Assessment of occupational stress among certified registered anesthetists in the Greater Accra region.

Background: Work-related stress is a prevailing concern within the community of Certified Registered Anesthetists (CRAs), significantly impacting both the health and professional performance of these individuals. This study aimed to assess work-related stress and its influencing factors among CRAs practicing in the Greater Accra region was examined. Methods: Using convenience sampling techniques, data were gathered from 140 participants via a Google form questionnaire distributed through WhatsApp. Descriptive statistics were employed to analyze the collected data, focusing on frequencies and proportions for categorical variables. For continuous variables, bivariate analysis (Chi-square) and ordinal logistic regression were conducted using STATA 16. A p-value <0.05 was considered significant. Results: Among the 140 CRAs, 20 individuals (14.3%) reported experiencing mild stress levels according to the Weiman Occupational Stress Scale. Approximately 3 out of 4 CRAs (73.6%) reported having moderate stress levels, and 12.1% reported severe stress levels. This indicated that the majority of CRAs experienced moderate levels of stress, which was notably affected by the type of health facility and the use of inadequate or sub-standard equipment in the hospitals. Conclusion: Based on these findings, the study recommends educational programs and counseling for CRAs to heighten awareness of the demanding nature of their job. Additionally, it suggests the provision of proper resources and standard equipment for CRAs. Facility-level motivation for CRAs is also advised to alleviate their stress. Finally, the study proposes further investigations into the factors contributing to work-related stress among CRAs.

The epidemiological and economic burden of diabetes in Ghana: A scoping review to inform health technology assessment.

Diabetes remains one of the four major causes of morbidity and mortality globally among non-communicable diseases (NCDs. It is predicted to increase in sub-Saharan Africa by over 50% by 2045. The aim of this study is to identify, map and estimate the burden of diabetes in Ghana, which is essential for optimising NCD country policy and understanding existing knowledge gaps to guide future research in this area. We followed the Arksey and O'Malley framework for scoping reviews. We searched electronic databases including Medline, Embase, Web of Science, Scopus, Cochrane and African Index Medicus following a systematic search strategy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews was followed when reporting the results. A total of 36 studies were found to fulfil the inclusion criteria. The reported prevalence of diabetes at national level in Ghana ranged between 2.80%- 3.95%. At the regional level, the Western region reported the highest prevalence of diabetes: 39.80%, followed by Ashanti region (25.20%) and Central region at 24.60%. The prevalence of diabetes was generally higher in women in comparison to men. Urban areas were found to have a higher prevalence of diabetes than rural areas. The mean annual financial cost of managing one diabetic case at the outpatient clinic was estimated at GHS 540.35 (2021 US $194.09). There was a paucity of evidence on the overall economic burden and the regional prevalence burden. Ghana is faced with a considerable burden of diabetes which varies by region and setting (urban/rural). There is an urgent need for effective and efficient interventions to prevent the anticipated elevation in burden of disease through the utilisation of existing evidence and proven priority-setting tools like Health Technology Assessment (HTA).

Rotavirus vaccine product switch in Ghana: An assessment of service delivery costs, switching costs, and cost-effectiveness.

Ghana introduced rotavirus vaccine (ROTARIX 1-dose presentation) into the routine national immunization program in 2012 and switched to a different product (ROTAVAC 5-dose presentation) in 2020. ROTAVAC has a lower price per dose (US$0.85 versus US$2.15 for ROTARIX) and smaller cold chain footprint but requires more doses per regimen (three versus two). This study estimates the supply chain and service delivery costs associated with each product, the costs involved in switching products, and compares the cost-effectiveness of both products over the next ten years. We estimated the supply chain and service delivery costs associated with ROTARIX and ROTAVAC (evaluating both the 5-dose and 10-dose presentations) using primary data collected from health facilities in six of the 14 regions in the country. We estimated the costs of switching from ROTARIX to ROTAVAC using information collected from key informant interviews and financial records provided by the government. All costs were reported in 2020 US$. We used the UNIVAC decision-support model to evaluate the cost-effectiveness (US$ per disability-adjusted life-year (DALY) averted from government and societal perspectives) of ROTARIX and ROTAVAC (5-dose or 10-dose presentations) compared to no vaccination, and to each other, over a ten-year period (2020 to 2029). We ran probabilistic sensitivity analyses and other threshold analyses. The supply chain and service delivery economic cost per dose was $2.40 for ROTARIX, $1.81 for ROTAVAC 5-dose, and $1.76 for ROTAVAC 10-dose. The financial and economic cost of switching from ROTARIX to ROTAVAC 5-dose was $453,070 and $883,626, respectively. Compared to no vaccination, the cost per DALY averted was $360 for ROTARIX, $298 for ROTAVAC 5-dose, and $273 for ROTAVAC 10-dose. ROTAVAC 10-dose was the most cost-effective option and would be cost-effective at willingness-to-pay thresholds exceeding 0.12 times the national GDP per capita ($2,206 in the year 2020). The switch from ROTARIX to ROTAVAC 5-dose in 2020 was cost-saving. Rotavirus vaccination is highly cost-effective in Ghana. A switch from ROTAVAC 5-dose to ROTAVAC 10-dose would be cost-saving and should be considered.

