deepAFT: A nonlinear accelerated failure time model with artificial neural network.

The Cox regression model or accelerated failure time regression models are often used for describing the relationship between survival outcomes and potential explanatory variables. These models assume the studied covariates are connected to the survival time or its distribution or their transformations through a function of a linear regression form. In this article, we propose nonparametric, nonlinear algorithms (deepAFT methods) based on deep artificial neural networks to model survival outcome data in the broad distribution family of accelerated failure time models. The proposed methods predict survival outcomes directly and tackle the problem of censoring via an imputation algorithm as well as re-weighting and transformation techniques based on the inverse probabilities of censoring. Through extensive simulation studies, we confirm that the proposed deepAFT methods achieve accurate predictions. They outperform the existing regression models in prediction accuracy, while being flexible and robust in modeling covariate effects of various nonlinear forms. Their prediction performance is comparable to other established deep learning methods such as deepSurv and random survival forest methods. Even though the direct output is the expected survival time, the proposed AFT methods also provide predictions for distributional functions such as the cumulative hazard and survival functions without additional learning efforts. For situations where the popular Cox regression model may not be appropriate, the deepAFT methods provide useful and effective alternatives, as shown in simulations, and demonstrated in applications to a lymphoma clinical trial study.

Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial.

BACKGROUND: Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease. METHODS: A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest. RESULTS: A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups. CONCLUSION: We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.

Urgent care-seeking and injury severity for intimate partner violence during COVID-19: a Canadian retrospective chart review.

BACKGROUND: Early reports raised alarms that intimate partner violence (IPV) increased during the COVID-19 pandemic, but initial studies showed that visits to emergency departments (EDs) decreased. This study assessed the impact of the prolonged pandemic and its associated restrictions on both rates of urgent care-seeking and injury severity for IPV. METHODS: Data from the Kingston Health Sciences Centre's (KHSC) ED were utilized to compare IPV presentations during 'Pre-COVID' (December 17, 2018 - March 16, 2020) and 'COVID' (March 17, 2020 - June 16, 2021), as well as three periods of heightened local restrictions: 'Lockdown-1' (March 17 - June 12, 2020), 'Lockdown-2' (December 26, 2020 - February 10, 2021) and 'Lockdown-3' (April 8 - June 2, 2021). The primary outcomes were incidence rate of IPV visits and injury severity, which was assessed using the Clinical Injury Extent Score (CIES) and Injury Severity Score (ISS). RESULTS: A total of 128 individuals were included. This sample had mean age of 34 years, was comprised of mostly women (97%), and represented a variety of intimate relationship types. Some individuals presented multiple times, resulting in a total of 139 acute IPV presentations. The frequency of IPV visits during COVID was similar to the Pre-COVID time period (67 vs. 72; p = 0.67). Incidence rate was 13% higher during COVID, though this difference was non-significant (6.66 vs. 5.90; p = 0.47). IPV visit frequency varied across lockdown periods (11 in Lockdown-1, 12 in Lockdown-2 and 6 in Lockdown-3), with the highest incidence rate during Lockdown-2 (12.71). There were more moderate and severe injuries during COVID compared to Pre-COVID, but mean CIES was not statistically significantly different (1.91 vs. 1.69; p = 0.29), nor was mean ISS (11.88 vs. 12.52; p = 0.73). CONCLUSIONS: During the 15-months following the start of COVID-19, there were small, but non-significant increases in both incidence rate and severity of IPV presentations to the KHSC ED. This may reflect escalation of violence as pandemic restrictions persisted and requires further investigation.

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED: The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Median sternotomy pain after cardiac surgery: To block, or not? A systematic review and meta-analysis.

