Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Clinical outcomes of hypomethylating agents and venetoclax in newly diagnosed unfit and relapsed/refractory paediatric, adolescent and young adult acute myeloid leukaemia patients.

Venetoclax (VEN) combined with hypomethylating agents (HMA) decitabine or azacitidine is used for adult acute myeloid leukaemia (AML), but its application in paediatric, adolescent and young adult (AYA) AML lacks prospective studies. We performed a retrospective chart review of paediatric and AYA AML patients treated with HMA + VEN at Cincinnati Children's Hospital Medical Centre. Twenty-seven patients received 30 HMA + VEN treatment courses for relapsed/refractory (R/R, n = 21) or newly diagnosed (n = 9) AML due to ineligibility for intensive chemotherapy. The R/R cohort had high-risk cytomolecular genetic alterations and prior extensive treatments, with 50% (n = 9) of relapse patients (n = 18) having undergone haematopoietic stem cell transplantation (HSCT). Venetoclax treatment using the 400 mg adult exposure-equivelant dosing (AED) had a median duration of 21 days (range 7-30 days). Grade 3-4 toxicities included neutropenia (90%), anaemia (64%), thrombocytopenia (64%) and febrile neutropenia (44%). The overall complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 73% (77% minimal residual disease [MRD] negativity <0.1%), with 60% undergoing HSCT. Among newly diagnosed patients (n = 9), 89% achieved CR/CRi (78% MRD negativity) and 78% proceeded to HSCT. The R/R cohort (n = 21) showed a 67% CR/CRi rate (71% MRD negativity), with 52% undergoing HSCT. These findings support the safety and efficacy of HMA + VEN in paediatric/AYA AML, indicating it as a viable option for patients unfit for intensive chemotherapy. Further studies are necessary to determine optimal venetoclax dosing, chemotherapy combinations and pharmacokinetics in this population.

Interventions on gender equity in the workplace: a scoping review.

BACKGROUND: Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity). METHODS: Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework. RESULTS: We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes. CONCLUSIONS: There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex. TRIAL REGISTRATION: Open Science Framework https://osf.io/x8yae .

The Predictive Validity of the Berlin Definition of Acute Respiratory Distress Syndrome for Patients With COVID-19-Related Respiratory Failure Treated With High-Flow Nasal Oxygen: A Multicenter, Prospective Cohort Study.

OBJECTIVES: The Berlin definition of acute respiratory distress syndrome (ARDS) was constructed for patients receiving invasive mechanical ventilation (IMV) with consideration given to issues related to reliability, feasibility, and validity. Notwithstanding, patients with acute respiratory failure (ARF) may be treated with high-flow nasal oxygen (HFNO) and may not fall within the scope of the original definition. We aimed to evaluate the predictive validity of the Berlin definition in HFNO-treated patients with COVID-19-related respiratory failure who otherwise met ARDS criteria. DESIGN: Multicenter, prospective cohort study. SETTING: Five ICUs of five centers in Argentina from March 2020 to September 2021. PATIENTS: We consecutively included HFNO-treated patients older than 18 years with confirmed COVID-19-related ARF, a Pa o2 /F io2 of less than 300 mm Hg, bilateral infiltrates on imaging, and worsening respiratory symptoms for less than 1 week. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the predictive validity of mortality at day 28 using the area under the receiver operating characteristics curve (AUC), compared the predictive validity across subgroups, and characterized relevant clinical outcomes. We screened 1,231 patients and included 696 ARDS patients [30 (4%) mild, 380 (55%) moderate, and 286 (41%) severe]. For the study cohort, the AUC for mortality at day 28 was 0.606 (95% CI, 0.561-0.651) with the AUC for subgroups being similar to that of the overall cohort. Two hundred fifty-six patients (37%) received IMV. By day 28, 142 patients (21%) had died, of whom 81 (57%) had severe ARDS. Mortality occurred primarily in patients who were transitioned to IMV. CONCLUSIONS: The predictive validity of the Berlin ARDS definition was similar for HFNO-treated patients as compared with the original population of invasively ventilated patients. Our findings support the extension of the Berlin definition to HFNO-treated patients with ARDS.

