Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.

Limitations of antifungal prophylaxis in preventing invasive Candida surgical site infections after liver transplant surgery.

Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks.

Risk Factors and Inequities in Transportation Injury and Mortality in the Canadian Census Health and Environment Cohorts (CanCHECs).

BACKGROUND: Road traffic injury contributes substantially to morbidity and mortality. Canada stands out among developed countries in not conducting a national household travel survey, leading to a dearth of national transportation mode data and risk calculations that have appropriate denominators. Since traffic injuries are specific to the mode of travel used, these risk calculations should consider travel mode. METHODS: Census data on mode of commute is one of the few sources of these data for persons aged 15 and over. This study leveraged a national data linkage cohort, the Canadian Census Health and Environment Cohorts, that connects census sociodemographic and commute mode data with records of deaths and hospitalizations, enabling assessment of road traffic injury associations by indicators of mode of travel (commuter mode). We examined longitudinal (1996-2019) bicyclist, pedestrian, and motor vehicle occupant injury and fatality risk in the Canadian Census Health and Environment Cohorts by commuter mode and sociodemographic characteristics using Cox proportional hazards models within the working adult population. RESULTS: We estimated positive associations between commute mode and same mode injury and fatality, particularly for bicycle commuters (hazard ratios for bicycling injury was 9.1 and for bicycling fatality was 11). Low-income populations and Indigenous people had increased injury risk across all modes. CONCLUSIONS: This study shows inequities in transportation injury risk in Canada and underscores the importance of adjusting for mode of travel when examining differences between population groups.

Comparison of the number of pedestrian and cyclist injuries captured in police data compared with health service utilisation data in Toronto, Canada 2016-2021.

INTRODUCTION: Pedestrian and cyclist injuries represent a preventable burden to Canadians. Police-reported collision data include information on where such collisions occur but under-report the number of collisions. The primary objective of this study was to compare the number of police-reported collisions with emergency department (ED) visits and hospitalisations in Toronto, Canada. METHODS: Police-reported collisions were provided by Toronto Police Services (TPS). Data included the location of the collision, approximate victim age and whether the pedestrian or cyclist was killed or seriously injured. Health services data included ED visits in the National Ambulatory Care Reporting System and hospitalisations from the Discharge Abstract Database using ICD-10 codes for pedestrian and cycling injuries. Data were compared from 2016 to 2021. RESULTS: Injuries reported in the health service data were higher than those reported in the TPS for cyclists and pedestrians. The discrepancy was the largest for cyclists treated in the ED, with TPS capturing 7.9% of all cycling injuries. Cyclist injuries not involving a motor vehicle have increased since the start of the pandemic (from 3629 in 2019 to 5459 in 2020 for ED visits and from 251 in 2019 to 430 for hospital admissions). IMPLICATIONS: While police-reported data are important, it under-reports the burden. There have been increases in cyclist collisions not involving motor vehicles and decreases in pedestrian injuries since the start of the pandemic. The results suggest that using police data alone when planning for road safety is inadequate, and that linkage with other health service data is essential.

Motor vehicle collision (MVC) emergency department (ED) visits and hospitalisations in Ontario during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic policy response dramatically changed local transportation patterns. This project investigated the impact of COVID-19 policies on motor vehicle collision (MVC)-related emergency department (ED) visits and hospitalisations in Ontario. METHODS: Data were collected on MVC-related ED visits and hospitalisations in Ontario between March 2016 and December 2022. Using an interrupted time series design, negative binomial regression models were fitted to the pre-pandemic data, including monthly indicator variables for seasonality and accounting for autocorrelation. Extrapolations simulated expected outcome trajectories during the pandemic, which were compared with actual observed outcome counts using the overall per cent change and mean monthly difference. Data were modelled separately for vehicle occupants, pedestrians and cyclists (MVC and non-MVC injuries). RESULTS: There was a 31.5% decrease in observed ED visits (95% CI -35.4 to -27.3) and a 6.0% decrease in hospitalisations (95% CI -13.2 to 1.6) among vehicle occupants, relative to expected counts during the pandemic. Results were similar for pedestrians. Among cyclist MVCs, there was an increase in ED visits (12.8%, 95% CI -8.2 to 39.4) and hospitalisations (46.0%, 95% CI 11.6 to 93.6). Among non-MVC cyclists, there was also an increase in ED visits (47.0%, 95% CI 12.5 to 86.8) and hospitalisations (50.1%, 95% CI 8.2 to 101.2). CONCLUSIONS: We observed fewer vehicle occupant and pedestrian collision injuries than expected during the pandemic. By contrast, we observed more cycling injuries than expected, especially in cycling injuries not involving motor vehicles. These observations may be attributable to changes in transportation patterns during the pandemic and increased uptake of recreational cycling.

