Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial.

BACKGROUND: The incidence of Gram-negative bacteraemia is rising globally and remains a major cause of morbidity and mortality. The majority of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. However, it remains unclear whether patients can step down to oral antibiotics after appropriate clinical response has been observed without compromising outcomes. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated adverse events, enhances patient quality of life and reduces healthcare costs. As current management of Gram-negative bacteraemia entails a duration of IV therapy with limited evidence to guide oral conversion, we aim to evaluate the clinical efficacy and economic impact of early stepdown to oral antibiotics. METHODS: This is an international, multicentre, randomised controlled, open-label, phase III, non-inferiority trial. To be eligible, adult participants must be clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. Randomisation to the intervention or standard arms will be performed with 1:1 allocation ratio. Participants randomised to the intervention arm (within 72 h from index blood culture collection) will be immediately switched to an oral fluoroquinolone or trimethoprim-sulfamethoxazole. Participants randomised to the standard arm will continue to receive IV therapy for at least 24 h post-randomisation before clinical re-assessment and decision-making by the treating doctor. The recommended treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Primary outcome is 30-day all-cause mortality, and the key secondary outcome is health economic evaluation, including estimation of total healthcare cost as well as assessment of patient quality of life and number of quality-adjusted life years saved. Assuming a 30-day mortality of 8% in the standard and intervention arms, with 6% non-inferiority margin, the target sample size is 720 participants which provides 80% power with a one-sided 0.025 α-level after adjustment for 5% drop-out. DISCUSSION: A finding of non-inferiority in efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV standard of care antibiotics may hypothetically translate to wider adoption of a more cost-effective treatment strategy with better quality of life outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05199324 . Registered 20 January 2022.

Cost-Effectiveness of Drug-Coated Balloon Angioplasty Compared With Conventional Balloon Angioplasty for Arteriovenous Access Flow Dysfunction.

OBJECTIVES: This study aimed to determine the cost-effectiveness of drug-coated balloon (DCB) angioplasty compared with conventional balloon angioplasty (cPTA) in patients with arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) dysfunction from a Singapore healthcare perspective. METHODS: Existing cost-effectiveness studies comparing DCB and cPTA have not incorporated AVF/AVG abandonment costs. This Markov model-based economic evaluation incorporated AVF/AVG creation and maturation costs on top of routine intervention costs to model a hypothetical cohort of 60-year-old AVF/AVG flow dysfunction patients. Effectiveness was measured in quality-adjusted life-years. Cost-effectiveness was assessed using incremental net monetary benefit (NMB) at a Singapore willingness-to-pay threshold of Singapore dollar (S$)87 000. Deterministic and probabilistic sensitivity analyses were performed to examine parameter uncertainty. To test hypotheses regarding cost-effectiveness, intervention counts per patient, cumulative incidence functions of AVF/AVG abandonment, and survival curves of death were compared between DCB and cPTA. RESULTS: DCB was not cost-effective at 3-year horizon (NMB = -S$1424), but was cost-effective at 1- and 6-year horizons (NMB = S$356 and S$3738, respectively). At 3 years, there was a 34.5% probability of DCB being cost-effective, but at 1- and 6-year horizons there was, respectively, 58.6% and 59.9% probability of DCB being cost-effective. DCB had graphically less AVF/AVG-abandonments, but this was not statistically significant (P = .21). Differences in other parameters were neither graphically nor statistically significant. CONCLUSIONS: With AVF/AVG abandonment considered, DCB may be weakly cost-effective compared with cPTA in treating AVF/AVG flow dysfunction. AV access creation and maturation costs could have important explanatory value in assessing DCB cost-effectiveness.

Cost-effectiveness of Web-Based and Home-Based Postnatal Psychoeducational Interventions for First-time Mothers: Economic Evaluation Alongside Randomized Controlled Trial.