Fertility preservation in pediatric solid tumors: A report from the Children's Oncology Group.

Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children's Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000 to 2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG-based solid tumor therapy. Internationally, many solid tumor therapies follow similar paradigms to COG studies, and risk stratifications may be generalizable to similar styles of therapy. In addition, this model may be applied to other international groups with the goal of standardizing fertility assessments.

Comparative effectiveness of alternative spontaneous breathing trial techniques: a systematic review and network meta-analysis of randomized trials.

BACKGROUND: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques. METHODS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis. RESULTS: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs. CONCLUSIONS: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs.

Higher versus lower oxygenation targets in adult ICU patients: A rapid practice guideline.

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) was to provide evidence-based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence-to-Decision framework to generate recommendations. A recently published updated systematic review and meta-analysis constituted the evidence base. Through teleconferences and web-based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta-analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all-cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health-related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM-RPG panel issued one conditional recommendation against the use of higher oxygenation targets: "We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO2 88%-92% or PaO2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients."

European Practice for CDI Treatment.

Clostridioides difficile infection (CDI) remains a significant cause of morbidity and mortality worldwide. Historically, two antibiotics (metronidazole and vancomycin) and a recent third (fidaxomicin) have been used for CDI treatment; convincing data are now available showing that metronidazole is the least efficacious agent. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) management guidance for CDI were updated in 2021. This guidance document outlines the treatment options for a variety of CDI clinical scenarios and for non-antimicrobial management (e.g., faecal microbiota transplantation, FMT). One of the main changes is that metronidazole is no longer recommended as first-line CDI treatment. Rather, fidaxomicin is preferred on the basis of reduced recurrence rates with vancomycin as an acceptable alternative. Recommended options for recurrent CDI now include bezlotoxumab as well as FMT.A 2017 survey of 20 European countries highlighted variation internationally in CDI management strategies. A variety of restrictions were in place in 65% countries prior to use of new anti-CDI treatments, including committee/infection specialist approval or economic review/restrictions. This survey was repeated in November 2022 to assess the current landscape of CDI management practices in Europe. Of 64 respondents from 17 countries, national CDI guidelines existed in 14 countries, and 11 have already/plan to incorporate the ESCMID 2021 CDI guidance, though implementation has not been surveyed in 6. Vancomycin is the most commonly used first-line agent for the treatment of CDI (n = 42, 66%), followed by fidaxomicin (n = 30, 47%). Six (9%) respondents use metronidazole as first-line agent for CDI treatment, whereas 22 (34%) only in selected low-risk patient groups. Fidaxomicin is more likely to be used in high-risk patient groups. Availability of anti-CDI therapy influenced prescribing in six respondents (9%). Approval pre-prescription was required before vancomycin (n = 3, 5%), fidaxomicin (n = 10, 6%), bezlotoxumab (n = 11, 17%) and FMT (n = 10, 6%). Implementation of CDI guidelines is rarely audited.Novel anti-CDI agents are being evaluated; it is not yet clear what will be the roles of these agents. The treatment of recurrent CDI is particularly troublesome, and several different live biotherapeutics are being developed, in addition to FMT.

Optimizing a mentorship program from the perspective of academic medicine leadership - a qualitative study.

