electrophilic aromatic halogenation onto etoposide (ETOP, 1), podophyllotoxin (PPT, 2), and 4-dimethylepipodophyllotoxin (DMEP, 3), and to bridge the gap of knowledge regarding the activity of these metabolically stable analogs. Five halogenated analogs (6-10) were synthesized. Analogs 8-10 displayed variable ability to inhibit DNA relaxation. Analog 9 was the only analog to show concentration-dependent enhancement of Top2-mediated DNA cleavage. Dose response assay results indicated that 8 and 10 were most effective at decreasing the viability of HCT-116 and A549 cancer cell lines in culture. Flow cytometry with 8 and 10 in HCT-116 cells provide evidence of sub-G1 cell populations indicative of apoptosis. Taken together, these results indicate C-2' halogenation of etoposide and its precursors, although metabolically stable, decreases overall activity relative to etoposide.

Mortality prediction model for the triage of COVID-19, pneumonia, and mechanically ventilated ICU patients: A retrospective study.

RATIONALE: Prediction of patients at risk for mortality can help triage patients and assist in resource allocation. OBJECTIVES: Develop and evaluate a machine learning-based algorithm which accurately predicts mortality in COVID-19, pneumonia, and mechanically ventilated patients. METHODS: Retrospective study of 53,001 total ICU patients, including 9166 patients with pneumonia and 25,895 mechanically ventilated patients, performed on the MIMIC dataset. An additional retrospective analysis was performed on a community hospital dataset containing 114 patients positive for SARS-COV-2 by PCR test. The outcome of interest was in-hospital patient mortality. RESULTS: When trained and tested on the MIMIC dataset, the XGBoost predictor obtained area under the receiver operating characteristic (AUROC) values of 0.82, 0.81, 0.77, and 0.75 for mortality prediction on mechanically ventilated patients at 12-, 24-, 48-, and 72- hour windows, respectively, and AUROCs of 0.87, 0.78, 0.77, and 0.734 for mortality prediction on pneumonia patients at 12-, 24-, 48-, and 72- hour windows, respectively. The predictor outperformed the qSOFA, MEWS and CURB-65 risk scores at all prediction windows. When tested on the community hospital dataset, the predictor obtained AUROCs of 0.91, 0.90, 0.86, and 0.87 for mortality prediction on COVID-19 patients at 12-, 24-, 48-, and 72- hour windows, respectively, outperforming the qSOFA, MEWS and CURB-65 risk scores at all prediction windows. CONCLUSIONS: This machine learning-based algorithm is a useful predictive tool for anticipating patient mortality at clinically useful timepoints, and is capable of accurate mortality prediction for mechanically ventilated patients as well as those diagnosed with pneumonia and COVID-19.

Use and performance of machine learning models for type 2 diabetes prediction in community settings: A systematic review and meta-analysis.

OBJECTIVE: We aimed to identify machine learning (ML) models for type 2 diabetes (T2DM) prediction in community settings and determine their predictive performance. METHOD: Systematic review of ML predictive modelling studies in 13 databases since 2009 was conducted. Primary outcomes included metrics of discrimination, calibration, and classification. Secondary outcomes included important variables, level of validation, and intended use of models. Meta-analysis of c-indices, subgroup analyses, meta-regression, publication bias assessments and sensitivity analyses were conducted. RESULTS: Twenty-three studies (40 prediction models) were included. Studies with high-, moderate-, and low- risk of bias were 3, 14, and 6 respectively. All studies conducted internal validation whereas none conducted external validation of their models. Twenty studies provided classification metrics to varying extents whereas only 7 studies performed model calibration. Eighteen studies reported information on both the variables used for model development and the feature importance. Twelve studies highlighted potential applicability of their models for T2DM screening. Meta-analysis produced a good pooled c-index (0.812). Sources of heterogeneity were identified through subgroup analyses and meta-regression. Issues pertaining to methodological quality and reporting were observed. CONCLUSIONS: We found evidence of good performance of ML models for T2DM prediction in the community. Improvements to methodology, reporting and validation are needed before they can be used at scale.

