Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa.

Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing SCA-related clinical events, documented treatment benefits include ∼50% reduction in malaria incidence. To identify associations and propose mechanisms by which hydroxyurea could be associated with lower malaria rates, infections were recorded across all clinical sites (Angola, Democratic Republic of Congo, Kenya, and Uganda). Hazard ratios (HR) with 95% confidence intervals (CIs) for baseline demographics, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. Over 3387 patient-years of hydroxyurea treatment, 717 clinical malaria episodes occurred in 336 of 606 study participants; over half were confirmed by blood smear and/or rapid diagnostic testing with 97.8% Plasmodium falciparum. In univariate analysis limited to 4 confirmed infections per child, malaria risk was significantly associated with absolute neutrophil count (ANC), splenomegaly, hemoglobin, and achieving MTD; age, malaria season, MTD dose, fetal hemoglobin, α-thalassemia, and glucose-6-phosphate dehydrogenase deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR, 1.37 per doubled value; 95% CI, 1.10-1.70; P = .0052), and ANC values <3.0 × 109/L were associated with lower malaria incidence. Compared with nonpalpable spleen, 1- to 4-cm splenomegaly also was associated with higher malaria risk (HR, 2.01; 95% CI, 1.41-2.85; P = .0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 × 109/L is salutary. Splenomegaly is an unexplained risk factor for malaria infections among children with SCA in Africa.

The presence of polycystic ovary syndrome increases the risk of maternal but not neonatal complications in women with type 2 diabetes in pregnancy.

AIMS: Our aims were, in the setting of type 2 diabetes mellitus (T2DM) in pregnancy, to investigate the association of polycystic ovary syndrome (PCOS) with perinatal outcomes and to examine whether treatment with metformin had a differential effect in those with and without PCOS. MATERIALS AND METHODS: We performed a retrospective cohort study using the metformin in women with type 2 diabetes in pregnancy (MiTy) trial data. We examined differences in maternal and neonatal outcomes among MiTy participants with and without PCOS using linear and logistic regression to adjust for potential confounders. We additionally examined the relative difference in the effect of metformin treatment on pregnancy outcomes among MiTy participants with PCOS versus those without PCOS. RESULTS: Among women with T2DM in pregnancy, PCOS was significantly associated with higher excess gestational weight gain (unadjusted 12.0 vs. 11.4 kg, adjusted mean difference 2.1 kg [0.3, 3.9], p = 0.021) and higher total insulin dose at 34-36 weeks (unadjusted 172 vs. 124 units per day, adjusted mean difference 44 units [15, 73], p = 0.004), but no difference was seen in neonatal outcomes. Unlike the non-PCOS subgroup, metformin treatment versus placebo in the PCOS subgroup was associated with an increase in extremely large-for-gestational-age infants (28.6 vs. 14.0%, p = 0.008 for interaction) and an increase in worsened pre-existing maternal hypertension (16.7 vs. 4.5%, p = 0.046 for interaction). CONCLUSIONS: Clinicians should be alerted to the potential for high insulin requirements and excess weight gain in pregnant patients with T2DM and comorbid PCOS. Moreover, metformin may not be as beneficial in this population as previously understood.

Baseline Gastric Volume in Fasting Diabetic Patients Is Not Higher than That in Nondiabetic Patients: A Cross-sectional Noninferiority Study.

BACKGROUND: The physiology of diabetes mellitus can increase the risk of perioperative aspiration, but there is limited and contradictory evidence on the incidence of "full stomach" in fasting diabetic patients. The aim of this study is to assess the baseline gastric content (using gastric ultrasound) in diabetic and nondiabetic patients scheduled for elective surgery who have followed standard preoperative fasting instructions. METHODS: This was a prospective, noninferiority study of 180 patients (84 diabetic and 96 nondiabetic patients). Bedside ultrasound was used for qualitative and quantitative assessment of the gastric antrum in the supine and right lateral decubitus positions. Fasting gastric volume was estimated based on the cross-sectional area of the gastric antrum and a validated model. The hypothesis was that diabetic patients would not have a higher baseline fasting gastric volume compared to nondiabetic patients, with a noninferiority margin of 0.4 ml/kg. Secondary aims included the comparison of the incidence of full stomach (solid content or more than 1.5 mL/kg of clear fluid), estimation of the 95th percentile of the gastric volume distribution in both groups, and examination of the association between gastric volume, glycemic control, and diabetic comorbidities. RESULTS: The baseline gastric volume was not higher in diabetic patients (0.81 ± 0.61 ml/kg) compared to nondiabetic patients (0.87 ± 0.53 ml/kg) with a mean difference of -0.07 ml/kg (95% CI, -0.24 to 0.10 ml/kg). A total of 13 (15.5%) diabetic and 11 (11.5%) nondiabetic patients presented more than 1.5 ml/kg of gastric volume (95% CI for difference, -7.1 to 15.2%). There was little correlation between the gastric volume and either the time since diagnosis or HbA1C. CONCLUSIONS: The data suggest that the baseline gastric volume in diabetic patients who have followed standard fasting instructions is not higher than that in nondiabetic patients.