BACKGROUND: Effective mentorship is an important contributor to academic success. Given the critical role of leadership in fostering mentorship, this study sought to explore the perspectives of departmental leadership regarding 1) current departmental mentorship processes; and 2) crucial components of a mentorship program that would enhance the effectiveness of mentorship. METHODS: Department Division Directors (DDDs), Vice-Chairs, and Mentorship Facilitators from the Department of Medicine at the University of Toronto Temerty Faculty of Medicine were interviewed between April and December 2021 using a semi-structured guide. Interviews were audio-recorded and transcribed verbatim, then coded. Analysis occurred in 2 steps: 1) codes were organized to identify emergent themes; then 2) the Social Ecological Model (SEM) was applied to interpret the findings. RESULTS: Nineteen interviews (14 DDDs, 3 Vice-Chairs, and 2 Mentorship Facilitator) were completed. Analysis revealed three themes: (1) a culture of mentorship permeated the department as evidenced by rigorous mentorship processes, divisional mentorship innovations, and faculty that were keen to mentor; (2) barriers to the establishment of effective mentoring relationships existed at 3 levels: departmental, interpersonal (mentee-mentor relationships), and mentee; and (3) strengthening the culture of mentorship could entail scaling up pre-existing mentorship processes and promoting faculty engagement. Application of SEM highlighted critical program features and determined that two components of interventions (creating tools to measure mentorship outcomes and systems for mentor recognition) were potential enablers of success. CONCLUSIONS: Establishing 'mentorship outcome measures' can incentivize and maintain relationships. By tangibly delineating departmental expectations for mentorship and creating systems that recognize mentors, these measures can contribute to a culture of mentorship.

Reciprocal Associations Between Science Efficacy, STEM Identity and Scientist Career Interest Among Adolescent Girls within the Context of Informal Science Learning.

Limited research has explored the longitudinal pathway to youth career interests via identity and efficacy together. This study examined the longitudinal associations between science efficacy, STEM (science, technology, engineering and math) identity, and scientist career interest among girls who are historically considered as an underrepresented group among scientists. The sample included 308 girls (M age = 15.22, SD age = 1.66; 42.8% White) from six STEM youth programs, each at a different informal science learning site within the U.K. and the U.S. Longitudinal structural equation modelling demonstrated that science efficacy consistently predicted STEM identity and scientist career interest, and similarly, STEM identity consistently predicted science efficacy over a two-year period. Scientist career interest at 12 months predicted science efficacy at 24 months. The coefficients of efficacy predicting STEM identity and scientist career interest were significantly larger compared to STEM identity and scientist career interest in predicting science efficacy from 12 months to 24 months. Further mediation analysis supported a significant pathway from STEM identity at 3 months to scientist career interest at 24 months via 12-month science efficacy. The findings highlight that science efficacy and STEM identity for girls relate to their scientist career interest and these longitudinal associations are reciprocal. This study suggests that science efficacy and STEM identity mutually influence each other, and enhancing science efficacy and STEM identity is key to promoting adolescents' interest in being a scientist.

Developmental Trajectories of Adolescents' Math Motivation: The Role of Mindset and Perceptions of Informal STEM Learning Site Inclusivity.

Motivation is a key factor in engagement, achievement, and career choices in science, technology, engineering, and mathematics (STEM). While existing research has focused on student motivation toward math in formal school programs, new work is needed that focuses on motivation for those involved in informal STEM programs. Specifically, the role of math mindset and perceived inclusivity of informal STEM sites (to those of varying gender and ethnic backgrounds) on longitudinal trajectories of adolescents' math motivation has not been explored. This study investigates longitudinal changes in math expectancy, interest, and utility values and the effects of math fixed mindset, math growth mindset, and perceptions of the inclusivity of informal STEM learning sites on these changes for adolescents participating in STEM programs at these informal sites in the United Kingdom and the United States (n = 249, MT1age = 15.2, SD = 1.59). Three latent growth curve models were tested. The data suggest that math expectancy, interest, and utility values declined over three years. Growth mindset positively predicted changes in utility, while fixed mindset negatively predicted changes in utility. Inclusivity positively influenced the initial levels of utility. Girls reported lower initial expectancy than boys. Age influenced both the initial levels and rate of change for expectancy. Older adolescents had lower levels of expectancy compared to their younger counterparts; however, they had a less steep decline in expectancy over three years. These findings suggest that designing inclusive learning environments and promoting growth mindset may encourage math motivation.

Predictors of Noninvasive Ventilation Failure in the Post-Extubation Period: A Systematic Review and Meta-Analysis.