Asthma, atopy and serious psychological distress: prevalence and risk factors among young people in the Melbourne atopy cohort study.

Background: While atopic conditions are associated with increased risk of mental health problems, the evidence that a range of allergic conditions are associated with psychological distress in young people is less clear.Methods: We recruited a longitudinal birth cohort study of 620 children with a family history of allergic disease. At the 18-year follow up, atopic sensitization was determined by skin prick testing. Surveys were used to determine psychological distress (Kessler 6), quality of life (SF12), respiratory symptoms and management, presence of current eczema and hay fever. Regression models were used to identify predictors of psychological distress and quality of life, while controlling for potential confounders.Results: Prevalence of serious psychological distress was quite low (n = 22, 5.3%), and there were no associations between psychological distress and current atopic sensitization, symptoms of hay fever, eczema or asthma. Smoking status and lower level of maternal education were associated with lower physical quality of life (SF12 PCS subscale). Psychological distress total score, lower maternal education, smoking, female sex, and current eczema were associated with worse mental quality of life (SF12 MCS subscale).Conclusion: We found relatively low levels of psychological distress in this cohort of young adults, despite a high prevalence of allergic diseases. Positive social factors may serve to buffer psychological distress amongst the cohort accounting for the low prevalence of serious psychological distress observed.

Using a nominal group technique to approach consensus on a resilience intervention for smoking cessation in a lower socioeconomic population.

BACKGROUND: Smoking prevalence remains inequitably high for lower SES (socioeconomic status) populations. The psychosocial interactive model of resilience theorises that resilience might be 'switched on' in order to support and/or maintain smoking cessation for these populations. This study aimed to develop a Resilience Intervention for Smoking Cessation (RISC) through reviewing the extant literature around efficacious interventions for smoking cessation. Deliberative democracy principles were then used to understand lay perspectives regarding this potential smoking cessation program. METHODS: Public health databases were searched to find efficacious psycho-social resilience interventions in the peer-reviewed literature for smoking cessation amongst lower SES populations. Potential components for RISC were selected based on evidence within the literature for their effectiveness. We then employed the Nominal Group Technique (NGT) to create discussion and consensus on the most socially appropriate and feasible components from the perspective of smokers from low SES areas. The NGT included 16 people from a lower SES population in southern metropolitan Adelaide who indicated they were seriously contemplating quitting smoking or had recently quit. Data were collected from multiple Likert ratings and rankings of the interventions during the NGT workshop and analysed descriptively. The Wilcoxon signed-ranked test was used where appropriate. Qualitative data were collected from participant reflections and group discussion, and analysed thematically. RESULTS: Six smoking cessation interventions, likely to enhance resilience, were selected as potential constituents for RISC: mindfulness training; setting realistic goals; support groups; smoke free environments; mobile phone apps; and motivational interviewing. Consensus indicated that mindfulness training and setting realistic goals were the most acceptable resilience enhancing interventions, based on perceived usefulness and feasibility. CONCLUSIONS: This research applied principles from deliberative democracy in order to illuminate lay knowledge regarding an appropriate and acceptable smoking cessation resilience program for a lower SES population. This process of collaborative and complex knowledge-generation is critically important to confront inequities as an ongoing challenge in public health, such as smoking cessation for disadvantaged groups. Further research should involve development and trial of this resilience program.

Enoxacin and Epigallocatechin Gallate (EGCG) Act Synergistically to Inhibit the Growth of Cervical Cancer Cells in Culture.