Sleep and Happiness in Urban-Dwelling Older Adults in Ghana: A Serial Multiple Mediation Model of Generalized Anxiety and Depressive Symptoms.

OBJECTIVE: Sleep problems (SP) are highly prevalent and seriously affect health and well-being in old age. The aim of this study was to examine the association between SP and happiness in an urban-dwelling older sample. The authors further explore the effects of generalized anxiety and depressive symptoms in the SP-happiness link using serial mediating modeling. METHODS: Data came from the 2016 to 2018 Aging, Health, Psychological Well-being, and Health-seeking Behavior Study in Ghana (n = 661). The authors measured happiness with the cross-culturally validated item on a five-point scale. The GAD-7 and the CESD-8, respectively, assessed generalized anxiety and depressive symptoms. Participants reported nighttime and daytime SP in the last 30 days. The SPSS-based Hayes' PROCESS macro program (Model 6) was constructed to quantify the hypothesized mediation effect. RESULTS: The analysis included 661 adults aged greater than or equal to 50 years (mean age = 65.53 [SD] = 11.89 years; 65.20% women). After full adjustment, path models showed that SP was negatively associated with happiness (ß = -0.1277, 95%CI = -0.15950 to -0.096). Bootstrapping estimates revealed that the SP-happiness link was serially mediated via generalized anxiety representing 8.77%, depressive symptoms yielding 18.95%, and anxiety symptoms→depressive symptoms accounting for 26.70% of the total effect. CONCLUSION: Generalized anxiety and depressive symptoms may explain the negative association between SP and happiness in urban-dwelling older adults in the sub-Saharan African (SSA) context. Interventions, social and clinical, to improve happiness through sleep quality should include ways to improve mental health. Longitudinal and cross-cultural data are warranted to assess the bi-directionality of this relationship.

Cost of inappropriate prescriptions for uncomplicated malaria in Ghana.

BACKGROUND: Malaria remains a common course of morbidity in many sub-Saharan African countries. While treatment options have improved in recent times, inappropriate prescription seems conventional among providers, increasing the burden on patients and society. This study examined the cost of inappropriate prescriptions for uncomplicated malaria treatment in Ghana. METHODS: This study used retrospective data collected from January to December 2016 in 27 selected facilities, under different ownership in three regions of the country, mainly Volta, Upper East and Brong Ahafo. Stratified random sampling technique was used to extract 1625 outpatient folders of patients diagnosed and treated for malaria. Two physicians independently reviewed patient folders according to the stated diagnoses. Malaria prescriptions were described as inappropriate when they do not adhere to the standard treatment guidelines. The economic cost was mainly treatment cost which was sourced as medication cost. Total and average costs for country were calculated using sample estimates and the total number of uncomplicated malaria cases that received inappropriate prescriptions. RESULTS: The study revealed that patients received an average of two prescriptions per malaria episode. Artemether-lumefantrine (AL) was the major malaria medication (79.5%) prescribed to patients. Other medications usually antibiotics and vitamins and minerals were included in the prescription. More than 50% of prescribers did not follow the guidelines for prescribing medications to clients. By facility type, inappropriate prescription was high in the CHPS compounds (59.1%) and by ownership, government (58.3%), private (57.5%) and mission facilities (50.7%). Thus, about 55% of malaria prescriptions were evaluated as inappropriate during the review period, which translates into economic cost of approximately US$4.52 million for the entire country in 2016. The total cost of inappropriate prescription within the study sample was estimated at US$1,088.42 while the average cost was US$1.20. CONCLUSION: Inappropriate prescription for malaria is a major threat to malaria management in Ghana. It presents a huge economic burden to the health system. Training and strict enforcement of prescribers' adherence to the standard treatment guideline is highly recommended.