OBJECTIVES: To identify factors associated with failure of noninvasive ventilation (NIV) in the post-extubation period. DATA SOURCES: We searched Embase Classic +, MEDLINE, and the Cochrane Database of Systematic Reviews from inception to February 28, 2022. STUDY SELECTION: We included English language studies that provided predictors of post-extubation NIV failure necessitating reintubation. DATA EXTRACTION: Two authors conducted data abstraction and risk-of-bias assessments independently. We used a random-effects model to pool binary and continuous data and summarized estimates of effect using odds ratios (ORs) mean difference (MD), respectively. We used the Quality in Prognosis Studies tool to assess risk of bias and the Grading of Recommendations, Assessment, Development and Evaluations to assess certainty. DATA SYNTHESIS: We included 25 studies ( n = 2,327). Illness-related factors associated with increased odds of post-extubation NIV failure were higher critical illness severity (OR, 3.56; 95% CI, 1.96-6.45; high certainty) and a diagnosis of pneumonia (OR, 6.16; 95% CI, 2.59-14.66; moderate certainty). Clinical and biochemical factors associated with moderate certainty of increased risk of NIV failure post-extubation include higher respiratory rate (MD, 1.54; 95% CI, 0.61-2.47), higher heart rate (MD, 4.46; 95% CI, 1.67-7.25), lower Pa o2 :F io2 (MD, -30.78; 95% CI, -50.02 to -11.54) 1-hour after NIV initiation, and higher rapid shallow breathing index (MD, 15.21; 95% CI, 12.04-18.38) prior to NIV start. Elevated body mass index was the only patient-related factor that may be associated with a protective effect (OR, 0.21; 95% CI, 0.09-0.52; moderate certainty) on post-extubation NIV failure. CONCLUSIONS: We identified several prognostic factors before and 1 hour after NIV initiation associated with increased risk of NIV failure in the post-extubation period. Well-designed prospective studies are required to confirm the prognostic importance of these factors to help further guide clinical decision-making.

Mortality As a Measure of Treatment Effect in Clinical Trials Recruiting Critically Ill Patients.

OBJECTIVES: All-cause mortality is a common measure of treatment effect in ICU-based randomized clinical trials (RCTs). We sought to understand the performance characteristics of a mortality endpoint by evaluating its temporal course, responsiveness to differential treatment effects, and impact when used as an outcome measure in trials of acute illness. DATA SOURCES: We searched OVID Medline for RCTs published from 1990 to 2018. STUDY SELECTION: We reviewed RCTs that had randomized greater than or equal to 100 patients, were published in one of five high-impact general medical or eight critical care journals, and reported mortality at two or more distinct time points. We excluded trials recruiting pediatric or neonatal patients and cluster RCTs. DATA EXTRACTION: Mortality by randomization group was recorded from the article or estimated from survival curves. Trial impact was assessed by inclusion of results in clinical practice guidelines. DATA SYNTHESIS: From 2,592 potentially eligible trials, we included 343 RCTs (228,784 adult patients). While one third of all deaths by 180 days had occurred by day 7, the risk difference between study arms continued to increase until day 60 (p = 0.01) and possibly day 90 (p = 0.07) and remained stable thereafter. The number of deaths at ICU discharge approximated those at 28-30 days (95% [interquartile range [IQR], 86-106%]), and deaths at hospital discharge approximated those at 60 days (99% [IQR, 94-104%]). Only 13 of 43 interventions (30.2%) showing a mortality benefit have been adopted into widespread clinical practice. CONCLUSIONS: Our findings provide a conceptual framework for choosing a time horizon and interpreting mortality outcome in trials of acute illness. Differential mortality effects persist for 60 to 90 days following recruitment. Location-based measures approximate time-based measures for trials conducted outside the United States. The documentation of a mortality reduction has had a modest impact on practice.

Fertility preservation in pediatric leukemia and lymphoma: A report from the Children's Oncology Group.