Cervical cancer is a major cause of death in females worldwide. While survival rates have historically improved, there remains a continuous need to identify novel molecules that are effective against this disease. Here, we show that enoxacin, a drug most commonly used to treat a broad array of bacterial infections, is able to inhibit growth of the cervical cancer cells. Furthermore, our data show that epigallocatechin gallate (EGCG), a plant bioactive compound abundant in green tea, and known for its antioxidant effects, similarly functions as an antiproliferative agent. Most importantly, we provide evidence that EGCG functions synergistically against cancer cell proliferation in combined treatment with enoxacin. These data collectively suggest that enoxacin and EGCG may be useful treatment options for cases of cervical cancer.

Does Resilience Moderate the Relationship Between Stress and Smoking Status?

BACKGROUND: There is a growing evidence that resilience to stress can promote nonsmoking. However, few studies have undertaken quantitative research to investigate whether resilience, generated by internal and external factors, moderates the impact of stress on the likelihood of smoking. OBJECTIVE: This study aims to help fill this knowledge gap in relation to smokers and ex-smokers, and those people who have never smoked. METHODS: A large online cross-sectional survey was administered in Australia (2015-2016) to collect data on demographic variables, levels of internal and external resilience, and stress from current and past smokers (n = 400) and those who have never-smoked (n = 921). Logistic regressions were employed to test our hypotheses. RESULTS: Most participants were female (82%) and ranged between 18 and 77 years. Higher levels of reported perceived stress and stress-related variables did significantly predict smoking. The combined impact of internal and external resilience factors predicted never-smoking and lessened the relationship between perceived stress and stress-related variables, and the likelihood of smoking. CONCLUSION: These results are important because they suggest that the social environment should be developed to augment social support and internal properties such as developing "a strong sense of purpose in life" to encourage people not to commence smoking, rather than focus on smoking cessation.

Adapting, Pilot Testing and Evaluating the Kick.it App to Support Smoking Cessation for Smokers with Severe Mental Illness: A Study Protocol.

(1) Background: While the prevalence of tobacco smoking in the general population has declined, it remains exceptionally high for smokers with severe mental illness (SMI), despite significant public health measures. This project aims to adapt, pilot test and evaluate a novel e-health smoking cessation intervention to assist relapse prevention and encourage sustained smoking cessation for young adults (aged 18⁻29 years) with SMI. (2) Methods: Using co-design principles, the researchers will adapt the Kick.it smartphone App in collaboration with a small sample of current and ex-smokers with SMI. In-depth interviews with smokers with SMI who have attempted to quit in the past 12 months and ex-smokers (i.e., those having not smoked in the past seven days) will explore their perceptions of smoking cessation support options that have been of value to them. Focus group participants will then give their feedback on the existing Kick.it App and any adaptations needed. The adapted App will then be pilot-tested with a small sample of young adult smokers with SMI interested in attempting to cut down or quit smoking, measuring utility, feasibility, acceptability, and preliminary outcomes in supporting their quit efforts. (3) Conclusions: This pilot work will inform a larger definitive trial. Dependent on recruitment success, the project may extend to also include smokers with SMI who are aged 30 years or more.

KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress.

Expression of E7 proteins encoded by carcinogenic, high-risk human papillomaviruses (HPVs) triggers increased expression of the histone H3 lysine 27 demethylase KDM6A. KDM6A expression is necessary for survival of high-risk HPV E7 expressing cells, including several cervical cancer lines. Here we show that increased KDM6A in response to high-risk HPV E7 expression causes epigenetic de-repression of the cell cycle and DNA replication inhibitor p21CIP1, and p21CIP1 expression is necessary for survival of high-risk HPV E7 expressing cells. The requirement for KDM6A and p21CIP1 expression for survival of high-risk HPV E7 expressing cells is based on p21CIP1's ability to inhibit DNA replication through PCNA binding. We show that ectopic expression of cellular replication factors can rescue the loss of cell viability in response to p21CIP1 and KDM6A depletion. Moreover, we discovered that nucleoside supplementation will override the loss of cell viability in response to p21CIP1 depletion, suggesting that p21CIP1 depletion causes lethal replication stress. This model is further supported by increased double strand DNA breaks upon KDM6A or p21CIP1 depletion and DNA combing experiments that show aberrant re-replication upon KDM6A or p21CIP1 depletion in high-risk HPV E7 expressing cells. Therefore, KDM6A and p21CIP1 expression are essential to curb E7 induced replication stress to levels that do not markedly interfere with cell viability.

