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Body composition assessment (ie, the measurement of muscle and adiposity) impacts several cancer-related outcomes including treatment-related toxicities, treatment responses, complications, and prognosis. Traditional modalities for body composition measurement include body mass index, body circumference, skinfold thickness, and bioelectrical impedance analysis; advanced imaging modalities include dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and positron emission tomography. Each modality has its advantages and disadvantages, thus requiring an individualized approach in identifying the most appropriate measure for specific clinical or research situations. Advancements in imaging approaches have led to an abundance of available data, however, the lack of standardized thresholds for classification of abnormal muscle mass or adiposity has been a barrier to adopting these measurements widely in research and clinical care. In this review, we discuss the different modalities in detail and provide guidance on their unique opportunities and challenges.

Sharks are the primary predator of large immature and mature sea turtles, yet the shark species responsible for both lethal and non-lethal injuries are rarely identified. Forensic analysis of bite wounds can be used to accurately assess size and potential shark species when combined with observations on species-specific feeding behavior, geographic distribution, and habitat preference. The objective of this study was to use forensic analysis of bite damage on sea turtles to infer shark size and species. Photographs from 13 cases of documented shark predation (n = 10) and scavenging (n = 3) attempts on sea turtles were retrospectively analyzed, including nesting, free-ranging, and/or dead stranded loggerhead Caretta caretta, green Chelonia mydas, Kemp’s ridley Lepidochelys kempii, and leatherback Dermochelys coriacea sea turtles in Florida and Alabama, USA, from 2010-2020. Mean interdental distance (IDD) and bite circumference (BC) of wound marks on sea turtles suggest that wounds were generated by white sharks Carcharodon carcharias in 3 cases, tiger sharks Galeocerdo cuvier in 3 cases, and bull shark(s) Carcharhinus leucas in one case. For 3 cases with less distinct wound patterns, 2 likely shark species were identified and thereafter narrowed down to a single species based on bite mark characteristics (e.g. punctures). Due to indistinct IDD and BC ranges of the bite patterns, a single shark species was not identified in 3 cases. Forensic analysis enables more accurate evaluations of which shark species prey on and scavenge sea turtles and is a useful technique for studying the behavioral interactions of sharks and turtles.

Background and ObjectivesNonvalvular atrial fibrillation (NVAF) is associated with an increased risk of dementia. Oral anticoagulants (OACs) are essential for stroke prevention in NVAF, and studies have shown a possible protective effect on dementia. However, findings have been inconsistent and hampered by methodological limitations. Thus, we assessed whether the use of OACs is associated with a decreased incidence of dementia in patients with NVAF. In addition, we explored the impact of the cumulative duration of OAC use on the incidence of dementia.MethodsUsing the UK Clinical Practice Research Datalink, we formed a cohort of all patients aged 50 years or older with an incident diagnosis of NVAF between 1988 and 2017 and no prior OAC use, with a follow-up until 2019. Patients were considered unexposed until 6 months after their first OAC prescription for latency considerations and exposed thereafter until the end of follow-up. We used time-dependent Cox regression models to estimate hazard ratios (HRs), adjusted for 54 covariates, with 95% CIs for dementia associated with OAC use, compared with nonuse. We also assessed whether the risk varied with the cumulative duration of OAC use, compared with nonuse, by comparing prespecified exposure categories defined in a time-varying manner and by modeling the HR using a restricted cubic spline.ResultsThe cohort included 142,227 patients with NVAF, with 8,023 cases of dementia over 662,667 person-years of follow-up (incidence rate 12.1, 95% CI 11.9–12.4 per 1,000 person-years). OAC use was associated with a decreased risk of dementia (HR 0.88, 95% CI 0.84–0.92) compared with nonuse. A restricted cubic spline also indicated a decreased risk of dementia, reaching a low at approximately 1.5 years of cumulative OAC use and stabilizing thereafter. Moreover, OAC use decreased the risk in patients aged 75 years and older (HR 0.84, 95% CI 0.80–0.89), but not in younger patients (HR 0.99, 95% CI 0.90–1.10).DiscussionIn patients with incident NVAF, OACs were associated with a decreased risk of dementia, particularly in elderly individuals. This warrants consideration when weighing the risks and benefits of anticoagulation in this population.Classification of EvidenceThis study provides Class II evidence that in patients with NVAF, OAC use (vs nonuse) is associated with a decreased risk of dementia.

