Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Cytoreductive Surgery with Bidirectional Intraoperative Chemotherapy (BDIC) Using Intravenous Ifosfamide Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients with Peritoneal Sarcomatosis: A Retrospective Cohort Study.

BACKGROUND: Peritoneal sarcomatosis (PS) is a rare tumor with limited therapeutic options. Bidirectional intraoperative chemotherapy (BDIC) using intravenous ifosfamide and doxorubicin-based hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is an emerging treatment for peritoneal malignancies. PATIENTS AND METHODS: Patients with PS who underwent CRS/BDIC using intravenous ifosfamide and HIPEC from January 2017 to July 2021 were retrospectively analyzed. The last follow-up date was May 2022. RESULTS: A total of 29 patients were included. Overall survival (OS) rates at 6, 12, 24, and 48 months after CRS/BDIC were 93.1%, 89.2%, 81.4%, and 73.3%, respectively. As of May 2022, 6 patients (20.6%) had died, including four (13.8%) with a proven recurrent tumor and two with incomplete tumor resection [completeness of cytoreduction (CC)-2 or CC-3]. Of the 20 patients (68.9%) with CC-0 or CC-1, 7 had locoregional tumor recurrence without distant metastasis, whereas the other 13 were alive with no evidence of recurrent tumor in May 2022. Disease recurrence rates were 15% at 6 months and 35% at 12, 24, and 48 months after CRS/BDIC. Clavien-Dindo class ≥ IIIa complications developed in 9 patients (31.0%) with no deaths. Leukopenia occurred in 5 patients (17.2%) and thrombocytopenia in 12 patients (41.3%); these hematologic abnormalities resolved. A total of 9 (31.0%) patients developed nephrotoxicity; all recovered except one, who progressed to chronic kidney disease. CONCLUSIONS: CRS/BDIC using intravenous ifosfamide and doxorubicin-based HIPEC is a potentially effective treatment for PS and has an acceptable rate of complications.

A comparison of computational algorithms for the Bayesian analysis of clinical trials.

BACKGROUND: Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. METHODS: Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. RESULTS: The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. CONCLUSION: Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

Total hip arthroplasty for adult patients with hip arthritis in Jordan: clinical profiles and patient characteristics.

PURPOSE: Total Hip Arthroplasty (THA) is one of the most commonly performed orthopaedic surgeries, with hip arthritis being the main indication. This procedure is usually performed when other non-surgical methods fail to relieve patients' hip pain and improve their quality of life. However, limited information exists to identify and compare the demographics and clinical characteristics of patients undergoing this procedure in Jordan. This study aims to identify these demographic and clinical characteristics and compare the findings in terms of gender differences. METHODOLOGY: This is a retrospective study that analysed the hospital records of 650 patients undergoing THA in tertiary referral hospital in Jordan over a four-year period from January 2019 to December 2022. The collected data were classified into three categories: demographic characteristics, perioperative variables, and patients' related health profiles. IBM's Statistical Package for the Social Sciences (SPSS) version 23 software (IBM, USA) and descriptive analysis were used for data analysis. RESULTS: Two-thirds of the sample studied were female (63.4%). In terms of bleeding profiles, the mean intraoperative blood loss was 542 millilitres. The major indication for THA was degenerative hip arthritis (50.5%), followed by hip dysplasia (40.3%).. Comparing the findings of the two gender groups, females were more likely to have degenerative and dysplastic hip arthritis (221 and 157, p = 0.04 and p = 0.1, respectively) when compared to males. Although males were more likely to lose more blood during the surgery (557 ml vs. 533 ml, p = 0.33, females needed more blood transfusions both during (21 vs. 6 patients, p = 0.12) and after the surgery (57 vs. 16 patients, p = 0.006). Furthermore, females were more likely to have comorbidities such hypertension (293 vs. 179 patients, p = 0.20), and hypothyroidism (313 vs 187, p = 0.36), and diabetes (85 vs. 38 patients, p = 0.15), among many other health conditions. However, in the study sample, male smokers outnumbered female smokers (132 vs. 63). CONCLUSION: Gender highly impacted the immediate surgical outcomes of patients who underwent THA. Females were more likely to need blood transfusions both during and after the surgery and had lower post-operative haemoglobin readings. In addition, females had more comorbidities and degenerative hip osteoarthritis. We believe that raising awareness about comorbidity management, preoperative smoking cessation, and perioperative blood transfusion management can improve medical and surgical outcomes.