BACKGROUND: Inadequate pain control after median sternotomy leads to reduced mobilization, increased respiratory complications, and longer hospital stays. Typically, postoperative pain is controlled by opioid analgesics that may have several adverse effects. Parasternal intercostal block (PSB) has emerged as part of a multimodal strategy to control pain after median sternotomy. However, the effectiveness of this intervention on postoperative pain control and analgesic use has not been fully established. METHODS AND RESULTS: We conducted a meta-analysis to assess the effect of PSB on postoperative pain and analgesic use in adult cardiac surgery patients undergoing median sternotomy. PubMed, Embase, Google Scholar, and the Cochrane database were searched with the following search strategy: ([postoperative pain] or [pain relief] OR [analgesics] or [analgesia] or [nerve block] or [regional block] or [local block] or [regional anesthesia] or [local anesthetic] or [parasternal block] and [sternotomy]) and (humans [filter]). Inclusion criteria were: patients who underwent cardiac surgery via median sternotomy, age >18 and parasternal block (continuous and single dose). Exclusion criteria were: noncardiac surgery, nonparasternal nerve blocks, and the use of NSAIDS in parasternal block. Quality assessment was performed by three independent reviewers via the Cochrane risk of bias assessment tool. Of 1165 total citations, 18 were found to be relevant. Of these 18 citations, 7 citations (N = 2223 patients) reported postoperative pain scores in an extractable format and 11 citations (N = 2155 patients) reported postoperative opioid use in an extractable format. For postoperative opioid use, morphine equivalent doses were calculated for all studies and postoperative pain scores were standardized to a 10-point visual analog scale for comparison between studies; both these were reported as total opioid use or cumulative score ranging from 24 to 72 h postoperative. All data analyses were run using a random effects model, using a restricted maximum likelihood estimator, to obtain summary standardized mean differences with 95% confidence interval (CI's). For studies which only reported median and interquatile range (IQR), the median was standard deviation was estimated by IQR/1.35. Following median sternotomy both postoperative pain (SMD [95% CI] -0.49 [-0.92 to -0.06]) and postoperative morphine equivalent use (SMD [95% CI] -1.68 [-3.11 to -0.25]) were significantly less in the PSB group. CONCLUSION: Our meta-analysis suggests that parasternal nerve block significantly reduces postoperative pain and opioid use.

Simultaneous glomerular filtration rate determination using inulin, iohexol, and 99mTc-DTPA demonstrates the need for customized measurement protocols.

Urinary inulin clearance is considered the gold standard of glomerular filtration rate (GFR) measurement but plasma clearance of less expensive and more accessible tracers is more commonly performed. Many plasma sampling protocols exist but little is known about their accuracy. Here, the study objectives were to compare plasma iohexol and 99mTc-DTPA GFR with varying sampling strategies to the GFR measured by urinary inulin and to identify protocols with the greatest accuracy according to clinical characteristics. GFR was measured simultaneously using urinary inulin, plasma iohexol, and plasma 99mTc DTPA clearance. Blood was sampled from 2 to 10 hours after injection. For each method, bias, precision, and accuracy (P30 and mean absolute error) were calculated for the entire cohort and for eGFR-EPI creatinine subgroups (<30, 30-59, and ≥60 ml/min/1.73m2) and the edema stage using urinary inulin clearance as the gold standard. The mean inulin GFR of the 77 participants was 33 ml/min/1.73m2. Delay of both the initial and the final samples in plasma iohexol protocols yielded the highest accuracy in the setting of low GFR (<30 ml/min/1.73m2). Early initial and final samples yielded the highest accuracy in the setting of high GFRs (≥60 ml/min/1.73m2). No sampling strategy was accurate in edematous patients. Thus, our study demonstrates that customization of GFR protocols according to the anticipated level of GFR are required to optimize protocol accuracy.

