Secondary Sensitivity Analyses Research Articles

Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables

BackgroundThere are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis—the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3. MethodsClinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASLD, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline. These were compared with 24 biomarker, imaging, and algorithm-based NITs with both known cutoffs for MASH F2-F4 and re-optimized cutoffs for MASH F2-F3. ResultsNFS at a − 1.455 cutoff attained an AUC of 0.59, the highest sensitivity (90.9 %, 95 % CI 84.3–95.4), and NPV of 87.2 %. FIB4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and PPV (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other NITs. ConclusionsWe report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.

Bispectral Index Changes Following Boluses of Commonly Used Intravenous Medications During Volatile Anesthesia Identified From Retrospective Data.

Although patients are commonly monitored for depth of anesthesia, it is unclear to what extent administration of intravenous anesthetic medications may affect calculated bispectral (BIS) index values under general anesthesia. In a retrospective analysis of electronic anesthesia records from an academic medical center, we examined BIS index changes associated with 14 different intravenous medications, as administered in routine practice, during volatile-based anesthesia using a novel screening approach. Discrete-time windows were identified in which only a single drug bolus was administered, and subsequent changes in the BIS index, concentration of volatile anesthetic, and arterial pressure were analyzed. Our primary outcome was change in BIS index, following drug administration. Adjusted 95% confidence intervals were compared to predetermined thresholds for clinical significance. Secondary sensitivity analyses examined the same outcomes, with available data separated according to differences in baseline volatile anesthetic concentrations, doses of the administered medications, and length of time window. The study cohort was comprised of data from 20,170 distinct cases, 54.7% of patients were men, with a median age of 55. In the primary analysis, ketamine at a median dose of 20 mg was associated with a median (confidence limits) increase in BIS index of 3.8 (2.5-5.0). Midazolam (median dose 2 mg) was associated with a median decrease in BIS index of 3.0 (1.5-4.5). Neither of these drug administrations occurred during time periods associated with changes in volatile anesthetic concentration. Analysis for dexmedetomidine was confounded by concomitant decreases in volatile anesthetic concentration. No other medication analyzed, including propofol and common opioids, was associated with a significant change in BIS index. Secondary analyses revealed that similar BIS index changes occurred when midazolam and ketamine were administered at different volatile anesthetic concentrations and different doses, and these changes persisted 11 to 20 minutes postadministration. Modest, but persistent changes in BIS index occurred following doses of ketamine (increase) and midazolam (decrease) during periods of stable volatile anesthetic administration.

Sensitivity Analysis of Transient Critical Heat Flux by RIA Under High-Pressure Flow Boiling Conditions in TRTL

A reactivity-initiated accident (RIA) is a design-basis accident under which critical heat flux (CHF) is likely to be exceeded. The operational margin for RIAs is currently determined using steady-state CHF lookup tables, which provide conservative estimates relative to transient CHF phenomena. The Transient Reactor Test Loop (TRTL) facility at Oregon State University is capable of performing out-of-pile rapid heating experiments representative of a RIA at conditions representative of a pressurized water reactor (PWR). To further our understanding of and ability to predict transient CHF under PWR conditions, we performed a sensitivity analysis on a RELAP5-3D model of the TRTL facility coupled to the RAVEN code framework to define a proposed experimental test matrix to be performed at the TRTL facility. We then implemented a flow boiling CHF correlation into RELAP5-3D and performed a secondary sensitivity analysis inspecting the impact of the built-in RELAP5-3D CHF and heat transfer multipliers on both the prediction of CHF and key safety parameters, such as peak cladding temperature and heat flux. The results show that the multiplier with the highest influence toward the prediction of CHF occurrence and the safety parameters is the transient CHF multiplier. Operational performance envelopes have been developed for each of the test matrix cases and will be used for validation once the experiments are performed. The TRTL facility is currently performing shakedown testing to verify system performance prior to proceeding with the experimental campaign. Restart testing results include pump curve restart testing, pressure tests, and heater rod thermocouple transients.