The cardiac glycoside convallatoxin inhibits the growth of colorectal cancer cells in a p53-independent manner.

Cardiac glycosides are plant-derived molecules that have shown antiproliferative properties against cancer cells, though the mechanism of action is not completely understood. We show that one cardiac glycoside, convallatoxin, presents antiproliferative effects against colorectal cancer cells in culture and that the resulting cell death is independent of the p53 tumor suppressor. Our data suggest that convallatoxin may be useful in the treatment of cancers that harbor inactivating mutations in the p53 signaling pathway.

TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.

OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants. RESULTS: For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16). CONCLUSION: We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.

High-performance detection and early prediction of septic shock for alcohol-use disorder patients.

BACKGROUND: The presence of Alcohol Use Disorder (AUD) complicates the medical conditions of patients and increases the difficulty of detecting and predicting the onset of septic shock for patients in the ICU. METHODS: We have developed a high-performance sepsis prediction algorithm, InSight, which outperforms existing methods for AUD patient populations. InSight analyses a combination of singlets, doublets, and triplets of clinical measurements over time to generate a septic shock risk score. AUD patients obtained from the MIMIC III database were used in this retrospective study to train InSight and compare performance with the Modified Early Warning Score (MEWS), the Simplified Acute Physiology Score (SAPS II), and the Systemic Inflammatory Response Syndrome (SIRS) for septic shock prediction and detection. RESULTS: From 4-fold cross validation, InSight performs particularly well on diagnostic odds ratio and demonstrates a relatively high Area Under the Receiver Operating Characteristic (AUROC) metric. Four hours prior to onset, InSight had an average AUROC of 0.815, and at the time of onset, InSight had an average AUROC value of 0.965. When applied to patient populations where AUD may complicate prediction methods of sepsis, InSight outperforms existing diagnostic tools. CONCLUSIONS: Analysis of the higher order correlations and trends between relevant clinical measurements using the InSight algorithm leads to more accurate detection and prediction of septic shock, even in cases where diagnosis may be confounded by AUD.

Family-Level Sampling of Mitochondrial Genomes in Coleoptera: Compositional Heterogeneity and Phylogenetics.

Mitochondrial genomes are readily sequenced with recent technology and thus evolutionary lineages can be densely sampled. This permits better phylogenetic estimates and assessment of potential biases resulting from heterogeneity in nucleotide composition and rate of change. We gathered 245 mitochondrial sequences for the Coleoptera representing all 4 suborders, 15 superfamilies of Polyphaga, and altogether 97 families, including 159 newly sequenced full or partial mitogenomes. Compositional heterogeneity greatly affected 3rd codon positions, and to a lesser extent the 1st and 2nd positions, even after RY coding. Heterogeneity also affected the encoded protein sequence, in particular in the nad2, nad4, nad5, and nad6 genes. Credible tree topologies were obtained with the nhPhyML ("nonhomogeneous") algorithm implementing a model for branch-specific equilibrium frequencies. Likelihood searches using RAxML were improved by data partitioning by gene and codon position. Finally, the PhyloBayes software, which allows different substitution processes for amino acid replacement at various sites, produced a tree that best matched known higher level taxa and defined basal relationships in Coleoptera. After rooting with Neuropterida outgroups, suborder relationships were resolved as (Polyphaga (Myxophaga (Archostemata + Adephaga))). The infraorder relationships in Polyphaga were (Scirtiformia (Elateriformia ((Staphyliniformia + Scarabaeiformia) (Bostrichiformia (Cucujiformia))))). Polyphagan superfamilies were recovered as monophyla except Staphylinoidea (paraphyletic for Scarabaeiformia) and Cucujoidea, which can no longer be considered a valid taxon. The study shows that, although compositional heterogeneity is not universal, it cannot be eliminated for some mitochondrial genes, but dense taxon sampling and the use of appropriate Bayesian analyses can still produce robust phylogenetic trees.