Overview and Diagnostic Accuracy of Near Infrared Spectroscopy in Carotid Endarterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: Carotid endarterectomy is recommended for the prevention of ischaemic stroke due to carotid stenosis. However, the risk of stroke after carotid endarterectomy has been estimated at 2% - 5%. Monitoring intra-operative cerebral oxygenation with near infrared spectroscopy (NIRS) has been assessed as a strategy to reduce intra- and post-operative complications. The aim was to summarise the diagnostic accuracy of NIRS to detect intra-operative ischaemic events, the values associated with ischaemic events, and the relative contribution of external carotid contamination to the NIRS signal in adults undergoing carotid endarterectomy. DATA SOURCES: EMBASE, MEDLINE, Cochrane Centre Register of Controlled Trials, and reference lists through May 2019 were searched. REVIEW METHODS: Non-randomised and randomised studies assessing NIRS as an intra-operative monitoring tool in carotid endarterectomy were included. Studies using NIRS as the reference were excluded. Risk of bias was assessed using the Newcastle Ottawa Scale, RoB-2, and QUADAS-2. RESULTS: Seventy-six studies were included (n = 8 480), under local (n = 1 864) or general (n = 6 582) anaesthesia. Seven studies were eligible for meta-analysis (n = 524). As a tool for identifying intra-operative ischaemia, specificity increased with more stringent NIRS thresholds, while there was unpredictable variation in sensitivity across studies. A Δ20% threshold under local anaesthesia resulted in pooled estimates for sensitivity and specificity of 70.5% (95% confidence interval, CI, 54.1 - 82.9) and 92.4% (95% CI 85.5 - 96.1) compared with awake neurological monitoring. These studies had low or unclear risk of bias. NIRS signal consistently dropped across clamping and recovered to pre-clamp values upon de-clamp in most studies, and larger decreases were observed in patients with ischaemic events. The contribution of extracranial signal to change in signal across clamp varied from 3% to 50%. CONCLUSION: NIRS has low sensitivity and high specificity to identify intra-operative ischaemia compared with awake monitoring. Extracranial signal contribution was highly variable. Ultimately, data from high quality studies are desperately needed to determine the utility of NIRS.

Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels.

BACKGROUND: The Wnt/ß-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/ß-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). METHODS: GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. RESULTS: The median [IQR] age was 64 years [53.0-71.0], and the median [IQR] mGFR was 32.6 [21.7-60.6] mL/min. DKK1 decreased (r = 0.6, p < 0.001) and sclerostin increased (r = -0.4, p < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D3 in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. CONCLUSION: The results of this study demonstrate opposing trends in Wnt/ß-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

Accuracy of Shorter Iohexol Glomerular Filtration Rate Measurement Protocols in Individuals with Preserved Kidney Function.

BACKGROUND: Measuring glomerular filtration rate (mGFR) using exogenous tracers is recommended in a number of settings. Plasma one-compartment multi-sample protocols (MSP) are the most commonly used with iohexol being the dominant tracer. The accuracy of MSP protocols has mostly been evaluated in the setting of reduced GFR where delayed initial and final samples are recommended. Much less is known about MSPs when GFR is not decreased, and the default protocol tends to include initial sampling at 120 minutes (min) and final sampling at 240 min post iohexol injection. The recent KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease includes research recommendations for the development of shorter more efficient mGFR protocols. The objective of this study was to assess the performance of shorter MSPs with earlier initial (60 and 90 min) and final (150, 180, and 210 min) sampling times in individuals with preserved GFR. Reference mGFR was calculated using 5 samples collected between 120-240 min. METHODS: Four different combinations of shorter sampling strategies were investigated. Performance was evaluated using measurements of bias, precision, and accuracy (P2, P5, and mean absolute error). RESULTS: The mean reference mGFR of the 43 participants was 102.3 ± 13.7 ml/min/1.73m2. All shorter mGFRs had biases less than 1 ml/min/1.73m2 and mean absolute error less than 1.6 ml/min/1.73m2. All shorter mGFRs were within 5% of the reference mGFR, and the majority were within 2%. CONCLUSIONS: These results demonstrate that shortening the mGFR procedure in individuals with preserved GFR provides similar results to the current standard while significantly decreasing procedure time.

Serum total testosterone is associated with phosphate and calcium excretion in response to oral phosphate loading in healthy middle-aged males.