A retrospective multicentre clinical study on management of isolated splenic vein thrombosis: risks and benefits of anticoagulation.

INTRODUCTION: Isolated splenic vein thrombosis (iSVT) is a common complication of pancreatic disease. Whilst patients remain asymptomatic, there is a risk of sinistral portal hypertension and subsequent bleeding from gastric varices if recanalisation does not occur. There is wide variation of iSVT treatment, even within single centres. We report outcomes of iSVT from tertiary referral hepatobiliary and pancreatic (HPB) units including the impact of anticoagulation on recanalisation rates and subsequent variceal bleeding risk. METHODS: A retrospective cohort study including all patients diagnosed with iSVT on contrast-enhanced CT scan abdomen and pelvis between 2011 and 2019 from two institutions. Patients with both SVT and portal vein thrombosis at diagnosis and isolated splenic vein thrombosis secondary to malignancy were excluded. The outcomes of anticoagulation, recanalisation rates, risk of bleeding and progression to portal vein thrombosis were examined using CT scan abdomen and pelvis with contrast. RESULTS: Ninety-eight patients with iSVT were included, of which 39 patients received anticoagulation (40%). The most common cause of iSVT was acute pancreatitis n = 88 (90%). The recanalisation rate in the anticoagulation group was 46% vs 15% in patients receiving no anticoagulation (p = 0.0008, OR = 4.7, 95% CI 1.775 to 11.72). Upper abdominal vascular collaterals (demonstrated on CT scan angiography) were significantly less amongst patients who received anticoagulation treatment (p = 0.03, OR = 0.4, 95% CI 0.1736 to 0.9288). The overall rate of upper GI variceal-related bleeding was 3% (n = 3/98) and it was independent of anticoagulation treatment. Two of the patients received therapeutic anticoagulation. CONCLUSION: The current data supports that therapeutic anticoagulation is associated with a statistically significant increase in recanalisation rates of the splenic vein, with a subsequent reduction in radiological left-sided portal hypertension. However, all patients had a very low risk of variceal bleeding regardless of anticoagulation. The findings from this retrospective study should merit further investigation in large-scale randomised clinical trials.

Impact of Prehospital Pain Management on Emergency Department Management of Injured Children.

OBJECTIVE: Provision of analgesia for injured children is challenging for Emergency Medical Services (EMS) clinicians. Little is known about the effect of prehospital analgesia on emergency department (ED) care. We aimed to determine the impact of prehospital pain interventions on initial ED pain scale scores, timing and dosing of ED analgesia for injured patients transported by EMS. METHODS: This is a planned, secondary analysis of a prospective multicenter cohort of children with actual or suspected injuries transported to one of 11 PECARN-affiliated EDs from July 2019-April 2020. Using Wilcoxon rank sum for continuous variables and chi-square testing for categorical variables, we compared the change in EMS-to-ED pain scores and timing and dosing of ED-administered opioid analgesia in those who did and those who did not receive prehospital pain interventions. RESULTS: We enrolled 474 children with complete prehospital and ED pain management data. Prehospital interventions were performed on 262/474 (55%) of injured children and a total of 88 patients (19%) received prehospital opioids. Children who received prehospital opioids with or without adjunctive non-pharmacologic pain management experienced a greater reduction in pain severity and were more likely to receive ED opioids in higher doses earlier and throughout their ED care. Non-pharmacologic pain interventions alone did not impact ED care. CONCLUSIONS: We demonstrate that prehospital opioid analgesia is associated with both a significant reduction in pain severity at ED arrival and the administration of higher doses of opioid analgesia earlier and throughout ED care.