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38–1.27, p = 0.23 ). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing “no symptoms” to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32–0.96, p = 0.03 ). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group ( p = 0.29 ). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) ( p = 0.92 ). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Retinoic acid (RA), a metabolite of vitamin A, is a small molecule and morphogen that is required for embryonic development. While normal RA signals are required for hepatic development in a variety of vertebrates, a role for RA during mammalian hepatic specification has yet to be defined. To examine the requirement for RA in murine liver induction, we performed whole embryo culture with the small molecule RA inhibitor, BMS493, to attenuate RA signaling immediately prior to hepatic induction and through liver bud formation. BMS493 treated embryos demonstrated a significant loss of hepatic specification that was confined to the prospective dorsal anterior liver bud. Examination of RA attenuated embryos demonstrates that while the liver bud displays normal expression of foregut endoderm markers and the hepato-pancreatobiliary domain marker, PROX1, the dorsal/anterior liver bud excludes the critical hepatic marker, HNF4α, indicating that RA signals are required for dorsal/anterior hepatic induction. These results were confirmed and extended by careful examination of Rdh10lt;supgt;trex/trexlt;/supgt; embryos, which carry a genetic perturbation in RA synthesis. At E9.5 Rdh10lt;supgt;trex/trexlt;/supgt; embryos display a similar yet more significant loss of the anterior/dorsal liver bud. Notably the anterior/dorsal liver bud loss correlates with the known dorsal-ventral gradient of the RA synthesis enzyme, Aldh1a2. In addition to altered hepatic specification, the mesoderm surrounding the liver bud is disorganized in RA abrogated embryos. Analysis of E10.5 Rdh10lt;supgt;trex/trexlt;/supgt; embryos reveals small livers that appear to lack the dorsal/caudal lobes. Finally, addition of exogenous RA prior to hepatic induction results in a liver bud that has failed to thicken and is largely unspecified. Taken together our ex vivo and in vivo evidence demonstrate that the generation of normal RA gradients is required for hepatic patterning, specification, and growth.

Vitamin K antagonists (VKAs) are frequently prescribed to patients with congenital heart disease (CHD) for atrial arrhythmias or Fontan palliation, but there is a paucity of data regarding time spent in the therapeutic range (TTR). We sought to determine the TTR in patients with CHD and atrial arrhythmias or Fontan palliation prescribed VKAs and explore associations with thromboembolic and bleeding events.A multicentre North American cohort study was conducted on patients with CHD who received VKAs for sustained atrial arrhythmia or Fontan palliation. TTR was calculated using the Rosendaal linear interpolation method. Generalized estimating equations were used to explore factors associated with time outside the therapeutic range.A total of 567 patients, aged 33 ± 17 years, 56% female, received VKAs for 11.5 ± 8.4 years for atrial arrhythmias (63.0%) or Fontan palliation (58.0%). CHD was simple, moderate, and complex in 10.8%, 20.3%, and 69.0%, respectively. Site investigators perceived good control over international normalized ratio (INR) levels in most patients (75.3%), with no or minor compliance or adherence issues (85.6%). The mean TTR was 41.9% (95% confidence interval [CI], 39.0%-44.8%). Forty-seven (8.3%) and 34 (6.0%) patients had thromboembolic and bleeding events, respectively. Thromboembolic events were associated with a higher proportion of time below the therapeutic range (31.3% vs 19.1%, P = 0.003) and bleeding complications with a higher proportion of time above the therapeutic range (32.5% vs 19.5%, P = 0.006).Patients with CHD who receive VKAs spend42% of their time with INR levels in the therapeutic range, with repercussions regarding thromboembolic and bleeding complications.

Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race.We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models.The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORObesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

Compte tenu du rôle incontournable que jouent les municipalités dans la nécessaire transition écologique, la formation relative à l’environnement des élu.e.s des municipalités québécoises se doit d’être adaptée au contexte local et politique. Dans la foulée d’une recherche qualitative basée sur des observations non participantes et des entretiens semi-dirigés auprès d’élu·e·s, et dans le cadre de laquelle un regard critique a été porté sur l’offre de formation actuelle en ce domaine, il nous a été possible de dégager les préférences des élu.e.s en matière de contextes et de stratégies de formation. Ces préférences, examinées à la lumière de fondements et de pratiques documentés en éducation relative à l’environnement, permettent d’identifier les principales caractéristiques d’un processus de formation continue adéquat pour ces apprenant.e.s adultes aux fonctions politiques particulières en matière d’environnement. Given the essential role that municipalities play towards ecological transition, environmental training for elected officials of Quebec municipalities must be adapted to the local and political context. In the wake of qualitative research based on non-participant observations and semi-structured interviews with local elected officials, and within an environmental education framework, a critical analysis was conducted regarding current training activities offered to elected officials in terms of learning, contexts and strategies. These preferences examined in the light of documented principals and practices in environmental education, make it possible to identify the main characteristics of a continuing education process for adult learners with political functions in regard to the environment.

The clinical success of combined androgen deprivation therapy (ADT) and radiation therapy (RT) in prostate cancer (PCa) created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in PCa cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at steady state in asynchronously growing PCa cells. Our data indicate that the clinical benefit of ADT and RT is not due to the direct regulation of DDR gene transcription by AR.

In an evolving infectious disease outbreak, there are two priorities: rapid and accurate detection of the causative agent and characterization of its spread. The polymerase chain reaction (PCR) assay is an effective and portable diagnostic method that can quickly provide information associated with virulence, transmissibility, and pathogenicity. Compared to genomic sequencing, PCR requires less infrastructure, funding, and training. However, the development of sensitive and specific primer sequences is costly, particularly those with subspecies resolution. The recentmpox (monkeypox) virusoutbreak underscores the need for the rapid development of clade-specific primers, particularly when there are differences in morbidity and mortality rates. Current mpox assays use primer sequences that also bind to the broaderOrthopoxvirusgenus, resulting in suspect diagnoses, delays in treatment, and poor allocation of scarce healthcare resources.Additionally, these orthopox-based primer sets cannot distinguish between different mpox clades and cannot illuminate intra-clade evolution over the course of the outbreak. Here, we present thein silicodesign andin vitrotesting of novel clade-specific mpox assays.

Background Hospitalized children face pain and anxiety associated with the environment and procedures. Objective This review aimed to assess the impact of music, play, pet and art therapies on pain and anxiety in hospitalized paediatric patients. RCTs assessing the impact of music, play, pet, and/or art therapies on pain and/or anxiety in hospitalized paediatric patients were eligible. Methods Database searching and citation screening was completed to identify studies. A narrative synthesis was used to summarize study findings and certainty of evidence was assessed using GRADE. Of the 761 documents identified, 29 were included spanning music (n = 15), play (n = 12), and pet (n = 3) therapies. Results A high certainty of evidence supported play in reducing pain and moderate certainty for music and pet. A moderate certainty of evidence supported music and play in reducing anxiety. Conclusion Complementary therapies utilized alongside conventional medical treatment may mitigate pain and anxiety in hospitalized paediatric patients.

Supplementary Figure 1: Assessment of kidney cancer cell lines A498, 786-O, and A704 via flow cytometry revealed surface expression of P-gp in all lines; Supplementary Figure 2: 786-O and A704 cells were transduced with lentiviral FR1, and flow cytometric analysis shows increased surface FR1 expression; Supplementary Figure 3: NCI/ADR-RES or NCI/ADR-RES-FR cells with known FR levels were treated with increasing concentrations (10-9 M to 10-5 M) of vintafolide for 2 h; Supplementary Figure 4: Ovarian tumors positive for P-gp tend to express lower levels of FR; Supplementary Table 1: P-gp inhibitor elacridar reverses P-gp-mediated DAVLBH and vintafolide resistance; Supplementary Table 2: Functional multi-drug transporter efflux assay.