Androgen receptors are expressed in the kidney and serum testosterone is negatively associated with serum phosphate in males, suggesting a role of testosterone in renal phosphate handling. In this cross-sectional study, we examined the association of serum total and free testosterone with acute phosphate and calcium excretion in males in response to an oral phosphate challenge. Thirty-five healthy adult males with normal baseline testosterone levels consumed a 500 mg phosphorus drink and the urinary excretion of minerals, as well as levels of relevant circulating parameters, were assessed at baseline and hourly for 4 h. Serum total testosterone was positively associated with overall phosphate excretion (r = 0.35, p = 0.04) and calcium excretion (r = 0.44, p = 0.00) in response to the challenge. Serum free testosterone was positively associated with post-challenge calcium excretion (r = 0.34, p = 0.048), but significance was not reached for phosphate excretion (r = 0.31, p = 0.07). Serum total and free testosterone were not associated with parathyroid hormone, fibroblast growth factor-23, or vitamin D-key factors implicated in phosphate and calcium regulation. Overall, higher serum total testosterone levels in healthy middle-aged males are associated with a greater capacity to acutely excrete phosphate and calcium after a single oral phosphate challenge, suggesting potential ramifications of testosterone deficiency related to mineral homeostasis.

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study.

OBJECTIVES: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Multicenter ICU study. PATIENTS: Adults requiring invasive mechanical ventilation secondary to COVID-19. INTERVENTION: Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao2/Fio2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events. CONCLUSIONS: In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao2/Fio2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

HEART + score: integrating carotid ultrasound to chest pain assessment in the emergency department.

OBJECTIVES: The HEART score is a clinical decision tool that stratifies patients into categories of low, moderate, and high-risk of major adverse cardiac events in the emergency department (ED) but cannot identify underlying cardiovascular disease in patients without prior history. The presence of atherosclerosis can easily be detected at the bedside using carotid ultrasound. Plaque quantification is well established, and plaque composition can be assessed using ultrasound grayscale pixel distribution analysis. This study aimed to determine whether carotid plaque burden and/or composition correlated with risk of events and could improve the sensitivity of the HEART score in risk stratifying ED patients with chest pain. METHODS: The HEART score was calculated based on history, electrocardiogram, age, risk factors, and initial troponin in patients presenting to the ED with chest pain (n = 321). Focused carotid ultrasound was performed, and maximum plaque height and total plaque area were used to determine plaque burden (quantity). Plaque composition (% blood, fat, muscle, fibrous, calcium-like tissue) was assessed by pixel distribution analysis. RESULTS: Carotid plaque height and area increased with HEART score (p < 0.0001). Carotid plaque % fibrous and % calcium also increased with HEART score. The HEART score had a higher area under the curve (AUC = 0.84) in predicting 30-day events compared to the plaque variables alone (AUCs < 0.70). Integrating plaque quantity into the HEART score slightly increased test sensitivity (62-69%) for 30-day events and reclassified 11 moderate-risk participants to high-risk (score 7-10). CONCLUSION: Plaque burden with advanced composition features (fibrous and calcium) was associated with increased HEART score. Integrating plaque assessment into the HEART score identified subclinical atherosclerosis in moderate-risk patients.

RéSUMé: OBJECTIFS: Le score HEART est un outil de décision clinique qui stratifie les patients en catégories de risque faible, modéré et élevé d'événements cardiaques indésirables majeurs à l'urgence (ED), mais ne peut pas identifier les maladies cardiovasculaires sous-jacentes chez les patients sans antécédents. La présence d'athérosclérose peut facilement être détectée au chevet du patient à l'aide de l'échographie carotide. La quantification de la plaque est bien établie et la composition de la plaque peut être évaluée à l'aide d'une analyse échographique de la distribution des pixels en niveaux de gris. Cette étude visait à déterminer si la charge et/ou la composition de la plaque carotidienne étaient corrélées avec le risque d'événements et pouvaient améliorer la sensibilité du score HEART chez les patients souffrant de douleurs thoraciques stratifiés. MéTHODES: Le score HEART a été calculé sur la base des antécédents, de l'électrocardiogramme, de l'âge, des facteurs de risque et de la troponine initiale chez les patients présentant une douleur thoracique à l'urgence (n = 321). L'échographie carotidienne focalisée a été effectuée, et la hauteur maximale de la plaque et la surface totale de la plaque ont été utilisées pour déterminer la charge de plaque (quantité). La composition de la plaque (% de sang, de graisse, de muscle, de tissu fibreux, de type calcique) a été évaluée par analyse de la distribution des pixels. RéSULTATS: La hauteur et la surface de la plaque carotide ont augmenté avec le score HEART (p<0,0001). Le pourcentage de plaque carotide fibreuse et le pourcentage de calcium ont également augmenté avec le score HEART. Le score HEART avait une zone plus élevée sous la courbe (ASC = 0,84) pour prédire les événements de 30 jours par rapport aux seules variables de la plaque (CCU < 0,70). L'intégration de la quantité de plaque dans le score HEART a légèrement augmenté la sensibilité au test (62 % à 69 %) pour les événements de 30 jours et a reclassé 11 participants à risque modéré à risque élevé (score de 7 à 10). CONCLUSION: La charge de plaque avec des caractéristiques de composition avancées (fibreuse et calcique) était associée à une augmentation du score HEART. Intégrer l'évaluation de la plaque dans le score HEART a identifié l'athérosclérose subclinique chez les patients à risque modéré.