Radon exposure and risk of neurodegenerative diseases among male miners in Ontario, Canada: A cohort study.

BACKGROUND: Environmental radon has been examined as a risk factor for neurodegenerative diseases in a small number of previous studies, but the findings have been inconsistent. This study aims to investigate the association between occupational radon exposure and neurodegenerative disease in a cohort of male miners with work experience in multiple ore types in Ontario, Canada. METHODS: Radon exposure (1915-1988) was assessed using two job-exposure matrices (JEM) constructed from using historical records for 34,536 Ontario male miners. Neurodegenerative outcomes were ascertained between 1992 and 2018. Poisson regression models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between cumulative radon exposure in working level months (WLM) and each neurodegenerative outcome. RESULTS: Levels of cumulative radon exposure showed variability among cohort members with a mean of 7.5 WLM (standard deviation 24.4). Miners in uranium mines or underground jobs had higher levels and more variability in exposure than workers in non-uranium work or surface jobs. Compared to the reference group (radon < 1 WLM), increased rates of Alzheimer's (RR 1.23, 95% CI 1.05-1.45) and Parkinson's disease (RR 1.43, 95% CI 1.08-1.89) were observed among workers with >1-5 WLM and >5-10 WLM, respectively, but not among higher exposed workers (>10 WLM). CONCLUSION: This study did not observe a positive monotonic dose-response relationship between cumulative radon exposure and Alzheimer's or Parkinson's disease in Ontario mining workers. There was no association observed with motor neuron disease.

Comparative Effectiveness of Integrated Peer Support and Clinical Staffing Models for Community-Based Residential Mental Health Rehabilitation: A Prospective Observational Study.

This observational study compared the outcomes of consumers receiving community-based residential mental health rehabilitation support in Australia under a clinical staffing model and an integrated staffing model where Peer Support Workers are the majority component of the staffing profile. Reliable and clinically significant (RCS) change between admission and discharge in functional and clinical assessment measures were compared for consumers receiving care under the clinical (n = 52) and integrated (n = 93) staffing models. Covariate analyses examined the impact of known confounders on the outcomes of the staffing model groups. No statistically significant differences in RCS improvement were identified between the staffing models. However, logistic regression modelling showed that consumers admitted under the integrated staffing model were more likely to experience reliable improvement in general psychiatric symptoms and social functioning. The findings support the clinical and integrated staffing models achieving at least equivalent outcomes for community-based residential rehabilitation services consumers.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Diagnosis of venous thromboembolism in pregnancy: a review of current guidelines.

Venous thromboembolic disease (VTE) is the leading cause of maternal death throughout the developed world. International and national guidance for the diagnosis and management of VTE in pregnancy is varied and limited, which can result in problems in clinical practice. The imaging challenges of VTE in the general population are challenging but become more complex in pregnancy due to the physiological changes in the circulatory system, which alter clinical judgment and test performance. As an additional factor, the relative radiation risks to the mother and fetus arising from diagnostic tests need to be assessed and communicated to the patient in a clear and understandable way. The purpose of this review is fourfold. We propose to review and summarise the current imaging guidelines available for this condition; critically review the evidence base within the current literature; address the issues of test performance of imaging examinations used for VTE in pregnancy; and address the question of radiation risk and how to communicate this information to patients.

Findings and lessons learnt implementing a cardiovascular disease quality improvement program in Australian primary care: a mixed method evaluation.