Modeling multiple correlated end-organ disease trajectories: A tutorial for multistate and joint models with applications in diabetes complications.

State-of-the-art biostatistics methods allow for the simultaneous modeling of several correlated non-fatal disease processes over time, but there is no clear guidance on the optimal analysis in most settings. An example occurs in diabetes, where it is not known with certainty how microvascular complications of the eyes, kidneys, and nerves co-develop over time. In this article, we propose and contrast two general model frameworks for studying complications (sequential state and parallel trajectory frameworks) and review multivariate methods for their analysis, focusing on multistate and joint modeling. We illustrate these methods in a tutorial format using the long-term follow-up from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study public data repository. A formal comparison of prediction error and discrimination is included. Multistate models are particularly advantageous for determining the order and timing of complications, but require discretization of the longitudinal outcomes and possibly a very complex state space process. Intermittent observation of the states must be accounted for, and discretization is a probable disadvantage in this setting. In contrast, joint models can account for variations of continuous biomarkers over time and are particularly designed for modeling complex association structures between the complications and for performing dynamic predictions of an outcome of interest to inform clinical decisions (eg, a late-stage complication). We found that both models have helpful features that can better-inform our understanding of the complex trajectories that complications may take and can therefore help with decision making for patients presenting with diabetes complications.

Reducing transfusion utilization for children with sickle cell anemia in sub-Saharan Africa with hydroxyurea: Analysis from the phase I/II REACH trial.

Children with sickle cell anemia (SCA) in Africa frequently require transfusions for SCA complications. Despite limited blood supplies, strategies to reduce their transfusion needs have not been widely evaluated or implemented. We analyzed transfusion utilization in children with SCA before and during hydroxyurea treatment. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a longitudinal Phase I/II trial of hydroxyurea in children with SCA from Angola, Democratic Republic of Congo, Kenya, and Uganda. After enrollment, children had a two-month pre-treatment screening period followed by 6 months of fixed-dose hydroxyurea (15-20 mg/kg/day), 18 months of dose escalation, and then stable dosing at maximum tolerated dose (MTD). Characteristics associated with transfusions were analyzed with univariate and multivariable models. Transfusion incidence rate ratios (IRR) across treatment periods were calculated. Among 635 enrolled children with 4124 person-years of observation, 258 participants (40.4%) received 545 transfusions. The transfusion rate per 100 person-years was 43.2 before hydroxyurea, 21.7 on fixed-dose, 14.5 during dose escalation, and 10.8 on MTD. During MTD, transfusion incidence was reduced by 75% compared to pre-treatment (IRR 0.25, 95% confidence interval [CI] 0.18-0.35, p < .0001), and by 50% compared to fixed dose (IRR 0.50, 95% CI 0.39-0.63, p < .0001). Hydroxyurea at MTD decreases transfusion utilization in African children with SCA. If widely implemented, universal testing and hydroxyurea treatment at MTD could potentially prevent 21% of all pediatric transfusions administered in sub-Saharan Africa. Increasing hydroxyurea access for SCA should decrease the transfusion burden and increase the overall blood supply.

Optimizing practices to prevent urinary tract infection after cystoscopy and urodynamics in women: A quality improvement study.