Low vitamin D concentrations and BMI are causal factors for primary biliary cholangitis: A mendelian randomization study.

Observational studies have identified associations between smoking, alcohol use, body mass index (BMI), and the levels of vitamin D with primary biliary cholangitis (PBC). However, there was a lack of randomization control studies to estimate the causal relationship. This study was to investigate the causal estimates for the effects of those risk factors on PBC. The genetic instrument variants were extracted from genome-wide association studies in European ancestry. Two-sample mendelian randomization (MR) and multivariable mendelian randomization were used to determine genetically causal estimates. Primary analyses consisted of random-effects and fix-mode inverse-variance-weighted methods, followed by secondary sensitivity analyses to verify the results. Our study showed that BMI was a causal factor for PBC (OR 1.35; 95% CI=1.03-1.77; p=0.029). In addition, we found that serum vitamin D levels had a protective effect on PBC after adjusting for BMI (OR 0.51; 95% CI=0.32-0.84; p=0.007). However, we failed to identify evidence supporting that genetic causal effect of smoking and alcohol intake were associated with PBC in European countries. Our results enriched findings from previous epidemiology studies and provided evidence from MR that serum vitamin D concentrations and BMI were independent causal factors for PBC, suggesting that ensuing vitamin D sufficiency and healthy lifestyles might be a cost-effective measure for early intervention for PBC.

Characterisation of Deficits and Sex Differences in Verbal and Visual Memory/Learning in Bipolar Disorder.

Cognitive impairment is consistently reported in bipolar disorder (BD), but few studies have characterised which memory component processes are affected. Further, it is unknown whether the component processes underlying memory impairment are moderated by sex. The present study examined diagnosis and sex differences in both verbal and visual memory/learning domains in patients with BD and psychiatrically healthy controls. Verbal and visual memory/learning were measured using the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R). 114 patients with BD (n = 50 males, n = 64 females), were compared to 105 psychiatrically healthy controls (n = 42 males, n = 63 females). Patients with BD had worse performance in verbal and visual immediate and total recall, verbal and visual delayed free recall, and verbal recognition discrimination scores, but there were no group differences in learning slopes and cumulative learning index scores. There were trends for BD females to outperform BD males in visual memory/learning free recall and cumulative learning, but these results did not survive multiple testing correction. These findings did not change in a secondary sensitivity analysis comparing only strictly euthymic BD patients to controls (n = 64). The present study found trait-like verbal and visual memory/learning impairment in BD that was attributable to deficient encoding and/or consolidation processes rather than deficits in learning. We did not find marked sex differences in either visual or verbal memory/learning measures, although some trend level effects were apparent and deserve exploration in future studies.

Safety of yellow fever vaccination in pregnancy: findings from a cohort of active duty US military women.

Yellow fever (YF) is a rare viral disease that can be prevented through receipt of a live attenuated vaccine. In the US military, service members must receive the YF vaccine before assignment to endemic areas, putting active duty service women at heightened risk for inadvertent exposure during preconception or pregnancy. Few studies have investigated the safety of YF vaccination in pregnancy to date, and none in a military population. Department of Defense Birth and Infant Health Research program data were used to identify pregnancies and infants among active duty US military women, 2003-2014. Multivariable regression models estimated associations with YF vaccine exposure during preconception/pregnancy and adverse outcomes (e.g. spontaneous abortion, birth defects). Sensitivity analyses were performed that excluded pregnancies exposed to other live vaccines. For analyses of birth defects only, a secondary sensitivity analysis was performed that excluded infants diagnosed with chromosomal anomalies. Of the 196 802 pregnancies and 160 706 singleton infants identified, 1347 (0.7%) and 1132 (0.7%), respectively, were exposed to the YF vaccine. No increased risks for adverse pregnancy or infant outcomes were observed in the main analysis. In sensitivity analyses that excluded pregnancies exposed to other live vaccines, preconception YF vaccine exposure was associated with birth defects [adjusted risk ratio (aRR) = 1.71, 95% confidence interval (CI) = 1.08-2.73]; this association was attenuated when further excluding infants with chromosomal anomalies (aRR = 1.59, 95% CI = 0.97-2.62). Overall, YF vaccine exposure did not appear to be associated with most adverse outcomes among this population of pregnant military women. A tenuous association between preconception YF vaccine exposure and birth defects was observed in sensitivity analyses, which may warrant further investigation.