Ceragenin-coated endotracheal tubes for the reduction of ventilator-associated pneumonia: a prospective, longitudinal, cross-over, interrupted time, implementation study protocol (CEASE VAP study).

BACKGROUND: Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes. METHODS: In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay. ETHICS AND DISSEMINATION: This study has been approved by the Health Sciences Research Ethics Board at Queen's University. The results of this study will be actively disseminated through manuscript publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT05761613.

Frailty, Outcomes, Recovery and Care Steps of Critically Ill Patients (FORECAST): a prospective, multi-centre, cohort study.

PURPOSE: Frailty is common in critically ill patients but the timing and optimal method of frailty ascertainment, trajectory and relationship with care processes remain uncertain. We sought to elucidate the trajectory and care processes of frailty in critically ill patients as measured by the Clinical Frailty Scale (CFS) and Frailty Index (FI). METHODS: This is a multi-centre prospective cohort study enrolling patients ≥ 50 years old receiving life support > 24 h. Frailty severity was assessed with a CFS, and a FI based on the elements of a comprehensive geriatric assessment (CGA) at intensive care unit (ICU) admission, hospital discharge and 6 months. For the primary outcome of frailty prevalence, it was a priori dichotomously defined as a CFS ≥ 5 or FI ≥ 0.2. Processes of care, adverse events were collected during ICU and ward stays while outcomes were determined for ICU, hospital, and 6 months. RESULTS: In 687 patients, whose age (mean ± standard deviation) was 68.8 ± 9.2 years, frailty prevalence was higher when measured with the FI (CFS, FI %): ICU admission (29.8, 44.8), hospital discharge (54.6, 67.9), 6 months (34.1, 42.6). Compared to ICU admission, aggregate frailty severity increased to hospital discharge but improved by 6 months; individually, CFS and FI were higher in 45.3% and 50.6% patients, respectively at 6 months. Compared to hospital discharge, 18.7% (CFS) and 20% (FI) were higher at 6 months. Mortality was higher in frail patients. Processes of care and adverse events were similar except for worse ICU/ward mobility and more frequent delirium in frail patients. CONCLUSIONS: Frailty severity was dynamic, can be measured during recovery from critical illness using the CFS and FI which were both associated with worse outcomes. Although the CFS is a global measure, a CGA FI based may have advantages of being able to measure frailty levels, identify deficits, and potential targets for intervention.

Relationship Between Macular Thickness and Visual Acuity in the Treatment of Diabetic Macular Edema With Anti-VEGF Therapy: Systematic Review.