OBJECTIVE: The objective of this study was to reduce the incidence of urinary tract infection (UTI) in women undergoing outpatient cystoscopy and/or urodynamic studies (UDS) at our centre by identifying and then altering modifiable risk factors through an analysis of incidence variability among physicians. METHODS: This was a quality improvement study involving adult women undergoing outpatient cystoscopy and/or UDS at an academic tertiary urogynecology practice. Prophylactic practices for cystoscopy/UDS were surveyed and division and physician-specific UTI rates following cystoscopy/UDS were established. In consultation with key stakeholders, this delineated change concepts based on associations between prophylactic practices and UTI incidence, which were then implemented while monitoring counterbalance measures. RESULTS: Two "Plan-Do-Study-Act-Cycles" were conducted whereby 212 and 210 women were recruited, respectively. Change concepts developed and implemented were: (1) to perform routine urine cultures at the time of these outpatient procedures, and (2) to withhold routine prophylactic antibiotics for outpatient cystoscopy/UDS, except in patients with signs of cystitis. There was no change in the incidence of early presenting UTI (9.0% vs. 9.2%, p = 0.680), but there were significantly fewer antibiotic-related adverse events reported (8.5% vs. 1.5%, p = 0.001). There was no significant change in the total incidence of UTI rates between cycles (7.8% vs. 5.6%, p = 0.649). CONCLUSIONS: No specific strategies to decrease the incidence of UTI following outpatient cystoscopy/UDS were identified, however, risk factor-specific antibiotic prophylaxis, as opposed to universal antibiotic prophylaxis, did not increase UTI incidence.

Linking Acute Physiology to Outcomes in the ICU: Challenges and Solutions for Research.

ICU clinicians rely on bedside physiological measurements to inform many routine clinical decisions. Because deranged physiology is usually associated with poor clinical outcomes, it is tempting to hypothesize that manipulating and intervening on physiological parameters might improve outcomes for patients. However, testing these hypotheses through mathematical models of the relationship between physiology and outcomes presents a number of important methodological challenges. These models reflect the theories of the researcher and can therefore be heavily influenced by one's assumptions and background beliefs. Model building must therefore be approached with great care and forethought, because failure to consider relevant sources of measurement error, confounding, coupling, and time dependency or failure to assess the direction of causality for associations of interest before modeling may give rise to spurious results. This paper outlines the main challenges in analyzing and interpreting these models and offers potential solutions to address these challenges.

Do Thresholds for Invasive Ventilation in Hypoxemic Respiratory Failure Exist? A Cohort Study.

Rationale: Invasive ventilation is a significant event for patients with respiratory failure. Physiologic thresholds standardize the use of invasive ventilation in clinical trials, but it is unknown whether thresholds prompt invasive ventilation in clinical practice. Objectives: To measure, in patients with hypoxemic respiratory failure, the probability of invasive ventilation within 3 hours after meeting physiologic thresholds. Methods: We studied patients admitted to intensive care receiving FiO2 of 0.4 or more via nonrebreather mask, noninvasive positive pressure ventilation, or high-flow nasal cannula, using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019) and the Amsterdam University Medical Centers Database (AmsterdamUMCdb) (2003-2016). We evaluated 17 thresholds, including the ratio of arterial to inspired oxygen, the ratio of saturation to inspired oxygen ratio, composite scores, and criteria from randomized trials. We report the probability of invasive ventilation within 3 hours of meeting each threshold and its association with covariates using odds ratios (ORs) and 95% credible intervals (CrIs). Measurements and Main Results: We studied 4,726 patients (3,365 from MIMIC, 1,361 from AmsterdamUMCdb). Invasive ventilation occurred in 28% (1,320). In MIMIC, the highest probability of invasive ventilation within 3 hours of meeting a threshold was 20%, after meeting prespecified neurologic or respiratory criteria while on vasopressors, and 19%, after a ratio of arterial to inspired oxygen of <80 mm Hg. In AmsterdamUMCdb, the highest probability was 34%, after vasopressor initiation, and 25%, after a ratio of saturation to inspired oxygen of <90. The probability after meeting the threshold from randomized trials was 9% (MIMIC) and 13% (AmsterdamUMCdb). In MIMIC, a race/ethnicity of Black (OR, 0.75; 95% CrI, 0.57-0.96) or Asian (OR, 0.6; 95% CrI, 0.35-0.95) compared with White was associated with decreased probability of invasive ventilation after meeting a threshold. Conclusions: The probability of invasive ventilation within 3 hours of meeting physiologic thresholds was low and associated with patient race/ethnicity.

Evaluating the Validity of the Responses to Illness Severity Quantification Score to Discriminate Illness Severity and Level of Care Transitions in Hospitalized Children with Severe Acute Malnutrition.