Developing a Quality Assurance Framework for Neuro-Ophthalmology Using a Multisite Data Registry.

BACKGROUND: Quality assurance (QA) in neuro-ophthalmology (NOPH) is often lacking. We aimed to assess the quality of referral assessment and time to consult for common neuro-ophthalmological conditions by implementing a quality-assurance registry, NODE (Neuro-ophthalmology Database), in a tertiary neuro-ophthalmology clinic. Australian standardized triage categories, namely, P1 (consult ≤30 days), P2 (consult ≤30-60 days), and P3 (consult ≤60-90 days), were developed and validated for neuro-ophthalmological conditions. METHODS: We collected data from NODE on 676 patients at the Alfred Hospital, Melbourne and developed a consensus on the assignation of NOPH conditions to triage categories using a modified Delphi approach. A panel of 7 experienced neuro-ophthalmologists scored conditions and assignation to triage categories. Consensus was considered when ≥75% of the panel strongly agreed or agreed. We analyzed the mean days from referral to triage and from triage to the initial consultation and compared that with the developed triage category standard. RESULTS: Most patients presenting to the service were female (64%). Common diagnoses were idiopathic intracranial hypertension (IIH) (19%), optic neuropathy (ON) (14%), nonspecific headaches (11%), cranial nerve defects (CND) (8%), and papilledema (7%). Consensus on triage category assignment was reached after 2 rounds of scoring from expert panel members. The mean time from referral to triage was performed in <5 days for all the common diagnosis at the NOPH clinic. The mean days (±SD) from P1 category triage to initial consult for IIH was 15 (±12) days, acute ON 16 (±14) days, CND was 20 (±15) days, and papilledema was 20 (±19) days. The mean days from P2 triage to initial consultant for nonspecific headaches was 22 (±20) days and for EOMD was 48 (±22) days. The mean time (days) from P3 triage to initial consultant for nonocular myasthenia gravis was 38 days (±29) days and for visual snow was 54 (±31) days. CONCLUSIONS: We have established a consensus agreement on triage categories for neuro-ophthalmological conditions, which can be further validated using a larger panel of experts. We established a NOPH registry that will serve as a framework to benchmark quality of care between NOPH services. Data from our NOPH registry demonstrated that most conditions are appropriately triaged and seen.

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial.

BACKGROUND: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. OBJECTIVE: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. DESIGN: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). SETTING: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. PARTICIPANTS: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. INTERVENTION: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. MEASUREMENTS: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. RESULTS: In the intention-to-treat analysis, RT-PCR-confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR-confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. LIMITATION: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. CONCLUSION: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR-confirmed COVID-19 for medical masks when compared with HRs of RT-PCR-confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

SARS-CoV-2 Exposure from Health Care Workers to Infants: Effects and Outcomes.

OBJECTIVE: This study aimed to evaluate the risk and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission from positive health care workers (HCW) to infants in the neonatal intensive care unit (NICU) and the postnatal ward. STUDY DESIGN: We conducted a retrospective analysis of infants in NICU and the postnatal ward postexposure to a COVID-19 positive HCW between May 1 and July 31, 2020. HCW had the detection of SARS-CoV-2 after being symptomatic. Infants exposed to these HCW were tested for SARS-CoV-2 and were classified as confirmed positive when test was positive 24 hours after exposure; confirmed negative when test was negative with no escalation of respiratory support provided; and probable if test was negative. However, infant required escalation of respiratory support. Infants were followed at 14 days postexposure then at the end of the study period for admitted infants. RESULTS: A total of 31 infants were exposed to SARS-CoV-2 positive HCWs (42 exposure incidences). The median age at exposure was 21 days. None of the infants was confirmed positive. Nine infants were classified as probable cases of whom five infants with underlying chronic illnesses died, two were discharged home, and two were still admitted. Of the 22 confirmed negative cases, 15 were discharged and were well on follow-up, and 7 were still admitted. CONCLUSION: No active transmission of infection from infected HCW to admitted infants was identified. Although some infants had respiratory escalation postexposure none were confirmed positive. Adhering to personal protective equipment by HCW or low susceptibility of infants to SARS-CoV-2 infection may explain the lack of transmission. KEY POINTS: · There are no reported cases of transmission of SARS-CoV-2 infection from infected HCW to infants admitted to the NICU in our study.. · Adherence to personnel protective equipment is important to prevent transmission of SARS-CoV-2. · When an infant is exposed to a HCW who is positive for SARS-CoV-2 and has escalation of respiratory support, SARS-CoV-2 as a cause should be investigated.