Recruiting palliative patients for a large qualitative study: some ethical considerations and staff dilemmas.

This article reports on the processes of staff members in referring patients to a study that explored the experience of palliative patients, family members, and health professionals with the implementation of a family meeting model as an instrument of spiritual care. The reported qualitative study was undertaken in two large metropolitan Australian hospitals. Criteria other than those set by the study protocol were employed by staff members referring patients. These included subjective opinions of who was suitable to refer and perceptions of patients' attitudes to religion or spirituality. Such practices raise ethical issues and may compromise studies that have received ethics approval.

Smoking prevalence, its determinants and short-term health implications in the Australian Defence Force.

The objectives of this study were to determine the prevalence of smoking, identify the effects of deployment on smoking behavior and risk factors for smoking, and determine the short-term health outcomes associated with smoking in Australian Defence Force (ADF) personnel. Participants were randomly sampled from ADF members who deployed to the Solomon Islands between 2003 and 2005 and from a nondeployed comparison group. In total, 435 of 995 (44%) eligible individuals completed the study questionnaires. The prevalence of current smoking was highest in those who had completed less formal education and those who served in the Navy. Nearly two-thirds (63%) of current or former smokers smoked more while on overseas deployment. Current smokers were more likely to report current wheeze, shortness of breath, and persistent cough compared with nonsmokers. The ADF should continue to address cigarette smoking through its health promotion and health review programs and implement activities to reduce cigarette smoking on deployment.

ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy.

BACKGROUND: Autophagy is characterized by the sequestration of cytoplasm and organelles into multimembrane vesicles and subsequent degradation by the cell's lysosomal system. It is linked to many physiological functions in human cells including stress response, protein degradation, organelle turnover, caspase-independent cell death and tumor suppression. Malignant transformation is frequently associated with deregulation of autophagy and several tumor suppressors can modulate autophagic processes. The tumor suppressor p53 can induce autophagy after metabolic or genotoxic stress through transcriptionally-dependent and -independent mechanisms. In this study we expand on the former mechanism by functionally characterizing a p53 family target gene, ISG20L1 under conditions of genotoxic stress. RESULTS: We identified a p53 target gene, ISG20L1, and show that transcription of the gene can be regulated by all three p53 family members (p53, p63, and p73). We generated an antibody to ISG20L1 and found that it localizes to the nucleolar and perinucleolar regions of the nucleus and its protein levels increase in a p53- and p73-dependent manner after various forms of genotoxic stress. When ectopically expressed in epithelial cancer-derived cell lines, ISG20L1 expression decreased clonogenic survival without a concomitant elevation in apoptosis and this effect was partially rescued in cells that were ATG5 deficient. Knockdown of ISG20L1 did not alter 5-FU induced apoptosis as assessed by PARP and caspase-3 cleavage, sub-G1 content, and DNA laddering. Thus, we investigated the role of ISG20L1 in autophagy, a process commonly associated with type II cell death, and found that ISG20L1 knockdown decreased levels of autophagic vacuoles and LC3-II after genotoxic stress as assessed by electron microscopy, biochemical, and immunohistochemical measurements of LC3-II. CONCLUSIONS: Our identification of ISG20L1 as a p53 family target and discovery that modulation of this target can regulate autophagic processes further strengthens the connection between p53 signaling and autophagy. Given the keen interest in targeting autophagy as an anticancer therapeutic approach in tumor cells that are defective in apoptosis, investigation of genes and signaling pathways involved in cell death associated with autophagy is critical.