The roles of study setting, response bias, and personality in subjective memory complaints of cognitively normal older adults.

This study investigated subjective memory complaints in older adults and the roles of setting, response bias, and personality. Cognitively normal older adults from two settings completed questionnaires measuring memory complaints, response bias, and personality. (A) Neuroimaging study with community-based recruitment and (B) academic memory clinic. Cognitively normal older adults who (A) volunteer for research (N = 92) or (B) self-referred to a memory clinic (N = 20). Neuropsychological evaluation and adjudication of normal cognitive status were done by the neuroimaging study or memory clinic. This study administered self-reports of subjective memory complaints, response bias, five-factor personality, and depressive symptoms. Primary group differences were examined with secondary sensitivity analyses to control for sex, age, and education differences. There was no significant difference in over-reporting response bias between study settings. Under-reporting response bias was higher in volunteers. Cognitive complaints were associated with response bias for two cognitive complaint measures. Neuroticism was positively associated with over-reporting in evaluation-seekers and negatively associated with under-reporting in volunteers. The relationship was reversed for Extraversion. Under-reporting bias was positively correlated with Agreeableness and Conscientiousness in volunteers. Evaluation-seekers do not show bias toward over-reporting symptoms compared to volunteers. Under-reporting response bias may be important to consider when screening for memory impairment in non-help-seeking settings. The Memory Functioning Questionnaire was less sensitive to reporting biases. Over-reporting may be a facet of higher Neuroticism. Findings help elucidate psychological influences on self-perceived cognitive decline and help seeking in aging and may inform different strategies for assessment by setting.

Percutaneous Mitral Valve Repair versus Optimal Medical Therapy in Patients with Functional Mitral Regurgitation: A Systematic Review and Meta-Analysis.

Objectives To compare percutaneous mitral valve repair (PMVR) with optimal medical therapy (OMT) in patients with heart failure (HF) and severe functional mitral regurgitation (FMR). Background Many patients with HF and FMR are not suitable for surgical valve replacement and remain symptomatic despite maximal OMT. PMVR has recently emerged as an alternative solution. Methods We performed a systematic review and a meta-analysis to address this question. Cochrane CENTRAL, MEDLINE, and Scopus were searched for randomized (RCT) and nonrandomized studies comparing PMVR with OMT in patients with HF and FMR. Primary endpoint was all-cause midterm mortality (at 1 and 2 years). Secondary endpoints were 30-day mortality and cardiovascular mortality and HF hospitalizations, at maximum follow-up. Studies including mixed cohort of degenerative and functional MR were allowed initially but were excluded in a secondary sensitivity analysis for each of the study's end points. This meta-analysis was performed following the publication of two RCTs (MITRA-FR and COAPT). Results Eight studies (six observational, two RCTs) comprising 3,009 patients were included in the meta-analysis. In comparison with OMT, PMVR significantly reduced 1-year mortality (RR: 0.70 [0.56, 0.87]; p=0.002; I2=47.6%), 2-year mortality (RR: 0.63 [0.55, 0.73]; p<0.001; I2=0%), and cardiovascular mortality (RR: 0.32 [0.23, 0.44]; p<0.001; I2=0%). No significant difference between PMVR+OMT and OMT was noted in HF hospitalization (HR: 0.69 [0.40, 1.20]; p=0.19; I2=85%) and 30-day mortality (RR: 1.13 [0.68, 1.87]; p=0.16; I2=0%). Conclusions In comparison with OMT, PMVR significantly reduces 1-year mortality, 2-year mortality, and cardiovascular mortality in patients with HF and severe MR.