XLSX file - 155K, Proliferation assay EC50 results for MK-1775 in diverse tumor cell lines.

Legends for Supplementary Figures 1-4 and Supplementary Tables 1 & 2

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PDF file - 724K, S1. MK-1775 treatment inhibits proliferation in diverse tumor cell lines. S2. DNA damage induction by MK-1775 treatment requires mitogen stimulation. S3. The MK-1775 response of three sensitive cell lines.

Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775–induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC50 of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, γH2AX and pCHK1S345, induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity. Mol Cancer Ther; 12(8); 1442–52. ©2013 AACR.

Hydrologic response in a watershed is driven by precipitation. Multi-site rainfall generators can be used to model watersheds using spatially varied rainfall inputs to better analyze how the rainfall variability affects runoff generation. This study adopted both a single-site rainfall generator (CLIGEN) and a multi-site rainfall generator to generate two rainfall data sequences, which were then used to drive the Soil and Water Assessment Tool (SWAT) for runoff simulation. The 148-km2 Walnut Gulch Experimental Watershed and its two sub-watersheds were selected to evaluate the hydrologic response. Runoff calibration was done against measured runoff in the watershed. Statistics showed that the single-site and multi-site rainfall generators gave similar results regarding annual precipitation. However, the multi-site generator performed much better than the single-site generator in both mean summer flow and for the different return period flows. The runoff derived from the single-site generator was significantly over-estimated in all three watersheds. As for the multi-site generator, the derived runoff was satisfactorily predicted in the smaller watersheds but only overestimated in the largest watershed. This indicated that in small to medium sized watersheds, the spatial variability of rainfall could play an important role for hydrologic response because of the heterogeneity of convective rainfall in this semi-arid region, which makes the application of multi-site rainfall generator a better option than the single-site generator.

Aims The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis. Methods and results We show that ADCY9 is expressed in the endothelium of mouse aorta and femoral arteries. We demonstrate that ADCY9 inactivation in cultured endothelial cells paradoxically increases cAMP accumulation in response to the adenylate cyclase activators forskolin and vasoactive intestinal peptide (VIP). Reciprocally, ADCY9 overexpression decreases cAMP production. Using mouse femoral artery arteriography, we show that Adcy9 inactivation potentiates VIP-induced endothelial-dependent vasodilation. Moreover, Adcy9 inactivation reduces mouse atheroma endothelial permeability in different vascular beds. ADCY9 overexpression reduces forskolin-induced phosphorylation of Ser157-vasodilator-stimulated phosphoprotein (VASP) and worsens thrombin-induced fall of RAP1 activity, both leading to increased endothelial permeability. ADCY9 inactivation in thrombin-stimulated human coronary artery endothelial cells results in cAMP accumulation, increases p-Ser157-VASP, and inhibits endothelial permeability. MLC2 phosphorylation and actin stress fibre increases in response to thrombin were reduced by ADCY9 inactivation, suggesting actin cytoskeleton regulation. Finally, using the Miles assay, we demonstrate that Adcy9 regulates thrombin-induced endothelial permeability in vivo in normal and atherosclerotic animals. Conclusion Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis.