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.

Importance: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures: Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

Prognostic Factors Associated With Development of Venous Thromboembolism in Critically Ill Patients-A Systematic Review and Meta-Analysis.

OBJECTIVE: To identify prognostic factors for the development of venous thromboembolism in the ICU. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to March 1, 2021. STUDY SELECTION: We included English-language studies describing prognostic factors associated with the development of venous thromboembolism among critically ill patients. DATA EXTRACTION: Two authors performed data extraction and risk-of-bias assessment. We pooled adjusted odds ratios and adjusted hazard ratios for prognostic factors using random-effects model. We assessed risk of bias using the Quality in Prognosis Studies tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. DATA SYNTHESIS: We included 39 observational cohort studies involving 729,477 patients. Patient factors with high or moderate certainty of association with increased odds of venous thromboembolism include older age (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29 per 10 yr), obesity (adjusted odds ratio, 1.25; 95% CI, 1.18-1.32), active malignancy (adjusted odds ratio, 1.70; 95% CI, 1.18-2.44), history of venous thromboembolism (adjusted odds ratio, 4.77; 95% CI, 3.42-6.65), and history of recent surgery (adjusted odds ratio, 1.77; 95% CI, 1.26-2.47). ICU-specific factors with high or moderate certainty of association with increased risk of venous thromboembolism include sepsis (adjusted odds ratio, 1.41; 95% CI, 1.12-1.78), lack of pharmacologic venous thromboembolism prophylaxis (adjusted odds ratio, 1.80; 95% CI, 1.14-2.84), central venous catheter (adjusted odds ratio, 2.93; 95% CI, 1.98-4.34), invasive mechanical ventilation (adjusted odds ratio, 1.74; 95% CI, 1.36-2.24), and use of vasoactive medication (adjusted odds ratio, 1.86; 95% CI, 1.23-2.81). CONCLUSIONS: This meta-analysis provides quantitative summaries of the association between patient-specific and ICU-related prognostic factors and the risk of venous thromboembolism in the ICU. These findings provide the foundation for the development of a venous thromboembolism risk stratification tool for critically ill patients.

Type 2 Diabetes and all-cause mortality among Spanish women with breast cancer.

PURPOSE: To explore the effect of type 2 diabetes mellitus (T2DM) on the risk of death among women with breast cancer (BC). METHODS: A survival analysis was conducted among a cohort of women diagnosed with BC between 2006 and 2012 in Spain (n = 4,493). Biopsy or surgery confirmed BC cases were identified through the state population-based cancer registry with information on patients' characteristics and vital status. Physician-diagnosed T2DM was confirmed based on primary health care clinical history. Cox regression analyses were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for all-cause death. Analyses were adjusted for age, hospital size, several clinical characteristics (including BC stage and histology, among others) and treatment modalities. RESULTS: Among the 4,493 BC women, 388 (8.6%) had coexisting T2DM. Overall, 1,299 (28.9%) BC women died during the completion of the follow-up and 785 (17.5%) did so during the first five years after BC diagnosis, resulting in a five-year survival rate of 82.5%. The death rate was higher in women with T2DM (43.8% died during whole period and 26.0% during the first five years) when compared with women without T2DM (27.5% and 16.7%, respectively). Accordingly, all-cause mortality was higher in women with T2DM (aHR: 1.22; 95% CI 1.03-1.44), especially if T2DM was diagnosed before BC (aHR:1.24; 95% CI 1.03-1.50) and in women with BC diagnosed before 50 years (aHR: 2.38; 95% CI 1.04-5.48). CONCLUSIONS: T2DM was associated with higher all-cause mortality among Spanish women with BC, particularly when the T2DM diagnosis was prior to the BC.

Using rumination and activity data for early detection of anaplasmosis disease in dairy heifer calves.