Does exercise impact gut microbiota composition in men receiving androgen deprivation therapy for prostate cancer? A single-blinded, two-armed, randomised controlled trial

IntroductionA potential link exists between prostate cancer (PCa) disease and treatment and increased inflammatory levels from gut dysbiosis. This study aims to examine if exercise favourably alters gut microbiota in...

Use of non-steroidal anti-inflammatory drugs, aspirin and the risk of depression: The “Seguimiento Universidad de Navarra (SUN)” cohort

BackgroundThe potential effect of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) to prevent depression remains largely unknown, in spite of the implication of inflammation in depression. This study aimed to investigate whether the habitual intake of aspirin and other NSAIDs was prospectively associated with a reduction in the observed incidence of depression. MethodsA dynamic cohort including 22,564 Spanish university graduates (mean age: 37 years) initially free of depression was followed during an average of 8.7 years. Exposure to NSAIDs was assessed with specific repeated questionnaires throughout follow-up, starting in the 2-year follow-up questionnaire. Incident cases of depression were defined as either a new validated medical diagnosis of depression or reporting the initiation of habitual use of antidepressants. ResultsWe identified 772 incident cases of depression. Regular intake of aspirin and other NSAIDs was not associated with depression risk. Only in secondary sensitivity analyses using a definition of the outcome with higher specificity (a validated medical diagnosis of depression), an inverse association of aspirin with depression was found [HR (95%CI): 0.20 (0.04–0.87)]. However, these results were non-significant after adjustment for multiple testing. LimitationsA possible underestimation of incident depression and a limited ability to detect all possible residual confounding. ConclusionsRegular use of NSAIDs was not associated with the incidence of depression. Further longitudinal controlled studies are necessary to clarify a potential role of aspirin use in depression risk.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p=0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p=0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p=0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p=0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.

In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death. Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. Two-year survival without neurological impairment occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50th percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not. In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy

IntroductionExercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and...

Sex, Age, and Graft Size as Predictors of ACL Re-tear

Objectives:The minimum size required for a successful quadrupled hamstring autograft ACL reconstruction remains controversial. The risks of ACL re-tear in younger patients who tend to participate in a higher level of sports activity, and female athletes who have numerous predisposing factors, are poorly defined. Purpose: To identify risk factors for graft re-tears within 2 years of ACL surgery. The hypotheses are that female sex, a smaller size graft, and younger patients will increase the odds of failure. Study Design Cohort Study. Level of evidence, 3.Methods:A cohort of 503 athletes undergoing primary, autograft hamstring ACL reconstruction, performed by a single surgeon using the same surgical technique and rehabilitation protocol, between September-December 2012, was followed for a total duration of 2 years. Return to play was allowed between 6 and 12 months post-surgery upon completion of functional testing. Exclusion criteria included infections, revisions, double bundle techniques, multi-ligament injuries, non-compliance, BTB/allografts/hybrid grafts. Primary outcome consisted of binary data (ACL graft re-tear or no tear) as measured on physical exam (Lachman and pivot shift) and MRI. Multivariate logistic regression statistical analysis with model fitting was used to investigate the predictive value of sex, age, and graft size on ACL re-tear. Secondary sensitivity analyses were performed on the adolescent subgroup, age and graft size as categorical variables, and testing for interactions among variables. Sample size was calculated based on the rule of 10 events per independent variable for logistic regression.Results:The mean age of the 503 athletes was 27.5 (SD 10.6; range = 12-61). There were 235 females (47%) and 268 males (53%) with a 6% rate of re-tears (28 patients; 17 females). Mean graft size was 7.9 (SD 0.6; range = 6-10). Univariate analyses of graft size, sex, and age only in the model showed that younger age (odds ratio [OR] = 0.86; 95% confidence interval [CI] = 0.80-0.93; P = .001] and smaller graft size (OR = 0.36; 95% CI = 0.18-0.70; P = .003) were significantly predictive of re-tear. Female sex was correlated with re-tear but was not significant (OR = 1.8; 95% CI = 0.84-3.97; P = .13). Multivariate analysis with all 3 variables in the model showed similar significant results. Graft size < 8 mm (OR = 2.95; 95% CI = 1.33-6.53; P = .008) and age < 25 (OR = 7.01; 95% CI = 2.40-20.53; P = .001) were significantly predictive of re-tear. Entire model was statistically significant (Omnibus test P = .001; Hosmer-Lemeshow statistic P = .68; Receiver Operating Curve [ROC] = 0.8).Conclusion:Surgeons should counsel their patients who are female, younger than 25 and with a graft size less than 8 mm accordingly and consider modifying their surgical or rehabilitation techniques to mitigate these re-tear risks.