Background: Health economic evaluations are needed to assess the impact on the healthcare system of emerging treatment patterns for advanced prostate cancer. The objective of this study is to review the scientific literature identifying cost-effectiveness and cost analyses that are assessing treatments for metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC). Methods: On 29 June 2021, we searched the scientific (MEDLINE, Embase, and EBSCO) and grey literature for health economic studies targeting mHSPC and nmCRPC. We used the CHEC-extended checklist and the Welte checklist for risk-of-bias assessment and transferability analysis, respectively. Results: We retained 20 cost-effectiveness and 4 cost analyses in the mHSPC setting, and 14 cost-effectiveness and 6 cost analyses in the nmCRPC setting. Docetaxel in combination with androgen deprivation therapy (ADT) was the most cost-effective treatment in the mHSPC setting. Apalutamide, darolutamide, and enzalutamide presented similar results vs. ADT alone and were identified as cost-effective treatments for nmCRPC. An increase in costs as patients transitioned from nmCRPC to mCRPC was noted. Conclusions: We concluded that there is an important unmet need for health economic evaluations in the mHSPC and nmCRPC setting incorporating real-world data to support healthcare decision making.

BACKGROUND: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function. OBJECTIVES: We investigated the association between change in plasma vitE (∆vitE) and pulmonary function decline [forced expiratory volume in the first second (FEV(1))] and examined genetic and nongenetic factors associated with ∆vitE. METHODS: We studied 1144 men randomly assigned to vitE in SELECT (Selenium and Vitamin E Cancer Prevention Trial). ∆vitE was the difference between baseline and year 3 vitE concentrations measured with GC-MS. FEV(1) was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGA(ex)). We used mixed-effects linear regression modeling to examine the ∆vitE–FEV(1) association. RESULTS: Higher ∆vitE was associated with lower baseline α-tocopherol (α-TOH), higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (as opposed to African) (all P

The goal of this study was to evaluate the effectiveness of two approaches to protect the viability of probiotic cells during granola bar manufacturing and storage: microencapsulation (ME) and inclusion in chocolate chips. In the process used, hot honey (138 °C) was blended with cereal ingredients, resulting in an initial blend temperature of 52 °C. Chocolate chips carrying probiotics were added; however, when the blend was cooled to 42 °C. The viability of Lacticaseibacillus rhamnosus R0011 probiotic was assessed by flow cytometry (FC) and plating (CFU). There was an uneven distribution of inoculated probiotic bacteria throughout the cereal bars, resulting in variability in the CFU data. By providing total and viable counts, FC assessed the correct number of inoculated cells in the sample, which enabled the accurate calculation of survival levels. Spray coating with ME increased survival during manufacturing, but ME in alginate particles was detrimental. Including the cultures in chocolate improved the stability of the probiotics during storage at 25 °C, but only in the first 4 weeks. FC analyses showed that viability losses during bar manufacturing could be linked to damage to the cell membrane, but less so during storage.

Background There are an estimated 11 million burn injuries requiring medical attention every year worldwide. Although potentially deadly, burn injuries are now considered a chronic disease with multiple lifetime physical and psychological sequelae. However, it remains unclear how these events affect patients’ utility scores. We aimed to conduct a systematic review to summarize the utility scores of burn injury survivors. Methods We conducted on March 18th, 2020 a systematic review of the published literature using a search strategy designed in collaboration with a research librarian. Our search strategy aimed to identify studies that provided burn injury survivors’ utility scores via a standardized indirect instrument. Results We identified 15 studies that reported burn injury survivors’ utility scores. Most studies used the EQ-5D instruments to assess patients’ utility scores. Results varied substantially between studies, ranging from a low of 0.11 to a high of 0.94. Our review identified two key trends. First, utility scores seem to be negatively correlated with the severity of the burn injury. Second, utility scores in adults tend to increase in function of the time since injury. Conclusion Unfortunately, due to differences in study design and settings, patient populations and instruments used to assess patients’ utility scores, we were unable to combine all study results into a single value. In spite of this limit, results we identified support previous trends identified by others regarding the relationship between utility scores and the burn injury severity and/or the time since injury.