Certain chemotherapy agents, radiation, and surgery can all negatively impact future fertility. Consults regarding treatment-related risk for infertility and gonadal late effects of these agents should occur at the time of diagnosis as well as during survivorship. Counseling on fertility risk has traditionally varied significantly across providers and institutions. We aim to provide a guide to standardize the assignment of gonadotoxic risk, which can be used in counseling patients both at the time of diagnosis and in survivorship. Gonadotoxic therapies were abstracted from 26 frontline Children's Oncology Group (COG) phase III protocols for leukemia/lymphoma, in use from 2000-2022. A stratification system based on gonadotoxic therapies, sex, and pubertal status was used to assign treatments into minimal, significant, and high level of increased risk for gonadal dysfunction/infertility. Risk levels were assigned to protocols and different treatment arms to aid oncologists and survivor care providers in counseling patients regarding treatment-related gonadotoxicity. Males were most commonly at high risk, with at least one high-risk arm in 14/26 protocols (54%), followed by pubertal females (23% of protocols) and prepubertal females (15% of protocols). All patients who received direct gonadal radiation or hematopoietic stem cell transplant (HSCT) were considered at high risk. Partnering with patients and their oncology/survivorship team is imperative for effective fertility counseling both prior to and post treatment, and this comprehensive guide can be used as a tool to standardize and improve reproductive health counseling in patients undergoing COG-based leukemia/lymphoma care.

Male pediatric, adolescent, and young adult reproductive survivorship.

As pediatric, adolescent, and young adult cancer survival rates increase, emphasis is placed on reducing late effects, including reproductive complications and potential impact to fertility. Male survivors are at risk of abnormalities in sperm, hormone deficiencies, and sexual dysfunction. This can impact one's progression into puberty and ability to have a biological child and impacts quality of life following treatment. Access to reproductive care is important and requires patient assessment and appropriate referral to reproductive specialists. This review addresses reproductive complications associated with therapy, standard-of-care testing, and therapeutic interventions. The psychologic impact on psychosexual functioning is also addressed.

Fertility assessment and treatment in adolescent and young adult cancer survivors.

In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status, and may under- or overestimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Posttreatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

BACKGROUND: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. OBJECTIVE: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. METHODS: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. RESULTS: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). CONCLUSIONS AND RELEVANCE: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Association of early mobility with the incidence of deep-vein thrombosis and mortality among critically ill patients: a post hoc analysis of PREVENT trial.

BACKGROUND: This study assessed the mobility levels among critically ill patients and the association of early mobility with incident proximal lower-limb deep-vein thrombosis and 90-day mortality. METHODS: This was a post hoc analysis of the multicenter PREVENT trial, which evaluated adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis with an expected ICU stay ≥ 72 h and found no effect on the primary outcome of incident proximal lower-limb deep-vein thrombosis. Mobility levels were documented daily up to day 28 in the ICU using a tool with an 8-point ordinal scale. We categorized patients according to mobility levels within the first 3 ICU days into three groups: early mobility level 4-7 (at least active standing), 1-3 (passive transfer from bed to chair or active sitting), and 0 (passive range of motion). We evaluated the association of early mobility and incident lower-limb deep-vein thrombosis and 90-day mortality by Cox proportional models adjusting for randomization and other co-variables. RESULTS: Of 1708 patients, only 85 (5.0%) had early mobility level 4-7 and 356 (20.8%) level 1-3, while 1267 (74.2%) had early mobility level 0. Patients with early mobility levels 4-7 and 1-3 had less illness severity, femoral central venous catheters, and organ support compared to patients with mobility level 0. Incident proximal lower-limb deep-vein thrombosis occurred in 1/85 (1.3%) patients in the early mobility 4-7 group, 7/348 (2.0%) patients in mobility 1-3 group, and 50/1230 (4.1%) patients in mobility 0 group. Compared with early mobility group 0, mobility groups 4-7 and 1-3 were not associated with differences in incident proximal lower-limb deep-vein thrombosis (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI] 0.16, 8.90; p = 0.87 and 0.91, 95% CI 0.39, 2.12; p = 0.83, respectively). However, early mobility groups 4-7 and 1-3 had lower 90-day mortality (aHR 0.47, 95% CI 0.22, 1.01; p = 0.052, and 0.43, 95% CI 0.30, 0.62; p < 0.0001, respectively). CONCLUSIONS: Only a small proportion of critically ill patients with an expected ICU stay ≥ 72 h were mobilized early. Early mobility was associated with reduced mortality, but not with different incidence of deep-vein thrombosis. This association does not establish causality, and randomized controlled trials are required to assess whether and to what extent this association is modifiable. TRIAL REGISTRATION: The PREVENT trial is registered at ClinicalTrials.gov, ID: NCT02040103 (registered on 3 November 2013) and Current controlled trials, ID: ISRCTN44653506 (registered on 30 October 2013).