Association of Mild Cognitive Impairment With Exposure to General Anesthesia for Surgical and Nonsurgical Procedures: A Population-Based Study

ObjectiveTo examine whether exposure to general anesthesia for operations and procedures after the age of 40 years is associated with incident mild cognitive impairment (MCI) in elderly patients. Patients and MethodsA population-based, prospective cohort of Olmsted County, Minnesota, residents aged 70 to 89 years at enrollment, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. Anesthesia records after the age of 40 years until last evaluation for MCI were abstracted. Proportional hazards regression, adjusting for other known MCI risk factors, was used to assess whether exposure to surgical general anesthesia after the age of 40 years is associated with the incidence of MCI. ResultsOf 1731 participants (mean age, 79 years), 536 (31.0%) developed MCI during a median follow-up of 4.8 years. Anesthesia exposure was not associated with MCI when analyzed as a dichotomous variable (any vs none; adjusted hazard ratio [HR], 1.07; 95% CI, 0.83-1.37; P=.61), the number of exposures (adjusted HR, 1.05; 95% CI, 0.78-1.42; adjusted HR, 1.12; 95% CI, 0.86-1.47; and adjusted HR, 1.02; 95% CI, 0.76-1.34, for 1, 2-3, and ≥4 exposures compared with no exposure as the reference; P=.73), or the total cumulative duration of exposure (adjusted HR, 1.00; 95% CI, 0.98-1.01, per 60-minute increase; P=.83). In secondary sensitivity analyses, anesthesia after 60 years of age was associated with incident MCI (adjusted HR, 1.25; 95% CI, 1.02-1.55; P=.04), as was exposure in the previous 20 and 10 years. ConclusionWe found no significant association between cumulative exposure to surgical anesthesia after 40 years of age and MCI. However, these data do not exclude the possibility that anesthetic exposures occurring later in life may be associated with an increase in the rate of incident MCI.

A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola

To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola. In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included. Based upon the costs of screening 36,453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola. These data demonstrate that NBS and treatment for SCA appear to be highly cost-effective across all scenarios for Angola by the WHO criteria.

Early-onset neonatal group B streptococcus sepsis following national risk-based prevention guidelines.

Neonatal infection with group B streptococcus (GBS) is an important cause of infant mortality. Intrapartum antibiotics reduce early-onset GBS sepsis, but recommendations vary as to whether they should be offered following antenatal screening or based on risk factors alone. We aimed to determine the incidence of early-onset GBS sepsis in NewZealand fiveyears after the publication of national risk-based GBS prevention guidelines. Prospective surveillance of early-onset GBS sepsis (defined as infection in the first 48h of life) was undertaken between April 2009 and March 2011 through the auspices of the New Zealand Paediatric Surveillance Unit as part of a survey of infection presenting in the first week of life. There were 29 cases of confirmed early-onset GBS sepsis, including one case of meningitis, giving an incidence rate of 0.23 per 1000 (95% CI 0.16-0.33) live births. Three infants (10.3%) died. In 16 cases (55%), a maternal risk factor qualifying the mother for intrapartum antibiotics was present, but only five (31%) received this intervention. A retrospective review of the major hospital laboratory databases for this period identified two additional cases. A secondary sensitivity analysis taking account of these cases provided an estimated national incidence of 0.26 (95% CI 0.18-0.37) per1000 live births. Ten years after a similar survey and fiveyears after promoting a single, risk-based prevention protocol nationally, the incidence of early-onset GBS disease in New Zealand has more than halved, but opportunities remain to further reduce the rate.