BACKGROUND: There are discrepancies between evidence-based guidelines for screening and management of cardiovascular disease (CVD) and implementation in Australian general practice. Quality-improvement (QI) initiatives aim to reduce these gaps. This study evaluated a QI program (QPulse) that focussed on CVD assessment and management. METHODS: This mixed-methods study explored the implementation of guidelines and adoption of a QI program with a CVD risk-reduction intervention in 34 general practices. CVD screening and management were measured pre- and post-intervention. Qualitative analyses examined participants' Plan-Do-Study-Act (PDSA) goals and in-depth interviews with practice stakeholders focussed on barriers and enablers to the program and were analysed thematically using Normalisation Process Theory (NPT). RESULTS: Pre- and post-intervention data were available from 15 practices (n = 19,562 and n = 20,249, respectively) and in-depth interviews from seven practices. At baseline, 45.0% of patients had their BMI measured and 15.6% had their waist circumference recorded in the past 2 years and blood pressure, lipids and smoking status were measured in 72.5, 61.5 and 65.3% of patients, respectively. Most high-risk patients (57.5%) were not prescribed risk-reducing medications. After the intervention there were no changes in the documentation and prevalence of risk factors, attainment of BP and lipid targets or prescription of CVD risk-reducing medications. However, there was variation in performance across practices with some showing isolated improvements, such as recording waist circumference (0.7-32.2% pre-intervention to 18.5-69.8% post-intervention), BMI and smoking assessment. Challenges to the program included: lack of time, need for technical support, a perceived lack of value for quality improvement work, difficulty disseminating knowledge across the practice team, tensions between the team and clinical staff and a part-time workforce. CONCLUSION: The barriers associated with this QI program was considerable in Australian GP practices. Findings highlighted they were not able to effectively operationalise the intervention due to numerous factors, ranging from lack of internal capacity and leadership to competing demands and insufficient external support. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Reference Number ( ACTRN12615000108516 ), registered 06/02/2015.

Kidney function testing prior to contrast-enhanced CT: a comparative cost analysis of a personalised risk-stratified pathway versus a test all approach.

AIM: To map current contrast-enhanced computed tomography (CT) pathways, develop a risk-stratified pathway, and model associated costs and resource use. MATERIALS AND METHODS: Phase 1 comprised multicentre mapping of current practice and development of an alternative pathway, replacing pre-assessment of estimated glomerular filtration rate (eGFR) with a scan-day screening questionnaire for risk stratification and point of care (PoC) creatinine. Phase 2 measured resource use and analysis of routinely collected data, used to populate a model comparing the costs of current and risk-stratified pathways in Phase 3. RESULTS: Site variation across a range of processes within the clinical care pathway was identified. Data from a single centre suggested that 78% (n=347/447) could have avoided their pre-scan laboratory test as they did not have post-contrast acute kidney injury (AKI) risk factors. Only 24% of outpatients who underwent computed tomography (CT) would have identified risk factors, which would have prompted a scan-day PoC test. There was a 94% probability that the risk-stratified pathway was cost-saving, with an estimated 5-year potential cost saving of £69,620 (95% CI: -£13,295-£154,603). Although the cost of a laboratory serum creatinine test is cheaper than the PoC equivalent (£5.29 versus £5.96), the screening questionnaire ruled out the need for a large majority of the eGFR measurements specifically for the CT examination. CONCLUSION: The present study proposes an alternative pathway, which has the potential to improve the efficiency of the current CT pathway. A multicentre appraisal is required to demonstrate the impact of embedding this new pathway on a wider NHS level, particularly in light of new diagnostic guidance (DG37) published by NICE.

Metabolic health measurements of shift workers in a national cross-sectional study: Results from the Canadian Health Measures Survey.

BACKGROUND: Shift work exposure may be a concern for a range of health effects, including metabolic health outcomes such as insulin resistance, high body weight, and abdominal obesity. METHODS: We analyzed shift work and indicators of metabolic health (overweight/obesity defined by body mass index, self-reported changes in body mass index (BMI) in previous 1 and 10 years, waist circumference, waist-to-hip ratio, and insulin resistance assessed by the homeostasis model assessment 2 (HOMA-2-IR)) in the cross-sectional Canadian Health Measures Survey (CHMS). We analyzed descriptive characteristics of shift workers (regular night, evening, and rotating shift) and used multivariable linear regression to examine the association between two definitions of shift work exposure and measures of metabolic health, adjusted for age, sex, daily energy expenditure, sleep, and poor dietary quality. RESULTS: 5470 anthropometry (2637 fasting) participants in CHMS Cycles 1 and 2 were included, of whom 16.5% worked regular evening, night, or rotating shifts. Shift workers were younger and slept longer hours than non-shift workers. Bivariate associations showed inverse relationships between shift work and BMI, waist circumference, waist-to-hip ratio, and HOMA-2-IR. In adjusted analyses, BMI was inversely related to shift work, and other metabolic health outcomes showed no significant associations. CONCLUSIONS: Healthy worker effects (including self-selection of exposure) could explain inverse relationships, particularly as the cross-sectional design only allowed assessment of current exposure. Key strengths include the population-based design and measurement of metabolic health indicators. Results underscore the importance of consideration of the health of shift workers following departure from the exposed population.