Rose Gagnon,1,2 Kadija Perreault,1,2 Jason R Guertin,3,4 Simon Berthelot,4– 6 Bertrand Achou,7 Luc J Hébert1,2,8 1Centre for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris), Centre intégré universitaire de santé et de services sociaux (CIUSSS) de La Capitale-Nationale, Quebec City, Quebec, Canada; 2Department of Rehabilitation, Université Laval, Quebec City, Quebec, Canada; 3Department of Social and Preventive Medicine, Université Laval, Quebec City, Quebec, Canada; 4Centre de recherche du CHU de Québec – Université Laval, Quebec City, Quebec, Canada; 5Department of Family Medicine and Emergency Medicine, Université Laval, Quebec City, Quebec, Canada; 6CHU de Québec – Université Laval, Quebec City, Quebec, Canada; 7HEC Montreal, Montreal, Quebec, Canada; 8Department of Radiology and Nuclear Medicine, Université Laval, Quebec City, Quebec, CanadaCorrespondence: Luc J Hébert, Cirris, CIUSSS de la Capitale-Nationale, 525 Boulevard Wilfrid-Hamel, H-1410, Quebec City, Quebec, G1M 2S8, Canada, Tel +1 418 529-9141 ext 6579, Email lucj.hebert@fmed.ulaval.caBackground: Musculoskeletal disorders (MSKDs) are among the most disabling and costly non-fatal health conditions. They may lead to long-term consequences such as chronic pain, physical limitations, and poorer quality of life. They also account for a significant proportion of emergency department visits, representing between 18% and 25% of all visits, depending on country.Purpose: To assess the health-related quality of life of patients presenting to the emergency department with a MSKD, to convert their answers to utility scores and to explore the association between diverse socio-demographic and clinical variables and patients’ health-related quality of life.Patients and Methods: This is an analysis of cross-sectional data obtained during the baseline assessment performed as part of a 6-month pragmatic randomized controlled trial conducted in an academic emergency department. We included patients aged 18– 80 years with a minor MSKD. The main outcome measures were health-related quality of life (five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and utility scores (− 0.148 – worse than death, 0 – dead, 0.949 – perfect health) measured with the EQ-5D-5L. Possible associations were explored by comparing scores across subgroups based on certain socio-demographic (eg, age, gender, triage score) and clinical factors (eg, pain interference on function, pain intensity) and with reference values using descriptive statistics (mean, median), rankFD ANOVAs, and χ2 tests.Results: Sixty-nine participants completed the EQ-5D-5L. Mean and median utility scores were, respectively, 0.536 (95% CI: 0.479– 0.594) and 0.531 (IQR: 0.356– 0.760). Participants with higher levels of pain (< 4/10: 0.741, 95% CI: 0.501– 0.980; 4– 7/10: 0.572, 0.500– 0.644; > 7/10: 0.433, 0.347– 0.518) or pain interference on function (< 4/10: 0.685, 95% CI: 0.605– 0.764; 4– 7/10: 0.463, 0.394– 0.533; > 7/10: 0.294, 0.126– 0.463) presented significantly lower utility scores. No significant differences were found for other socio-demographic characteristics.Conclusion: In patients with MSKDs who present to the emergency department, higher levels of pain or pain interference are associated with decreased health-related quality of life. These findings need to be confirmed on a larger scale.Keywords: EQ-5D-5L, quality of life, pain, emergency services, musculoskeletal disorders

Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias.A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting.In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well.Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Tania Villeneuve,1 Xavier Trudel,1,2 Mahée Gilbert-Ouimet,2,3 Jacinthe Leclerc,4,5 Alain Milot,6 Hélène Sultan-Taïeb,7,8 Chantal Brisson,1,2 Jason Robert Guertin1,2 1Université Laval, Département de médecine sociale et préventive, Quebec City, Canada; 2Centre de recherche du Centre hospitalier universitaire de l’Université Laval, Quebec City, Canada; 3Université du Québec à Rimouski, Département des sciences de la santé, module des sciences infirmières, Lévis, Canada; 4Université du Québec à Trois-Rivières, Département des sciences infirmières, Trois-Rivières, Canada; 5Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec City, Canada; 6Université Laval, Département de médecine, Quebec City, Canada; 7Université du Québec à Montréal (UQAM), School of Management, Montreal, Canada; 8CINBIOSE, Montreal, CanadaCorrespondence: Jason Robert GuertinCentre de recherche du CHU de Québec – Université Laval, Axe Santé des Populations et Pratiques Optimales en Santé, Hôpital du Saint-Sacrement, 1050 Chemin Ste-Foy, local J1-09B, Québec City, Québec, G1S 4L8, CanadaTel +1 418-682-7511, poste 82516Email jason.guertin@fmed.ulaval.caBackground: Cost studies appear sporadically in the scientific literature and are rarely revised unless drastic technological advancements occur. However, health technologies and medical guidelines evolve over time. It is unclear if these changes render obsolete prior estimates. We examined this issue in a cost study in the context of patients’ first myocardial infarction (MI), a clinical area prone to such continuous evolution in care.Methods: We conducted a longitudinal cost analysis based on a Quebec cohort. Quebec health administrative databases were used to identify incident MI cases using diagnostic codes from the international classification of diseases (ICD-9 and ICD-10). Physician fees and hospitalization costs (ie, costs incurred by the hospital center) were derived from administrative databases and a university hospital’s finance department. All costs were converted to 2019 Canadian dollars. Nonparametric bootstraps were used to estimate 95% confidence intervals (CI) of the average costs of an episode of care. Generalized linear regressions were used to examine temporal trends of cost.Results: Our study sample consists of 261 patients hospitalized for a first MI. The average total cost for this first event was estimated at $5782 (95% CI: $5293 – $6373). Though total costs remained stable over time, physician fees increased by 123% ($1240 vs $2761) whereas total hospital length of stay dropped by 17% (6.6 vs 5.5 days) over the 21-year period.Conclusion: Patients’ first MI hospitalization impose an economic burden on the healthcare system. Though overall costs remained stable, our results suggest that some cost components varied over time.Keywords: cost study, methods, observational data, myocardial infarction, longitudinal study

Tania Villeneuve,1 Xavier Trudel,1,2 Mahée Gilbert-Ouimet,2,3 Jacinthe Leclerc,4,5 Alain Milot,6 Hélène Sultan-Taïeb,7,8 Chantal Brisson,1,2 Jason Robert Guertin1,2 1Université Laval, Département de médecine sociale et préventive, Quebec City, Canada; 2Centre de recherche du Centre hospitalier universitaire de l’Université Laval, Quebec City, Canada; 3Université du Québec à Rimouski, Département des sciences de la santé, module des sciences infirmières, Lévis, Canada; 4Université du Québec à Trois-Rivières, Département des sciences infirmières, Trois-Rivières, Canada; 5Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec City, Canada; 6Université Laval, Département de médecine, Quebec City, Canada; 7Université du Québec à Montréal (UQAM), School of Management, Montreal, Canada; 8CINBIOSE, Montreal, CanadaCorrespondence: Jason Robert GuertinCentre de recherche du CHU de Québec – Université Laval, Axe Santé des Populations et Pratiques Optimales en Santé, Hôpital du Saint-Sacrement, 1050 Chemin Ste-Foy, local J1-09B, Québec City, Québec, G1S 4L8, CanadaTel +1 418-682-7511, poste 82516Email jason.guertin@fmed.ulaval.caBackground: Cost studies appear sporadically in the scientific literature and are rarely revised unless drastic technological advancements occur. However, health technologies and medical guidelines evolve over time. It is unclear if these changes render obsolete prior estimates. We examined this issue in a cost study in the context of patients’ first myocardial infarction (MI), a clinical area prone to such continuous evolution in care.Methods: We conducted a longitudinal cost analysis based on a Quebec cohort. Quebec health administrative databases were used to identify incident MI cases using diagnostic codes from the international classification of diseases (ICD-9 and ICD-10). Physician fees and hospitalization costs (ie, costs incurred by the hospital center) were derived from administrative databases and a university hospital’s finance department. All costs were converted to 2019 Canadian dollars. Nonparametric bootstraps were used to estimate 95% confidence intervals (CI) of the average costs of an episode of care. Generalized linear regressions were used to examine temporal trends of cost.Results: Our study sample consists of 261 patients hospitalized for a first MI. The average total cost for this first event was estimated at $5782 (95% CI: $5293 – $6373). Though total costs remained stable over time, physician fees increased by 123% ($1240 vs $2761) whereas total hospital length of stay dropped by 17% (6.6 vs 5.5 days) over the 21-year period.Conclusion: Patients’ first MI hospitalization impose an economic burden on the healthcare system. Though overall costs remained stable, our results suggest that some cost components varied over time.Keywords: cost study, methods, observational data, myocardial infarction, longitudinal study

Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk.Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case–control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations.Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24–4.61; Ptrend < 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P < 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant (P = 0.25, 0.71, and 0.61, respectively).Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer.Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945–52. ©2017 AACR.

Supplementary Table S1. Mean self-reported dietary intake of selected choline- and carnitine-containing foods among colorectal cancer cases and controls; Supplementary Table S2. Correlation matrix for serum biomarkers among colorectal cancer cases and controls; Supplementary Table S3. ORs (95% CIs) of colorectal cancer ranked by quartile of serum biomarkers, with additional adjustment for usual alcohol intake and aspirin use; Supplementary Table S4. ORs (95% CIs) of colorectal cancer ranked by quartile of serum choline, excluding participants with colorectal cancer diagnoses during the first two and five years of follow-up; Supplementary Table S5. ORs (95% CIs) of colon cancer ranked by quartile of serum biomarkers

Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of the ANKLE1 gene. ANKLE1 is molecularly characterized as an endonuclease that efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1’s role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) cleavage. mtDNA degradation then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.

SUMMARYDNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following exposure to DNA damage. In contrast to the conventional model, which suggests that p53-deficient cells should be resistant to DNA damage-induced cell death, we find that p53-deficient cells die at high rates following DNA damage, but exclusively using non-apoptotic mechanisms. Our experimental data and computational modeling reveal that non-apoptotic death in p53-deficient cells has not been observed due to use of assays that are either insensitive to cell death, or that specifically score apoptotic cells. Using functional genetic screening – with an analysis that enables computational inference of the drug-induced death rate – we find in p53-deficient cells that DNA damage activates a mitochondrial respiration-dependent form of cell death, called MPT-driven necrosis. Cells deficient for p53 have high basal respiration, which primes MPT-driven necrosis. Finally, using metabolite profiling, we identified mitochondrial activity-dependent metabolic vulnerabilities that can be targeted to potentiate the lethality of DNA damage specifically in p53-deficient cells. Our findings reveal how the dual functions of p53 in regulating mitochondrial activity and the DNA damage response combine to facilitate the choice between apoptotic and non-apoptotic death.

Background: Neck dissections (ND) are a routine procedure in head and neck oncology. Given the post-operative functional impact that some patients experience, it is imperative to identify and track quality of life (QoL) symptomatology in order to tailor each patient’s therapeutic needs. To date, there is no validated francophone questionnaire for this patient-population. We therefore sought to translate and validate the Neck Dissection Impairment Index (NDII) in French. Methods: A three-phased approach was used. Phase 1: The NDII was translated from English to French using a “forward and backward” translational technique following international guidelines. Phase 2: A cognitive debriefing session was held with ten French-speaking otolaryngology patients to evaluate understandability and acceptability. Phase 3: The final version was administered prospectively to 30 patients with prior history of ND and 30 control patients. These patients were asked to complete the questionnaire 2 weeks after their first response. Test-retest reliability was calculated with Spearman’s correlation. Internal consistency was elicited using Cronbach’s alpha. Results: NDII was successfully translated and validated to French. Cronbach’s alpha revealed high internal consistency (0.92, lower 95% CL 0.89). The correlation for test-retest validity were strong or very-strong (0.61-0.91). Conclusion: NDII is an internationally recognized QoL tool for the identification of ND-related impairments. This validated French version will allow clinicians to adequately assess the surgery-related QoL effect of neck surgery in the French-speaking population, while allowing French institutions to conduct and/or participate in multi-site clinical trials requiring the NDII as an outcome measure.