Capsule Commentary on Michaelidis et al., Cost-Effectiveness of Decision Support Strategies in Acute Bronchitis

U sing cost-effectiveness analysis (CEA) to make decisions about health care resources faces significant political and popular opposition in the U.S. The Affordable Care Act (ACA) explicitly prohibits the use of Quality Adjusted Life Years in determining coverage or reimbursement or recommending treatments, and the executive director of the Patient Centered Outcomes Research Institute (PCORI) has distanced the organization from CEA altogether. Michaelidis, et al.’s cost-effectiveness analysis was based on estimates of effect derived from a cluster-randomized trial by Gonzales et al. that compared printed decision support (PDS) and computer-assisted decision support (CDS) with usual care. That article’s point estimates for the odds ratios of antibiotic prescribing were used in the base case (0.57 for the PDS strategy and 0.64 for CDS). However, the 95 % confidence intervals for the two strategies overlapped almost completely, indicating that the adjusted odds of antibiotic use were not different. The authors attempt to address this issue in a secondary sensitivity analysis and conclude that the PDS strategy cost $220 less per patient. Operationally, the only difference between the two interventions was that one had posters, while the other incurred computer programming costs. The cost difference seems to have resulted because the CEA also retained the point estimates from the original trial for rates of return to clinic within 30 days and use of chest x-rays. In both cases, the nominal rates were higher at the CDS sites than at the PDS sites. Yet the original study states BReturn visit rates...increased modestly at all study sites and were not significantly different among study sites.^ With no difference in prescriptions avoided and no difference in associated utilization, the cost difference comes down to the comparison between the direct costs of poster printing vs. computer programming. With Meaningful Use incentives driving health systems to adopt electronic decision support, it is useful to be reminded that more traditional means of physician education can be equally cost-effective. However, some would argue that a methodologically complex analysis like CEA was not required to determine that posters are probably less costly than computer programming time.

Implementation of an Advanced Practice Provider Service on an Allogeneic Stem Cell Transplant Unit: Impact on Patient Outcomes

Allogeneic stem cell transplantation (ASCT) is a complex medical procedure for some patients with hematologic malignancies. Most ASCTs occur at academic centers where either medical residents (house staff [HS]) or advanced practice providers (APPs) provide daily care. As a result of increasing work-hour regulations, APPs have assumed greater responsibilities, including those traditionally held by HS. In this study we evaluate ASCT patient outcomes by inpatient provider service. A retrospective, single-center chart review of ASCT patients was performed. ASCT patients admitted to an HS service from May 2011 to May 2012 (N = 86) were compared with ASCT patients admitted to a newly formed APP service from October 2012 to October 2013 (N = 81). As part of a secondary sensitivity analysis, we compared ASCT patients on the APP service to a subset of ASCT patients admitted to the HS service also from October 2012 to October 2013 (n = 27). Our primary outcomes were 100-day survival and relapse-free survival rates. Additional outcomes included length of stay (LOS), inpatient complications, and ordering behavior. Our primary pre- and post-analyses found no differences in 100-day overall survival and 100-day relapse-free survival rate between the services. The rate of pneumonia was lower on the APP service (15% versus 28%, P = .04), with no significant differences in other infectious complications. HS ordered more blood cultures (6.7 versus 4.2, P = .03) per patient than the APP service. There was no difference in LOS, readmission rates, or inpatient mortality. With regards to our secondary sensitivity analysis, no differences were found in 100-day overall survival and 100-day relapse-free survival rates between the services. There was a decreased LOS on the APP service (29.4 versus 37.2 days, P = .01). HS ordered more blood cultures (9.3 versus 4.2, P < .01) and more radiological films (8.1 versus 5.2, P = .05) per patient than the APP service. This increased ordering and LOS was associated with an increase in mean hospital charges on the HS service (P = .04). ASCT patients on an APP service had similar 100-day outcomes as those on the HS service. In the setting of limited resources, APPs are potential alternative providers for complex transplant inpatients.

HIV and helminths: time for a new direction

HIV and helminths: time for a new direction