Bovine anaplasmosis causes considerable economic losses in dairy cattle production systems worldwide, ranging from $300 million to $900 million annually. It is commonly detected through rectal temperature, blood smear microscopy, and packed cell volume (PCV). Such methodologies are laborious, costly, and difficult to systematically implement in large-scale operations. The objectives of this study were to evaluate (1) rumination and activity data collected by Hr-Tag sensors (SCR Engineers Ltd.) in heifer calves exposed to anaplasmosis; and (2) the predictive ability of recurrent neural networks in early identification of anaplasmosis. Additionally, we aimed to investigate the effect of time series length before disease diagnosis (5, 7, 10, or 12 consecutive days) on the predictive performance of recurrent neural networks, and how early anaplasmosis disease can be detected in dairy calves (5, 3, and 1 d in advance). Twenty-three heifer calves aged 119 ± 15 (mean ± SD) d and weighing 148 ± 20 kg of body weight were challenged with 2 × 107 erythrocytes infected with UFMG1 strain (GenBank no. EU676176) isolated from Anaplasma marginale. After inoculation, animals were monitored daily by assessing PCV. The lowest PCV value (14 ± 1.8%) and the finding of rickettsia on blood smears were used as a criterion to classify an animal as sick (d 0). Rumination and activity data were collected continuously and automatically at 2-h intervals, using SCR Heatime Hr-Tag collars. Two time series were built including last sequence of -5, -7, -10, or -12 d preceding d 0 or a sequence of 5, 7, 10, or 12 d randomly selected in a window from -50 to -15 d before d 0 to ensure a sequence of days in which PCV was considered normal (32 ± 2.4%). Long short-term memory was used as a predictive approach, and a leave-one-animal-out cross-validation (LOAOCV) was used to assess prediction quality. Anaplasmosis disease reduced 34 and 11% of rumination and activity, respectively. The accuracy, sensitivity, and specificity of long short-term memory in detecting anaplasmosis ranged from 87 to 98%, 83 to 100%, and 83 to 100%, respectively, using rumination data. For activity data, the accuracy, sensitivity, and specificity varied from 70 to 98%, 61 to 100%, and 74 to 100%, respectively. Predictive performance did not improve when combining rumination and activity. The use of longer time-series did not improve the performance of models to predict anaplasmosis. The accuracy and sensitivity in predicting anaplasmosis up to 3 d before clinical diagnosis (d 0) were greater than 80%, confirming the possibility for early identification of anaplasmosis disease. These findings indicate the great potential of wearable sensors in early identification of anaplasmosis diseases. This could positively affect the profitability of dairy farmers and animal welfare.

Impact of Anticoagulation on Mortality and Resource Utilization Among Critically Ill Patients With Major Bleeding.

OBJECTIVES: Patients with major bleeding are commonly admitted to the ICU. A growing number are on either oral or parenteral anticoagulation, but the impact of anticoagulation on patient outcomes is unknown. We sought to examine this association between anticoagulation therapy and mortality, as well as the independent effects of warfarin compared to direct oral anticoagulants. DESIGN: Analysis of a prospectively collected registry (2011-2017) of consecutive ICU patients admitted with major bleeding (as defined by International Society on Thrombosis and Haemostasis clinical criteria). SETTING: Two hospitals within a single tertiary care level hospital system. PATIENTS: We analyzed 1,598 patients identified with major bleeding, of which 245 (15.3%) had been using anticoagulation at the time of ICU admission. Of patients on anticoagulation, 149 were using warfarin, and 60 were using a direct oral anticoagulant. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome, in-hospital mortality, was analyzed using a multivariable logistic regression model. Patients with anticoagulation-associated major bleeding had higher in-hospital mortality (adjusted odds ratio, 1.49; 95% CI, 1.16-1.92). Among survivors, anticoagulation use was associated with longer median hospital length of stay, and higher mean costs. No differences in hospital mortality were seen between warfarin- and direct oral anticoagulant-associated major bleeding. Patients with warfarin-associated major bleeding had longer median length of stay (11 vs 6 d; p = 0.02), and higher total costs than patients with direct oral anticoagulant-associated major bleeding. CONCLUSIONS: Among ICU patients admitted with major bleeding, pre-admission anticoagulation use was associated with increased hospital mortality, prolonged length of stay, and higher costs among survivors. As compared to direct oral anticoagulants, patients with warfarin-associated major bleeding had increased length of stay and costs. These findings have important implications in the care of ICU patients with major bleeding.

Tele-Critical Care: An Update From the Society of Critical Care Medicine Tele-ICU Committee.