Estimating the cost of COVID-19 vaccine deployment and introduction in Ghana using the CVIC tool.

BACKGROUND: This study estimated cost of COVID-19 vaccine introduction and deployment in Ghana. METHODS: Using the WHO-UNICEF COVID-19 Vaccine Introduction and deployment Costing (CVIC) tool Ghana's Ministry of Health Technical Working Group for Health Technology Assessment (TWG-HTA) in collaboration with School of Public Health, University of Ghana, organized an initial two-day workshop that brought together partners to deliberate and agree on input parameters to populate the CVIC tool. A further 2-3 days validation with the Expanded Program of Immunization (EPI) and other partners to finalize the analysis was done. Three scenarios, with different combinations of vaccine products and delivery modalities, as well as time period were analyzed. The scenarios included AstraZeneca (40%), Johnson & Johnson (J&J) (30%), Moderna, Pfizer, and Sputnik V at 10% each; with primary schedule completed by second half of 2021 (Scenario 1); AstraZeneca (30%), J&J (40%), Moderna, Pfizer, and Sputnik V at 10% each with primary schedule completed by first half of 2022 (Scenario 2); and equal distribution (20%) among AstraZeneca, J&J, Moderna, Pfizer, and Sputnik V with primary schedule completed by second half of 2022 (Scenario 3). RESULTS: The estimated total cost of COVID-19 vaccination ranges between $348.7 and $436.1 million for the target population of 17.5 million. These translate into per person completed primary schedule cost of $20.9-$26.2 and per dose (including vaccine cost) of $10.5-$13.1. Again, per person completed primary schedule excluding vaccine cost was $4.5 and $4.6, thus per dose excluding vaccine also ranged from $2.2 - $2.3. The main cost driver was vaccine doses, including shipping, which accounts for between 78% and 83% of total cost. Further, an estimated 8,437-10,247 vaccinators (non-FTEs) would be required during 2021-2022 to vaccinate using a mix of delivery strategies, accounting for 8-10% of total cost. CONCLUSION: These findings provide the estimates to inform resource mobilization efforts by government and other partners.

Correction: How does it affect service delivery under the National Health Insurance Scheme in Ghana? Health providers and insurance managers perspective on submission and reimbursement of claims.

[This corrects the article DOI: 10.1371/journal.pone.0247397.].

How does it affect service delivery under the National Health Insurance Scheme in Ghana? Health providers and insurance managers perspective on submission and reimbursement of claims.

INTRODUCTION: In 2003, the Government of Ghana launched the National Health Insurance Scheme (NHIS) to enable all Ghanaian residents to have access to health services at the point of care without financial difficulty. However, the system has faced a number of challenges relating to delays in submission and reimbursement of claims. This study assessed views of stakeholders on claims submission, processing and re-imbursement under the NHIS and how that affected health service delivery in Ghana. METHODS: The study employed qualitative methods where in-depth interviews were conducted with stakeholders in three administrative regions in Ghana. Purposive sampling method was used to select health facilities and study participants for the interviews. QSR Nvivo 12 software was used to code the data into themes for thematic analysis. RESULTS: The results point to key barriers such as lack of qualified staff to process claims, unclear vetting procedure and the failure of National Health Insurance Scheme officers to draw the attention of health facility staff to resolve discrepancies on time. Participants perceived that lack of clarity, inaccurate data and the use of non-professional staff for NHIS claims vetting prolonged reimbursement of claims. This affected operations of credentialed health facilities including the provision of health services. It is perceived that unavailability of funds led to re-use of disposable medical supplies in health service delivery in credentialed health facilities. Stakeholders suggested that submission of genuine claims by health providers and regular monitoring of health facilities reduces errors on claims reports and delays in reimbursement of claims. CONCLUSION: Long delays in claims reimbursement, perceived vetting discrepancies affect health service delivery. Thus, effective collaboration of all stakeholders is necessary in order to develop a long-term strategy to address the issue under the NHIS to improve health service delivery.