Age Differences in Work-Disability Duration Across Canada: Examining Variations by Follow-Up Time and Context.

Purpose This study aimed to understand age differences in wage-replacement duration by focusing on variations in the relationship across different periods of follow-up time. Methods We used administrative claims data provided by six workers' compensation systems in Canada. Included were time-loss claims for workers aged 15-80 years with a work-related injury/illness during the 2011 to 2015 period (N = 751,679 claims). Data were coded for comparability across cohorts. Survival analysis examined age-related differences in the hazard of transitioning off (versus remaining on) disability benefits, allowing for relaxed proportionality constraints on the hazard rates over time. Differences were examined on the absolute (hazard difference) and relative (hazard ratios [HR]) scales. Results Older age groups had a lower likelihood of transitioning off wage-replacement benefits compared to younger age groups in the overall models (e.g., 55-64 vs. 15-24 years: HR 0.62). However, absolute and relative differences in age-specific hazard rates varied as a function of follow-up time. The greatest age-related differences were observed at earlier event times and were attenuated towards a null difference across later follow-up event times. Conclusions Our study provides new insight into the workplace injury/illness claim and recovery processes and suggests that older age is not always strongly associated with worse disability duration outcomes. The use of data from multiple jurisdictions lends external validity to our findings and demonstrates the utility of using cross-jurisdictional data extracts. Future work should examine the social and contextual determinants that operate during various recovery phases, and how these factors interact with age.

Bimodal Release Ondansetron Improves Stool Consistency and Symptomatology in Diarrhea-Predominant Irritable Bowel Syndrome: A Randomized, Double-Blind, Trial.

INTRODUCTION: Previous, small studies have suggested that ondansetron has beneficial effects in diarrhea-predominant irritable bowel syndrome (IBS-D). This randomized, double-blind study evaluated the efficacy and safety of daily 12 mg RHB-102, an investigational bimodal release ondansetron tablet, in IBS-D. METHODS: Men and women with IBS-D by the Rome III criteria, Bristol Stool Scale ≥6 on 2 or more days weekly, and average daily worst pain intensity ≥3/10 were randomized 60:40 to RHB-102 or placebo once daily for 8 weeks. The primary end point was overall stool consistency response for at least 4 of 8 weeks. Secondary end points included overall worst abdominal pain and overall composite response, defined as response on both abdominal pain and stool consistency end points. RESULTS: Overall stool consistency response rates were 56.0% and 35.3% (RHB-102 vs placebo, P = 0.036) and similar among male and female patients. Overall pain response (50.7% vs 39.2%) and composite response rates (40.0% vs 25.5%) favored RHB-102, although these differences were not statistically significant. Stool consistency response rates were enhanced in patients with baseline C-reactive protein above the median (2.09 mg/L), 59.5%, vs 23.1% (P = 0.009). Overall rates of adverse events were similar, with a higher rate of constipation in RHB-102 patients (13.3% vs 3.9%) that resolved rapidly on withholding treatment. DISCUSSION: RHB-102 was effective and safe in the treatment of men and women with IBS-D. Baseline C-reactive protein seemed to be predictive of response.

Blocking substance P signaling reduces musculotendinous and dermal fibrosis and sensorimotor declines in a rat model of overuse injury.