Purpose: To examine the relationship between central macular thickness (CMT) measured by optical coherence tomography (OCT) and visual acuity (VA) in patients with center-involving diabetic macular edema (DME) receiving antivascular endothelial growth factor (anti-VEGF) treatment. Methods: Peer-reviewed articles from 2016 to 2020 reporting intravitreal injections of bevacizumab, ranibizumab, or aflibercept that provided data on pretreatment (baseline) and final retinal thickness (CMT) and visual acuity (VA) were identified. The relationship between relative changes was assessed via a linear random-effects regression model controlling for treatment group. Results: No significant association between the logarithm of the minimum angle of resolution (logMAR) VA and CMT was found in 41 eligible studies evaluating 2667 eyes. The observed effect estimate was a 0.12 increase (95% CI, -0.124 to 2.47) in logMAR VA per 100 µm reduction in CMT after treatment change. There were no significant differences in logMAR VA between the anti-VEGF treatment groups. Conclusions: There was no statistically significant relationship between the change in logMAR VA and change in CMT as well as no significant effect of the type of anti-VEGF treatment on the change in logMAR VA. Although OCT analysis, including measurements of CMT, will continue to be an integral part of the management of DME, further exploration is needed on additional anatomic factors that might contribute to visual outcomes.

Neurological Impairment in Critically Ill Patients on Dialysis: Research Letter for the INCOGNITO-AKI Feasibility Study.

Background: Acute kidney injury (AKI) resulting in kidney replacement therapy is rising among critically ill adults. Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation (rSO2) may be a contributing factor. Objective: To assess the feasibility of testing the association between intradialytic rSO2 and acute and long-term neurological outcomes. Design: Longitudinal observational study. Setting and Participants: We enrolled patients initiating continuous kidney replacement therapy or intermittent hemodialysis in the Kingston Health Sciences Centre (KHSC) Intensive Care Unit (ICU). Measurements and Methods: rSO2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging. Results: Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSO2/vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors. Limitations: Enrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes. Conclusion: rSO2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up.

Contexte: L'insuffisance rénale aiguë (IRA) menant à une thérapie de remplacement rénal est en augmentation chez les adultes aux soins intensifs. Un séjour aux soins intensifs et la thérapie de remplacement rénal à long terme sont indépendamment liés à des déficits cognitifs aigus et prolongés ainsi qu'à des pathologies structurelles du cerveau. La faible saturation régionale du cerveau en oxygène (rSO2) pourrait être un facteur contributif. Objectif: Évaluer la possibilité de tester l'association entre la rSO2 intradialytique et les résultats neurologiques aigus et chroniques. Type d'étude: Étude observationnelle longitudinale. Cadre et sujets de l'étude: Nous avons recruté des patients qui entamaient une thérapie de remplacement rénal en continu ou une hémodialyse intermittente à l'unité des soins intensifs (USI) du Kingston Health Sciences Centre (KHSC). Mesures et méthodologie: La rSO2 a été surveillée pendant les 72 premières heures de thérapie de remplacement rénal en continu, ou tout au long de chaque séance d'hémodialyse intermittente. Nous avons mesuré les déficits neurologiques aigus par un dépistage quotidien du délirium et les atteintes neurocognitives à long terme à l'aide du robot Kinarm, de la Repeatable Battery for the Assessment of Neuropsychological Status et de l'imagerie par résonance magnétique cérébrale. Résultats: Sur les 484 patients hospitalisés à l'USI, 26 répondaient aux critères de sélection. Deux ont refusé de participer à l'étude et treize satisfaisaient à au moins un critère d'exclusion. Onze patients ont été inclus à l'étude. Huit patients sont décédés à l'USI, un est décédé deux mois après sa sortie de l'hôpital et un a refusé le suivi. Les taux de saisie des données étaient élevés: rSO2 et paramètres vitaux (91,3 %), dépistage du délirium et démographie (100 %). Des tests longitudinaux ont été effectués chez 50 % (1 de 2) des survivants. Limites: Le taux d'inscription était faible en raison de divers facteurs, ce qui a limité notre capacité à évaluer les résultats à long terme. Conclusion: Il est possible de collecter des données sur la rSO2 et le délirium chez les patients de soins intensifs qui suivent une thérapie de remplacement rénal; un taux de mortalité élevé a limité le suivi. Trial Registration: clinicaltrials.gov, registration number NCT04722939.

The 1,24,25(OH)3D3 metabolite in clinical and experimental CKD: Impact of calcitriol treatment.