OBJECTIVES: In 2014, the Tele-ICU Committee of the Society of Critical Care Medicine published an article regarding the state of ICU telemedicine, one better defined today as tele-critical care. Given the rapid evolution in the field, the authors now provide an updated review. DATA SOURCES AND STUDY SELECTION: We searched PubMed and OVID for peer-reviewed literature published between 2010 and 2018 related to significant developments in tele-critical care, including its prevalence, function, activity, and technologies. Search terms included electronic ICU, tele-ICU, critical care telemedicine, and ICU telemedicine with appropriate descriptors relevant to each sub-section. Additionally, information from surveys done by the Society of Critical Care Medicine was included given the relevance to the discussion and was referenced accordingly. DATA EXTRACTION AND DATA SYNTHESIS: Tele-critical care continues to evolve in multiple domains, including organizational structure, technologies, expanded-use case scenarios, and novel applications. Insights have been gained in economic impact and human and organizational factors affecting tele-critical care delivery. Legislation and credentialing continue to significantly influence the pace of tele-critical care growth and adoption. CONCLUSIONS: Tele-critical care is an established mechanism to leverage critical care expertise to ICUs and beyond, but systematic research comparing different models, approaches, and technologies is still needed.

Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: A 2-year randomized evaluation study.

BACKGROUND: Use of topical glaucoma medications has been reported to cause ocular surface (OS) discomfort and inflammation. This study explores the profile of inflammatory cytokines and OS symptoms induced in response to preserved and non-preserved drops. METHODS: Prospective, randomized evaluation on 36 treatment-naïve patients over 24 months of three differently preserved glaucoma drop preparations: Preservative-free (PF), polyquad (PQ) and benzalkonium chloride (BAK). Study participants were evaluated at baseline and then at 1, 3, 6, 12 and 24 months while on medication. At each visit, participants completed the OS disease index (OSDI) questionnaire, had basal tear sampling and impression cytology (IC) of the conjunctival epithelium. Quantitative polymerase chain reaction was performed to measure the gene expression of inflammatory cytokines [interleukin (IL)-6, IL-8, IL-10, IL-12A, IL-12B, IL-17A, IL-1ß and tumour necrosis factor-α] in the IC samples. Corresponding protein expression of cytokines in tear samples was assessed by the Becton-Dickinson cytometric bead arrays. RESULTS: Compared to PF and PQ groups, mRNA and protein expression of IL-6, IL-8 and IL-1ß increased in samples from the BAK group in a time-dependent fashion, whereas all other cytokines showed a non-significant increase. In the BAK group, there was a strong correlation between OSDI and the levels of IC/IL-1ß (r = .832, R2 = .692 and P = .040); IC/IL-10 (r = .925, R2 = .856 and P = .008) and tear/IL-1ß (r = .899, R2 = .808 and P = .014). CONCLUSIONS: BAK-preserved topical drops stimulate a sterile inflammatory response on the OS within 3 months which is maintained thereafter, whereas PF-drops and PQ-preserved drops showed no significant OS inflammation.

Viability of Staphylococcus aureus and expression of its toxins (SEC and TSST-1) in cheeses using Lactobacillus rhamnosus D1 or Weissella paramesenteroides GIR16L4 or both as starter cultures.

Staphylococcus aureus is one of the main causative agents of food poisoning. This bacterium is an important component of cheese microbiota and plays an important role in foodborne diseases. Another important component of the microbiota is the lactic acid bacterium, which actively participates in processes that define the physicochemical, sensorial, and microbiological features of cheese. Of the various microbiological interactions in cheese, the interaction between lactic acid bacteria and Staph. aureus is most relevant. To this end, we evaluated the viability of Staph. aureus strains and the expression of their enterotoxins in cheeses produced experimentally, using Weissella paramesenteroides GIR16L4 or Lactobacillus rhamnosus D1 or both as starter cultures. Over 7 d, we observed that the presence of lactic acid bacteria did not impair Staph. aureus growth. However, via qPCR we observed a change in the gene expression of staphylococcal enterotoxins, suggesting that molecular communication exists between Staph. aureus strains and lactic acid bacteria in cheese.

Outcomes of hospitalized hematologic oncology patients receiving rapid response system activation for acute deterioration.