OBJECTIVE: To evaluate the validity of the Responses to Illness Severity Quantification (RISQ) score to discriminate illness severity and transitions between levels of care during hospitalization. STUDY DESIGN: A prospective observational study conducted in Maiduguri, Nigeria, enrolled inpatients aged 1-59 months with severe acute malnutrition. The primary outcome was the RISQ score associated with the patient state. Heart and respiratory rate, oxygen saturation, respiratory effort, oxygen use, temperature, and level of consciousness are summed to calculate the RISQ score. Five states were defined by levels of care and hospital discharge outcome. The states were classified hierarchically, reflecting illness severity: hospital mortality was the most severe state, then intensive care unit (ICU), care in the stabilization phase (SP), care in the rehabilitation phase (RP), and lowest severity, survival at hospital discharge. A multistate statistical model examined performance of the RISQ score in predicting clinical states and transitions. RESULTS: Of 903 children enrolled (mean age, 14.6 months), 63 (7%) died. Mean RISQ scores during care in each phase were 3.5 (n = 2265) in the ICU, 1.7 (n = 6301) in the SP, and 1.5 (n = 2377) in the RP. Mean scores and HRs for a 3-point change in score at transitions: ICU to death, 6.9 (HR, 1.80); SP to ICU, 2.8 (HR, 2.00); ICU to SP, 2.0 (HR, 0.5); and RP to discharge, 1.4 (HR, 0.91). CONCLUSIONS: The RISQ score can discriminate between points of escalation or de-escalation of care and reflects illness severity in hospitalized children with severe acute malnutrition. Evaluation of clinical implementation and demonstration of benefit will be important before widespread adoption.

Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

Applying Quality Indicators to Examine Quality of Care During Active Surveillance in Low-Risk Prostate Cancer: A Population-Based Study.

BACKGROUND: Although a few studies have reported wide variations in quality of care in active surveillance (AS), there is a lack of research using validated quality indicators (QIs). The aim of this study was to apply evidence-based QIs to examine the quality of AS care at the population level. METHODS: QIs were measured using a population-based retrospective cohort of patients with low-risk prostate cancer diagnosed between 2002 and 2014. We developed 20 QIs through a modified Delphi approach with clinicians targeting the quality of AS care at the population level. QIs included structure (n=1), process of care (n=13), and outcome indicators (n=6). Abstracted pathology data were linked to cancer registry and administrative databases in Ontario, Canada. A total of 17 of 20 QIs could be applied based on available information in administrative databases. Variations in QI performance were explored according to patient age, year of diagnosis, and physician volume. RESULTS: The cohort included 33,454 men with low-risk prostate cancer, with a median age of 65 years (IQR, 59-71 years) and a median prostate-specific antigen level of 6.2 ng/mL. Compliance varied widely for 10 process QIs (range, 36.6%-100.0%, with 6 [60%] QIs >80%). Initial AS uptake was 36.6% and increased over time. Among outcome indicators, significant variations were observed by patient age group (10-year metastasis-free survival was 95.0% for age 65-74 years and 97.5% in age <55 years) and physician average annual AS volume (10-year metastasis-free survival was 94.5% for physicians with 1-2 patients with AS and 95.8% for those with ≥6 patients with AS annually). CONCLUSIONS: This study establishes a foundation for quality-of-care assessments and monitoring during AS implementation at a population level. Considerable variations appeared with QIs related to process of care by physician volume and Qis related to outcome by patient age group. These findings may represent areas for targeted quality improvement initiatives.

PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS: R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS: We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION: This immunotherapy combination was found to be active and safe in this clinically challenging patient population.

Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts.

BACKGROUND: The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. METHODS: This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008-2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003-2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF < 110, < 98, and < 88 on 28-day mortality. MIMIC-IV was used for the primary analysis and AmsterdamUMCdb for the secondary analysis. We obtained posterior means and 95% credible intervals (CrI) with nonparametric Bayesian G-computation. RESULTS: We studied 3,357 patients in the primary analysis. For invasive ventilation initiation thresholds SF < 110, SF < 98, and SF < 88, the predicted 28-day probabilities of invasive ventilation were 72%, 47%, and 19%. Predicted 28-day mortality was lowest with threshold SF < 110 (22.2%, CrI 19.2 to 25.0), compared to SF < 98 (absolute risk increase 1.6%, CrI 0.6 to 2.6) or SF < 88 (absolute risk increase 3.5%, CrI 1.4 to 5.4). In the secondary analysis (1,279 patients), the predicted 28-day probability of invasive ventilation was 50% for initiation threshold SF < 110, 28% for SF < 98, and 19% for SF < 88. In contrast with the primary analysis, predicted mortality was highest with threshold SF < 110 (14.6%, CrI 7.7 to 22.3), compared to SF < 98 (absolute risk decrease 0.5%, CrI 0.0 to 0.9) or SF < 88 (absolute risk decrease 1.9%, CrI 0.9 to 2.8). CONCLUSION: Initiating invasive ventilation at lower hypoxemia severity will increase the rate of invasive ventilation, but this can either increase or decrease the expected mortality, with the direction of effect likely depending on baseline mortality risk and clinical context.

Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Health State Utility Values Associated with Cochlear Implants in Adults: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: The cost-effectiveness of bilateral cochlear implants in adults remains uncertain despite established clinical benefits. In cost-effectiveness studies, benefit is often measured by change in health state utility value (HSUV), a single number summary of health-related quality of life anchored at 0 (state of being dead) and 1 (perfect health). Small differences in bilateral cochlear implant HSUV change conclusions of published models, and invalid estimates can therefore mislead policy and funding decisions. As such, we aimed to review and synthesize published HSUV estimates associated with cochlear implants. DESIGN: We included observational or experimental studies reporting HSUV for adult patients (age ≥18 years) with at least moderate-profound sensorineural hearing loss in both ears who received unilateral or bilateral cochlear implants. We searched MEDLINE, EMBASE, PsycINFO, and Cochrane Library databases up to May 1, 2021. Study and participant characteristics and HSUV outcomes were extracted. Narrative synthesis is reported for all studies. A Bayesian network meta-analysis was conducted to generate pooled estimates for the mean difference in HSUV for three comparisons: (1) unilateral cochlear implant versus preimplant, (2) bilateral cochlear implants versus preimplant, (3) bilateral versus unilateral cochlear implants. Our principal measure was pooled mean difference in HSUV. RESULTS: Thirty-six studies reporting unique patient cohorts were identified. Health Utilities Index, 3 (HUI-3) was the most common HSUV elicitation method. HSUV from 19 preimplant mean estimates (1402 patients), 19 unilateral cochlear implant mean estimates (1701 patients), and 5 bilateral cochlear implants mean estimates (83 patients) were pooled to estimate mean differences in HUI-3 HSUV by network meta-analysis. Compared with preimplant, a unilateral cochlear implant was associated with a mean change in HSUV of +0.17 (95% credible interval [CrI] +0.12 to +0.23) and bilateral cochlear implants were associated with a mean change of +0.25 (95% CrI +0.12 to +0.37). No significant difference in HSUV was detected for bilateral compared with unilateral cochlear implants (+0.08 [95% CrI -0.06 to +0.21]). Overall study quality was moderate. CONCLUSIONS: The findings of this review and network meta-analysis comprise the best-available resource for parameterization of cost-utility models of cochlear implantation in adults and highlight the need to critically evaluate the validity of available HSUV instruments for bilateral cochlear implant populations.Protocol registration: PROSPERO (CRD42018091838).

Secondary infections in critically ill patients with viral pneumonia due to COVID-19 and influenza: a historical cohort study.

PURPOSE: To compare the incidence and nature of secondary infections (SI) between critically ill patients with viral pneumonia due to COVID-19 and seasonal influenza and explore the association between SI and clinical outcomes. METHODS: We conducted a historical cohort study of patients admitted to the intensive care unit (ICU) at two tertiary care centers during the first wave of the COVID-19 pandemic and patients admitted with influenza during the 2018-2019 season. The primary outcome was the rate of SI. Secondary outcomes included rates of ICU and in-hospital mortality, organ-support-dependent disease, and length of ICU and hospital stay. RESULTS: Secondary infections developed in 55% of 95 COVID-19 patients and 51% of 47 influenza patients (unadjusted odds ratio [OR], 1.16; 95% confidence interval [CI], 0.57 to 2.33). After adjusting for baseline differences between cohorts, there were no significant differences between the COVID-19 cohort and the influenza cohort (adjusted OR, 1.00; 95% CI, 0.41 to 2.44). COVID-19 patients with SI had longer ICU and hospital stays and duration of mechanical ventilation. The SI incidence was higher in COVID-19 patients treated with steroids than in those not treated with steroids (15/20, 75% vs 37/75, 49%). CONCLUSION: Secondary infections were common among critically ill patients with viral pneumonia including COVID-19. We found no difference in the incidence of SI between COVID-19 and influenza in our cohort study, but SI in patients with COVID-19 were associated with worse clinical outcomes and increased healthcare resource use. The small cohort size precludes any causal inferences but may provide a basis for future research.