Purpose/Aim: Substance P-NK-1R signaling has been implicated in fibrotic tendinopathies and myositis. Blocking this signaling with a neurokinin 1 receptor antagonist (NK1RA) has been proposed as a therapeutic target for their treatment.Materials and Methods: Using a rodent model of overuse injury, we pharmacologically blocked Substance P using a specific NK1RA with the hopes of reducing forelimb tendon, muscle and dermal fibrogenic changes and associated pain-related behaviors. Young adult rats learned to pull at high force levels across a 5-week period, before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated or treated in task weeks 2 and 3 with the NK1RA, i.p. Control rats received vehicle or NK1RA treatments.Results: Grip strength declined in untreated HRHF rats, and mechanical sensitivity and temperature aversion increased compared to controls; these changes were improved by NK1RA treatment (L-732,138). NK1RA treatment also reduced HRHF-induced thickening in flexor digitorum epitendons, and HRHF-induced increases of TGFbeta1, CCN2/CTGF, and collagen type 1 in flexor digitorum muscles. In the forepaw upper dermis, task-induced increases in collagen deposition were reduced by NK1RA treatment.Conclusions: Our findings indicate that Substance P plays a role in the development of fibrogenic responses and subsequent discomfort in forelimb tissues involved in performing a high demand repetitive forceful task.

Trends in participation rates in case-control studies of occupational risk factors 1991-2017.

OBJECTIVE: Declining participation has been observed in previous epidemiological studies, could occupational risk factor epidemiology be particularly vulnerable to this trend? The objective of this study was to assess trends of participation rates in occupational case-control studies. METHODS: Five prominent occupational and epidemiological journals were pre-selected and all articles published between 1991 and 2017 were screened for case-control studies of occupational risk factors for chronic disease outcomes. The primary independent variable was median year of data collection, while the primary outcome variable was reported participation rate. We conducted linear regression, adjusting for study characteristics that included study gender mix, location of recruitment, disease outcome, and data collection method. RESULTS: A total of 180 studies published in the five journals were included in the final analysis. The mean participation was higher for cases (78.9%) than for controls (71.5%). In linear regression, a significant trend of decreasing participation was observed for both cases with a percent change of -0.50 per year (95% CI -0.75 to -0.25) for cases and a percent change of -0.95 per year (95% CI -1.23 to -0.67) for controls. After adjustment for study gender mix, location, disease outcome, and data collection method, the trend remained statistically significant for both case and control groups. CONCLUSION: Declining participation rates in case-control studies of occupational risk factors may reflect an overall decline of participation in population-based samples. Lower participation rates introduce the potential for bias and may deter future population-based studies of occupational risk factors.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Recognition and Treatment of Adrenal Insufficiency Secondary to Abiraterone: A Case Report and Literature Review.

OBJECTIVE: Abiraterone is a relatively noncytotoxic drug approved by the US Food and Drug Administration in 2011 for the treatment of metastatic prostate cancer (MPC). As an inhibitor of 17α-hydroxylase and C17,20-lyase (CYP17), abiraterone blocks androgen synthesis and glucocorticoid production. Decreased cortisol levels result in an increased ACTH release, which can lead to increased mineralocorticoid levels. While coadministration of abiraterone and glucocorticoids has been effective in reducing an apparent mineralocorticoid excess, adequate replacement of physiologic glucocorticoids, especially in times of acute stress, remains less well-defined. METHODS: A literature search was conducted using the PubMed and Google Scholar databases for abiraterone and adrenal insufficiency. Publications were selected based on the quality of the data and clinical relevance. We reviewed the landmark trials leading to FDA approval and establishment of the standard glucocorticoid replacement dosing. RESULTS: We present 2 patients with MPC on abiraterone therapy. These 2 patients required modification of the glucocorticoid therapy because of adverse effects. CONCLUSIONS: We found that a standard dose of prednisone of 5 mg/day as recommended previously may be inadequate to achieve physiologic glucocorticoid replacement in some patients with prostate cancer while on abiraterone treatment and as a result adrenal insufficiency due to inadequate dosing might be more common than initially thought. Additionally 10 mg of prednisone daily may cause adverse effects in some patients. Thus clinicians should be aware of the potential for development of adrenal insufficiency or symptoms of glucocorticoid excess in these patients receiving prednisone so that appropriate modifications in glucocorticoid dosing can be instituted without any delay. Prednisone dosing may need to be individualized in each patient receiving abiraterone therapy.