BACKGROUND: Patients with hematologic malignancies who are admitted to hospital are at increased risk of deterioration and death. Rapid response systems (RRSs) respond to hospitalized patients who clinically deteriorate. We sought to describe the characteristics and outcomes of hematologic oncology inpatients requiring rapid response system (RRS) activation, and to determine the prognostic accuracy of the SIRS and qSOFA criteria for in-hospital mortality of hematologic oncology patients with suspected infection. METHODS: We used registry data from two hospitals within The Ottawa Hospital network, between 2012 and 2016. Consecutive hematologic oncology inpatients who experienced activation of the RRS were included in the study. Data was gathered at the time of RRS activation and assessment. The primary outcome was in-hospital mortality. Logistical regression was used to evaluate for predictors of in-hospital mortality. RESULTS: We included 401 patients during the study period. In-hospital mortality for all included patients was 41.9% (168 patients), and 145 patients (45%) were admitted to ICU following RRS activation. Among patients with suspected infection at the time of RRS activation, Systemic Inflammatory Response Syndrome (SIRS) criteria had a sensitivity of 86.9% (95% CI 80.9-91.6) and a specificity of 38.2% (95% CI 31.9-44.8) for predicting in-hospital mortality, while Quick Sequential Organ Failure Assessment (qSOFA) criteria had a sensitivity of 61.9% (95% CI 54.1-69.3) and a specificity of 91.4% (95% CI 87.1-94.7). Factors associated with increased in-hospital mortality included transfer to ICU after RRS activation (adjusted odds ratio [OR] 3.56, 95% CI 2.12-5.97) and a higher number of RRS activations (OR 2.45, 95% CI 1.63-3.69). Factors associated with improved survival included active malignancy treatment at the time of RRS activation (OR 0.54, 95% CI 0.34-0.86) and longer hospital length of stay (OR 0.78, 95% CI 0.70-0.87). CONCLUSIONS: Hematologic oncology inpatients requiring RRS activation have high rates of subsequent ICU admission and mortality. ICU admission and higher number of RRS activations are associated with increased risk of death, while active cancer treatment and longer hospital stay are associated with lower risk of mortality. Clinicians should consider these factors in risk-stratifying these patients during RRS assessment.

A Multicentre and stratified study of the attitude of medical students towards organ donation in Spain.

INTRODUCTION: Medical students represent a new generation of medical thought, and if they have a favourable attitude towards organ donation this will greatly encourage its promotion. OBJECTIVE: To analyse the attitude of medical students in Spanish universities towards the donation of their own organs and to determine the factors affecting this attitude. MATERIAL AND METHODS: Type of study: A sociological, interdisciplinary, multicentre, and observational study in Spain. STUDY POPULATION: Students studying a degree in medicine enrolled in Spain (n = 34,000). SAMPLE SIZE: A sample of 9598 students (confidence of 99% and precision of ±1%), stratified by geographical area and academic year. Instrument of measurement: A validated questionnaire of attitude towards organ donation and transplantation (PCID-DTO RIOS) was self-administered and completed anonymously. RESULTS: The questionnaire completion rate was 95.7% (n = 9.275). 80% were in favour of donation, 2% against and 18% were undecided. The following main variables were related to a favourable attitude: being of the female sex (Odds Ratio = 1.739); being in the sixth year of the degree (OR = 2.506); knowing a donor (OR = 1.346); having spoken about the subject with one's family (OR = 2.132) and friends (OR = 1.333); having a family circle that is in favour, more specifically, having a father (OR = 1.841), mother (OR = 2.538) or partner in favour (OR = 2.192); being a blood donor (OR = 2.824); acceptance of the mutilation of the body if it were necessary (OR = 2.958); and being an atheist or an agnostic (OR = 1.766). CONCLUSIONS: Spanish medical students generally have a favourable attitude towards organ donation, although 20% are not in favour.

Impact of two nurse-led interventions targeting diet among breast cancer survivors: Results from a randomized controlled trial.

Breast cancer is the most common neoplasm among women worldwide. Improvements in early detection and treatment have resulted in improved survival rates; however, the continuation of unhealthy behaviours after diagnosis can increase the risk of second primary tumours. The aim of the study was to evaluate the effectiveness of two nurse-led health education interventions aiming at improving dietary behaviours among women diagnosed with breast cancer. Participants (n = 492) were included in a double-blind randomized controlled trial with three arms: a control group received usual care; women in the first intervention group received a booklet containing dietary advice; women in the second intervention group received the same booklet plus a tailored telephone intervention delivered by a trained nurse. One year after the intervention, women in both intervention groups were more likely to adhere to the recommendation of decreasing the consumption of animal fats compared with the control group (OR:5.0; 95% CI:1.5-16.9 and OR:6.6; 95% CI:2.0-22.6, respectively). Moreover, compared with the control group, the adjusted probability of eating the recommended amount of fruit and vegetables was higher in the second intervention group (OR:2.7; 95% CI:1.4-5.3). In summary, the booklet containing dietary advice for breast cancer survivors, either alone or supplemented with a nurse-led telephone intervention, was effective in promoting adherence to diet recommendations.