Calcitriol, and other vitamin D receptor activators, remain a primary treatment for elevated parathyroid hormone levels in patients with end stage kidney disease. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D3 and 1,25(OH)2D3 in rats with experimental kidney disease treated with calcitriol and in a cross-sectional analysis of patients requiring hemodialysis. Methods: Animals were stratified by creatinine into a time control group or calcitriol (20 ng/kg/day) for 3 weeks following CKD induction using a dietary adenine model (0.25% adenine). Hemodialysis patients were recruited and demographic data including calcitriol prescription was obtained by chart review and participant interview. Vitamin D metabolites were assessed using LC-MS/MS. In the rat model, 1,25(OH)2D3 levels increased substantially in calcitriol-treated rats yet there was no increase in its primary metabolite: 1,24,25(OH)2D3. A lower ratio of 1,24,25(OH)2D3:1,25(OH)2D3 (1,25-VMR) was associated with increased calcium levels in calcitriol treated rats. In hemodialysis patients (N = 86), the level of 1,25(OH)2D3 was substantially higher in calcitriol-treated patients yet there was no difference between groups in 1,24,25(OH)3D3, resulting in a marked decrease in the 1,25-VMR in calcitriol treated patients. In hemodialysis patients treated with calcitriol, 1,25(OH)2D3 and a lower ratio between 1,24,25(OH)3D3 and 1,25(OH)2D3 were associated with higher serum calcium levels. Impaired metabolism of exogenous calcitriol may contribute to the adverse effects associated with this treatment. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies.

Sex Differences in Phosphate Homeostasis: Females Excrete More Phosphate and Calcium After an Oral Phosphate Challenge.

CONTEXT: Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. OBJECTIVE: To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. DESIGN: Cross-sectional. SETTING: General community. PARTICIPANTS: 78 participants (40-76 years) with measured glomerular filtration rate >60 mL/min/1.73 m2 and no clinically diagnosed CVD and 14 young healthy adults. MAIN OUTCOME MEASURES: To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. RESULTS: Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. CONCLUSIONS: Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.

Focused carotid ultrasound to predict major adverse cardiac events among emergency department patients with chest pain.

BACKGROUND AND OBJECTIVE: Point-of-care focused vascular ultrasound (FOVUS), an assessment of carotid artery plaque, predicts coronary artery disease in outpatients referred for coronary angiography. Our primary objective was to determine the diagnostic accuracy of sonographer-performed FOVUS to predict major adverse cardiac events (MACE) within 30 days among patients with suspected cardiac ischemia in the emergency department (ED). METHODS: We conducted a prospective cohort study of patients with chest pain presenting to a tertiary care ED who had an electrocardiogram and cardiac troponin testing. The primary outcome was a composite of death, acute myocardial infarction, or re-vascularization at 30 days. A sonographer performed FOVUS scans in consenting eligible subjects. Emergency physicians, blinded to the sonographer FOVUS result, performed a second FOVUS on some subjects. RESULTS: We recruited 326 subjects (age 62.1 ± 13.5 years; 166 (52%) men), 319 of whom completed an FOVUS scan by the sonographer. Of these, 198 (62%) had a positive FOVUS scan and 41 (13%) had a 30-day MACE. The sensitivity was 83% (95% CI 71-94%), specificity 41% (95% CI 36-47%), positive-likelihood ratio 1.41 (95% CI 1.19-1.68), and negative-likelihood ratio 0.41 (95% CI 0.23-0.75). Among 71 subjects also scanned by an emergency physician, the Kappa was 0.50 (95% CI 0.31-0.70), suggesting moderate agreement between sonographer and emergency physician on the determination of significant carotid plaque. CONCLUSIONS: The presence of carotid plaque on sonographer-performed FOVUS is associated with 30-day MACE in ED patients presenting with chest pain. The prognostic performance of FOVUS is not sufficient to support its use as a stand-alone risk stratification tool in the ED. Future work should investigate FOVUS in conjunction with validated clinical decision rules for chest pain and the impact of enhanced training and quality improvement in the conduct of FOVUS by emergency physicians. REGISTRATION: This study was registered at clinicaltrials.gov (NCT02947360).