RéSUMé: OBJECTIF: Comparer l'incidence et la nature des infections secondaires entre les patients gravement malades atteints de pneumonie virale due à la COVID-19 et ceux atteints de la grippe saisonnière et explorer l'association entre les infections secondaires et les issues cliniques. MéTHODE: Nous avons réalisé une étude de cohorte historique de patients admis à l'unité de soins intensifs (USI) dans deux centres de soins tertiaires pendant la première vague de la pandémie de COVID-19 et de patients admis pour la grippe au cours de la saison 2018-2019. Le critère d'évaluation principal était le taux d'infections secondaires. Les critères d'évaluation secondaires comprenaient les taux de mortalité à l'USI et à l'hôpital, les maladies nécessitant un support d'organes et la durée du séjour à l'USI et à l'hôpital. RéSULTATS: Des infections secondaires se sont développées chez 55 % des 95 patients atteints de COVID-19 et 51 % des 47 patients grippaux (rapport des cotes [RC] non ajusté, 1,16; intervalle de confiance [IC] à 95 %, 0,57 à 2,33). Après ajustement pour tenir compte des différences initiales entre les cohortes, aucune différence significative n'a été observée entre la cohorte de COVID-19 et la cohorte de grippe (RC ajusté, 1,00; IC 95 %, 0,41 à 2,44). Les patients atteints de COVID-19 atteints d'infections secondaires ont séjourné plus longtemps aux soins intensifs et à l'hôpital et la durée de la ventilation mécanique était plus longue pour ces patients. L'incidence d'infections secondaires était plus élevée chez les patients atteints de COVID-19 traités par stéroïdes que chez ceux non traités par stéroïdes (15/20, 75 % vs 37/75, 49 %). CONCLUSION: Les infections secondaires étaient fréquentes chez les patients gravement malades atteints de pneumonie virale, y compris de COVID-19. Nous n'avons observé aucune différence dans l'incidence d'infections secondaires entre les patients atteints de COVID-19 et ceux atteints de grippe dans notre étude de cohorte, mais les infections secondaires chez les patients atteints de COVID-19 étaient associées à de moins bonnes issues cliniques et à une utilisation accrue des ressources de soins de santé. La petite taille de la cohorte exclut toute inférence causale, mais peut fournir une base pour les recherches futures.

A Clinical Comparison of 2 Bronchial Blockers Versus Double-Lumen Tubes for One-Lung Ventilation.

OBJECTIVES: To compare the quality of lung collapse, time, and number of attempts required to achieve lung isolation, and incidence of intraoperative malpositioning between the EZ blocker (EZB), Fuji Uniblocker (UB), and the left-sided double lumen tube (DLT). DESIGN: Prospective, randomized clinical trial. SETTING: Single tertiary-level, university-affiliated hospital. PARTICIPANTS: Eighty-nine patients undergoing elective open thoracotomies or video-assisted thoracoscopic surgery. INTERVENTIONS: The 89 patients were randomized to receive a DLT, UB, or EZB for one-lung ventilation. MEASUREMENTS AND MAIN RESULTS: The quality of lung collapse at the time of pleural opening and 10 and 20 minutes thereafter were assessed by the surgeon using the Lung Collapse Score (LCS; 0 = no lung collapse to 10 = best lung collapse). The time and number of attempts required to achieve lung isolation and the number of repositions required during surgery were measured. Tracheobronchial tree measurements were performed by radiologists from preoperative computed tomography imaging. The surgeon remained blinded to the type of device used. Twenty-nine patients were randomized to the DLT group and 30 patients to each of the EZB and UB groups. The LCSs among the groups at pleural opening and 10 minutes after pleural opening were not significantly different (p = 0.34 and p = 0.08, respectively). However, at 20 minutes after the pleural opening, the LCSs were significantly different among groups (p = 0.02), with median scores being significantly lower for DLT (9 [IQR 8-9]) than for EZB (9 [IQR 9-10]; p = 0.04) and UB (9.5 [IQR 9-10]; p = 0.02). Lung isolation was achieved fastest in the DLT group (p < 0.01). The frequency of difficult placement did not significantly differ among groups, although it occurred most frequently in UB (n = 7; 23.3%). Intraoperative repositioning also occurred most often with the UB (n = 15; 50.0%). The EZB had the greatest number of cases requiring >2 repositions (n = 4, 13.3%). There were no differences between preoperative airway measurements and time to isolation or incidence of intraoperative repositioning among the groups. CONCLUSIONS: The LCS was comparable among the 3 devices until 20 minutes after pleural opening, when better scores were obtained in the bronchial blocker groups. Lung isolation was achieved fastest with the DLT. The EZB had the highest incidence of cases requiring >2 intraoperative repositions, mostly occurring in R-sided surgery. For L-sided surgery, the EZB performed equally to the UB. This suggests that using the EZB for R-sided video-assisted thoracoscopic surgery may be suboptimal. Preoperative airway dimensions did not correlate with time to achieve isolation or incidence of intraoperative malpositioning.

Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial.

BACKGROUND: COVID-19 is more severe in transplant recipients. Variants of concern have supplanted wild-type virus. In transplant recipients, data are limited on 2-dose or 3-dose vaccine immunogenicity against variant viruses. OBJECTIVE: To assess neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses. DESIGN: Secondary analysis of a randomized, double-blind, controlled trial of a third dose of mRNA-1273 vaccine versus placebo. (ClinicalTrials.gov: NCT04885907). SETTING: Single-center transplant program. PATIENTS: Organ transplant recipients. INTERVENTION: Third dose of mRNA-1273 vaccine versus placebo. MEASUREMENTS: Sera were analyzed for neutralization against wild-type virus and the Alpha, Beta, and Delta variants using a surrogate virus neutralization assay and a spike-pseudotyped lentivirus assay. RESULTS: A total of 117 transplant recipients were analyzed (60 in the mRNA-1273 group and 57 in the placebo group). Sera were obtained before and 4 to 6 weeks after the third dose. After 2 doses, the proportion of patients with positive neutralization for all 3 variants was small compared with wild-type virus. After the third dose of mRNA-1273 vaccine, the proportion with a positive neutralization response versus placebo was improved for all 3 variants as measured by both assays. Based on the pseudovirus neutralization assay against the Delta variant, 33 of 60 (55%) patients were positive in the mRNA-1273 group versus 10 of 57 (18%) in the placebo group (difference, 37 [95% CI, 19 to 53] percentage points). The differences were 36 (CI, 17 to 51) percentage points for the Alpha variant and 31 (CI, 15 to 46) percentage points for the Beta variant. In the mRNA-1273 group, lower neutralization values were observed for variants compared with wild-type virus, especially the Beta variant. LIMITATIONS: There is no clear correlate of protection for neutralizing antibody. This was a secondary analysis. CONCLUSION: In organ transplant recipients, a third dose of mRNA vaccine increases neutralizing antibody response against SARS-CoV-2 variants compared with placebo. PRIMARY FUNDING SOURCE: Ajmera Transplant Centre.

Using self-reported health as a social determinants of health outcome: a scoping review of reviews.

Reducing disease prevalence rather than promoting health has long been the objective of significant population health initiatives, such as the social determinants of health (SDH) framework. However, empirical evidence suggests that people with diagnosed diseases often answer the self-reported health (SRH) question positively. In pursuit of a better proxy to understand, measure and improve health, this scoping review of reviews examines the potential of SRH to be used as an outcome of interest in population health policies. Following PRISMA-ScR guidelines, it synthesizes findings from 77 review papers (published until 11 May 2022) and reports a robust association between SDH and SRH. It also investigates inconsistencies within and between reviews to reveal how variation in population health can be explained by studying the impact of contextual factors, such as cultural, social, economic and political elements, on structural determinants such as socioeconomic situation, gender and ethnicity. These insights provide informed hypotheses for deeper explorations of the role of SDH in improving SRH. The review detects several gaps in the literature. Notably, more evidence syntheses are required, in general, on the pathway from contextual elements to population SRH and, in particular, on the social determinants of adolescents' SRH. This study reports a disease-oriented mindset in collecting, analysing and reporting SRH across the included reviews. Future studies should utilize the capability of SRH in interconnecting social, psychological and biological dimensions of health to actualize its full potential as a central public health measure.

Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa.

BACKGROUND: Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings. METHODS: We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell-related events, transfusions, and survival). RESULTS: A total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88). CONCLUSIONS: Hydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731 .).