BACKGROUND: The cost-effectiveness of interventions has attracted increasing interest among researchers. Although web-based and home-based psychoeducational interventions have been developed to improve first-time mothers' postnatal health outcomes, very limited studies have reported their cost-effectiveness. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of web-based and home-based postnatal psychoeducational interventions for first-time mothers during the early postpartum period. METHODS: A randomized controlled 3-group pretest and posttest design was adopted, and cost-effectiveness analysis from the health care's perspective was conducted. A total of 204 primiparas were recruited from a public tertiary hospital in Singapore from October 2016 to August 2017 who were randomly allocated to the web-based intervention (n=68), home-based intervention (n=68), or control (n=68) groups. Outcomes of maternal parental self-efficacy, social support, postnatal depression, anxiety, and health care resource utilization were measured using valid and reliable instruments at baseline and at 1 month, 3 months, and 6 months after childbirth. The generalized linear regression models on effectiveness and cost were used to assess the incremental cost-effectiveness ratios of the web-based and home-based intervention programs compared to routine care. Projections of cumulative cost over 5 years incurred by the 3 programs at various coverage levels (ie, 10%, 50%, and 100%) were also estimated. RESULTS: The web-based intervention program dominated the other 2 programs (home-based program and routine care) with the least cost (adjusted costs of SGD 376.50, SGD 457.60, and SGD 417.90 for web-based, home-based, and control group, respectively; SGD 1=USD 0.75) and the best improvements in self-efficacy, social support, and psychological well-being. When considering the implementation of study programs over the next 5 years by multiplying the average cost per first-time mother by the estimated average number of first-time mothers in Singapore during the 5-year projection period, the web-based program was the least costly program at all 3 coverage levels. Based on the 100% coverage, the reduced total cost reached nearly SGD 7.1 million and SGD 11.3 million when compared to control and home-based programs at the end of the fifth year, respectively. CONCLUSIONS: The web-based approach was promisingly cost-effective to deliver the postnatal psychoeducational intervention to first-time mothers and could be adopted by hospitals as postnatal care support. TRIAL REGISTRATION: ISRCTN registry ISRCTN45202278; https://www.isrctn.com/ISRCTN45202278.

A Systemic Review and Meta-analysis of Transabdominal Intravesical Prostatic Protrusion Assessment in Determining Bladder Outlet Obstruction and Unsuccessful Trial Without Catheter.

CONTEXT: Urodynamic study (UDS) provides the most objective assessment of bladder outlet obstruction (BOO) but is impractical to be recommended routinely in outpatient services. Intravesical prostatic protrusion (IPP) had been described to obstruct urinary flow by creating an anatomical ball-valve effect, but there remains a lack of pooled evidence that can objectively correlate with BOO in benign prostatic hyperplasia. OBJECTIVE: To update the current evidence on the predictive role of IPP in determining BOO and unsuccessful trial without catheter (TWOC). EVIDENCE ACQUISITION: A comprehensive literature search was performed to identify studies that evaluated IPP in diagnosing UDS-determined BOO and TWOC. The search included the PubMed/MEDLINE, EMBASE, and Cochrane Library up to January 2021. An updated systemic review and meta-analysis was performed. EVIDENCE SYNTHESIS: A total of 18 studies with 4128 patients were examined. Eleven studies with 1478 patients examined the role of IPP in UDS-determined BOO. The pooled area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.79-0.86), and at a cut-off of >10 mm, the sensitivity (Sn) and specificity (Sp) were 0.71 (95% CI: 0.61-0.78) and 0.77 (95% CI: 0.68-0.84), respectively. The probability-modifying plot revealed positive and negative likelihood ratios of 3.34 (95% CI: 2.56-4.36) and 0.35 (95% CI: 0.26-0.45), respectively. Seven studies with 2650 patients examined IPP in predicting unsuccessful TWOC, with a pooled AUC of 0.74 (95% CI: 0.70-0.84), with Sn of 0.51 (95% CI: 0.43-0.60) and Sp of 0.79 (95% CI: 0.73-0.84) at an IPP cut-off of >10 mm. Five studies compared prostate volume (PV) and IPP and revealed a lower AUC of PV at 0.71 (95% CI: 0.67-0.75), which was an inferior parameter in diagnosing BOO (p < 0.001). CONCLUSIONS: This systemic review provided evidence that IPP is a reliable clinical parameter that correlates strongly with underlying BOO and unsuccessful TWOC. PATIENT SUMMARY: In this review, we comprehensively reviewed all the literature to date on evaluating the clinical utility of intravesical prostatic protrusion (IPP). We have demonstrated that IPP correlates strongly with urodynamic study (UDS)-determined bladder outlet obstruction and failure of trial without catheter (TWOC). Outpatient IPP measurement is a quick, inexpensive, and reproducible clinical parameter that can determine the severity of benign prostatic hyperplasia. The clinical role of IPP in predicting failure of TWOC selects patients who are best treated with aggressive surgical approaches rather than conservative medical therapies. More importantly, IPP can facilitate the discriminatory use of invasive UDS, reserved for patients with a strong suspicion of concomitant detrusor abnormalities.