RéSUMé: CONTEXTE ET OBJECTIF: L'échographie vasculaire focalisée au point de service (FOVUS), une évaluation de la plaque de l'artère carotide, prédit la maladie coronarienne chez les patients externes référés pour une coronarographie. Notre objectif principal était de déterminer la précision diagnostique du FOVUS réalisé par un échographiste pour prédire les événements cardiaques indésirables majeurs (MACE) dans les 30 jours chez les patients présentant une suspicion d'ischémie cardiaque aux urgences. MéTHODES: Nous avons mené une étude de cohorte prospective de patients souffrant de douleurs thoraciques se présentant à un service d'urgence de soins tertiaires et ayant subi un électrocardiogramme et un test de troponine cardiaque. L'issue primaire était un critère composite de décès, d'infarctus aigu du myocarde ou de revascularisation à 30 jours. Un échographiste a effectué des scans FOVUS chez les sujets éligibles consentants. Les médecins urgentistes, aveuglés par le résultat FOVUS de l'échographiste, ont effectué un deuxième FOVUS sur certains sujets. RéSULTATS: Nous avons recruté 326 sujets (âge 62,1 ± 13,5 ans; 166 (52%) hommes), dont 319 ont effectué un examen FOVUS par l'échographiste. Parmi ceux-ci, 198 (62%) avaient un scan FOVUS positif et 41 (13%) avaient un MACE de 30 jours. La sensibilité était de 83% (IC à 95% 71%-94%), la spécificité de 41% (IC à 95% 36%-47%), le rapport de vraisemblance positif de 1,41 (IC à 95% 1,19­1,68) et le rapport de vraisemblance négatif de 0,41 (IC à 95% 0,23­0,75). Parmi les 71 sujets également examinés par un médecin urgentiste, le Kappa était de 0,50 (IC à 95%: 0,31­0,70), ce qui suggère une concordance modérée entre l'échographiste et le médecin urgentiste pour la détermination de la plaque carotide significative. CONCLUSIONS: La présence d'une plaque carotidienne sur un FOVUS effectué par un échographiste est associée à la MACE à 30 jours chez les patients des urgences présentant des douleurs thoraciques. La performance pronostique du FOVUS n'est pas suffisante pour justifier son utilisation comme outil autonome de stratification du risque dans les urgences. Des travaux futurs devraient étudier le FOVUS en conjonction avec des règles de décision clinique validées pour la douleur thoracique et l'impact d'une formation renforcée et d'une amélioration de la qualité dans la conduite du FOVUS par les médecins urgentistes. ENREGISTREMENT: Cette étude a été enregistrée sur clinicaltrials.gov (NCT02947360).

Intergenerational transfer of occupational risks on family farms.

BACKGROUND: Cultures of safety in farm work settings are under the authority of a responsible owner-operator, who establishes rules, attitudes, and behaviors for farm work practices. This novel analysis provides new evidence to show that risks that can lead to injury and are commonly practiced on Canadian farms are indeed transferred between generations. METHODS: Baseline data were provided by representatives from eligible and consenting farms (n = 589) in the province of Saskatchewan, Canada, during the first quarter of 2013. Mailed questionnaires were sent to participating farms and completed by a single respondent. Questionnaires included scaled assessments of hazards and safety practices by farm operators, and young workers on each farm. Descriptive and multiple regression analyses were used to examine relationships between farm owner-operator risks and safety practices and those reported for the young workers. FINDINGS: Graphical descriptive analyses showed that as farm owner-operator risks increased, so did those reported for children and young workers. Similarly, as farm owner-operator safe work practices increased, young worker hazards decreased, albeit more modestly. The young worker hazard scale increased by 0.20 (95% CI: 0.10-0.30) points, and decreased by 0.08 (95% CI: -0.016 to -0.000) points for each one-point increase in the owner-operator hazard and safe work practices scales, respectively. CONCLUSIONS: Occupational health and safety risks and protections experienced on farms appear to be transferred between generations. This suggests the need to target farm owner-operators, the responsible authority on the farm, as a focus of primary prevention strategies aimed at injury risks to children and young workers.