Systemic lupus erythematosus associated with development of macrophage activation syndrome and disseminated aspergillosis.

PURPOSE: Macrophage activation syndrome (MAS) is a rare illness, especially in critically ill adults. The diagnosis of MAS is challenging, requiring the expertise of multiple specialists, and treatments for MAS can be associated with catastrophic complications. CLINICAL FEATURES: We describe the case of a 31-yr-old Vietnamese student who was diagnosed with cutaneous systemic lupus erythematosus (SLE) in November 2020 and was initiated on treatment with low-dose corticosteroids and hydroxychloroquine as an outpatient. Ten days later, she presented to hospital with decreased consciousness, fever, periorbital swelling, and hypotension necessitating intubation. Computed tomography angiography (CTA) and lumbar puncture did not show a stroke or central nervous system infection. Serology and clinical presentation were consistent with MAS. She was initially treated with 4.5 g pulse methylprednisolone and subsequently with the interleukin-1 receptor antagonist, anakinra, and maintenance corticosteroids because of persistently elevated inflammatory markers. Her intensive care unit stay was complicated by aspiration, airway obstruction due to fungal tracheobronchitis necessitating extracorporeal membrane oxygenation (ECMO), and ring-enhancing cerebral lesions, and, ultimately, massive hemoptysis resulting in death. CONCLUSIONS: Four features of this case merit discussion, including the: 1) infrequent association of SLE with MAS; 2) short interval between SLE diagnosis and critical illness; 3) manifestation of fungal tracheobronchitis with airway obstruction; and 4) lack of response to antifungal treatment while receiving ECMO.

RéSUMé: OBJECTIF: Le syndrome d'activation macrophagique (SAM) est une maladie rare, en particulier chez les adultes gravement malades. Le diagnostic d'un SAM est difficile à poser, nécessitant l'expertise de plusieurs spécialistes, et les traitements de ce syndrome peuvent être associés à des complications catastrophiques. CARACTéRISTIQUES CLINIQUES: Nous décrivons le cas d'une étudiante vietnamienne de 31 ans ayant reçu un diagnostic de lupus érythémateux disséminé (LED) cutané en novembre 2020; un traitement par corticostéroïdes à faible dose et hydroxychloroquine a été amorcé en ambulatoire. Dix jours plus tard, elle s'est présentée à l'hôpital avec une diminution de la conscience, de la fièvre, un gonflement périorbitaire et une hypotension nécessitant une intubation. L'angiographie par tomodensitométrie et la ponction lombaire n'ont pas révélé d'accident vasculaire cérébral ou d'infection du système nerveux central. La sérologie et la présentation clinique correspondaient à celles d'un SAM. Elle a d'abord été traitée avec 4,5 g de méthylprednisolone en injection ponctuelle, puis avec un antagoniste du récepteur à l'interleukine-1, l'anakinra et des corticostéroïdes d'entretien en raison de marqueurs inflammatoires élevés persistants. Son séjour en soins intensifs a été compliqué par une aspiration, une obstruction des voies aériennes due à une trachéobronchite fongique nécessitant une oxygénation par membrane extracorporelle (ECMO) et des lésions cérébrales avec rehaussement en anneau, et finalement une hémoptysie massive entraînant la mort. CONCLUSION: Quatre caractéristiques de ce cas méritent d'être discutées, soit: 1) l'association peu fréquente du lupus érythémateux disséminé avec un syndrome d'activation macrophagique; 2) le court intervalle entre le diagnostic de LED et la maladie grave; 3) l'apparition d'une trachéobronchite fongique avec obstruction des voies aériennes; et 4) l'absence de réponse au traitement antifongique pendant le traitement par ECMO.