Academic school readiness in children born very preterm and associated risk factors.

BACKGROUND AND AIMS: Although the intelligence quotient (IQ) test is useful to assess general cognitive function, it may miss more specific and subtle deficits of learning, working memory, attention and executive function. This study aims to evaluate cognitive performance and academic school readiness (SR) concepts in preterm very low birth weight (PT/VLBW) children, compared to typically developing term controls and to evaluate factors affecting basic (SR) concepts in children with IQ>85. METHODS: A prospective cohort study of 123 PT/VLBW survivors with birth weights ≤1250 g and 74 term controls born between 2007 and 2009 in Singapore were assessed for school readiness using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), Bracken School Readiness Assessment (BSRA-3) and Beery-Buktenica Developmental Test of Visual Motor Integration (VMI) at age 5.5 years. Social risk composite score (SRCS) was calculated based on ethnicity, parental education and family income and marital status. Uni- and multi-variable regressions were conducted to evaluate risk factors associated with poor academic SR in the entire cohort and in those with IQ >85. RESULTS: Mean gestational age and birth weight of the 123 PT/VLBW children were 27.8 (2.3) weeks and 939 (194) grams while that of the 74 term controls were 38.8 (1.2) weeks and 3165 (402) grams. PT/VLBW survivors had statistically significant lower full composite scores on WPPSI-III (97.0 vs 114), BSRA-3 (98.5 vs 112.3) and VMI (107.2 vs 112.9) compared to controls. The differences remained significant in preterm and children with higher SRCS even after adjustment. CONCLUSIONS: Prematurity and high social composite risk scores were risk factors affecting academic SR and this difference persisted in PT/VLBW children with normal cognitive scores with IQ >85.

Cost-effectiveness analysis of liver resection versus transplantation for early hepatocellular carcinoma within the Milan criteria.

UNLABELLED: Both liver resection (LR) and cadaveric liver transplantation (CLT) are potentially curative treatments for patients with hepatocellular carcinoma (HCC) within the Milan criteria and with adequate liver function. Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of LR against CLT for patients with HCC within the Milan criteria using a decision analytic model. A Markov cohort model was developed to simulate a cohort of patients aged 55 years with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, undergoing LR or CLT, and followed up over their remaining life expectancy. Analysis was performed in different geographical cost settings: the USA, Switzerland and Singapore. Transition probabilities were obtained from systematic literature reviews, supplemented by databases from Singapore and the Organ Procurement and Transplantation Network (USA). Utility and cost data were obtained from open sources. LR produced 3.9 quality-adjusted life years (QALYs) while CLT had an additional 1.4 QALYs. The incremental cost-effectiveness ratio (ICER) of CLT versus LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland, and was above thresholds for cost-effectiveness in all three countries. Sensitivity analysis revealed that CLT-related 5-year cumulative survival, one-time cost of CLT, and post-LR 5-year cumulative recurrence rates were the most sensitive parameters in all cost scenarios. ICERs were reduced below threshold when CLT-related 5-year cumulative survival exceeded 84.9% and 87.6% in Singapore and the USA, respectively. For Switzerland, the ICER remained above the cost-effectiveness threshold regardless of the variations. CONCLUSION: In patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, LR is more cost-effective than CLT across three different costing scenarios: the USA, Switzerland, Singapore.