Poor Compliance With Postvasectomy Semen Testing: Analysis of Factors and Barriers.

OBJECTIVE: To ensure procedure success, American Urological Association Guidelines recommend postvasectomy semen analysis (PVSA); however, current literature suggests poor compliance. We sought to measure PVSA compliance and assess barriers to completion. METHODS: A retrospective review was performed of vasectomies at San Diego Veterans Administration Hospital and UC San Diego Health between 2006 and 2018. Patients received preprocedural counseling regarding semen analysis necessity. Postprocedural management included follow-up visit within 2-4 weeks and semen analysis after 15-20 ejaculations. Demographics and periprocedural variables were collected. Telephone interviews assessed patient reported reasons for noncompliance. Multivariable analysis was performed for factors associated with semen analysis. RESULTS: 503 men, mean age 38.8 years, underwent vasectomy at San Diego Veterans Administration Hospital (n = 331) and UC San Diego (n = 172). Overall, 80% completed clinical follow-up (n = 401) and 53% completed semen analysis (n = 268). The cohorts exhibited significantly different rates of semen analysis completion (46% vs 67%, P <.001) and clinical follow-up (64% vs 85%, P = .038). No difference was observed in age, fatherhood, or marital status. On multivariable analysis, fatherhood was the only factor associated with noncompliance of semen analysis (odds ratio 0.52, 95% confidence interval 0.33-0.83). Among men interviewed, the primary barriers to semen analysis completion were distance (38%), time constraints (34%), and forgetfulness (23%). Ninety-two% reported increased likelihood of completion with home-based semen testing. CONCLUSION: Patients demonstrated poor PVSA compliance despite preprocedural counseling. Given that distance and time constraints limited compliance, incorporating home-based semen testing may improve the quality of care for men undergoing vasectomy.

Diagnostic capacity, and predictive values of rapid diagnostic tests for accurate diagnosis of Plasmodium falciparum in febrile children in Asante-Akim, Ghana.

BACKGROUND: This study seeks to compare the performance of HRP2 (First Response) and pLDH/HRP2 (Combo) RDTs for falciparum malaria against microscopy and PCR in acutely ill febrile children at presentation and follow-up. METHODS: This is an interventional study that recruited children < 5 years who reported to health facilities with a history of fever within the past 72 h or a documented axillary temperature of 37.5 °C. Using a longitudinal approach, recruitment and follow-up of participants was done between January and May 2012. Based on results of HRP2-RDT screening, the children were grouped into one of the following three categories: (1) tested positive for malaria using RDT and received anti-malarial treatment (group 1, n = 85); (2) tested negative for malaria using RDT and were given anti-malarial treatment by the admitting physician (group 2, n = 74); or, (3) tested negative for malaria using RDT and did not receive any anti-malarial treatment (group 3, n = 101). Independent microscopy, PCR and Combo-RDT tests were done for each sample on day 0 and all follow-up days. RESULTS: Mean age of the study participants was 22 months and females accounted for nearly 50%. At the time of diagnosis, the mean body temperature was 37.9 °C (range 35-40.1 °C). Microscopic parasite density ranged between 300 and 99,500 parasites/µL. With microscopy as gold standard, the sensitivity of HRP2 and Combo-RDTs were 95.1 and 96.3%, respectively. The sensitivities, specificities and predictive values for RDTs were relatively higher in microscopy-defined malaria cases than in PCR positive-defined cases. On day 0, participants who initially tested negative for HRP2 were positive by microscopy (n = 2), Combo (n = 1) and PCR (n = 17). On days 1 and 2, five of the children in this group (initially HRP2-negative) tested positive by PCR alone. On day 28, four patients who were originally HRP2-negative tested positive for microscopy (n = 2), Combo (n = 2) and PCR (n = 4). CONCLUSION: The HRP2/pLDH RDTs showed comparable diagnostic accuracy in children presenting with an acute febrile illness to health facilities in a hard-to-reach rural area in Ghana. Nevertheless, discordant results recorded on day 0 and follow-up visits using the recommended RDTs means improved malaria diagnostic capability in malaria-endemic regions is necessary.

Targeted community based interventions improved malaria management competencies in rural Ghana.

BACKGROUND: Malaria is one of the most challenging public health concerns in the developing world. To address its impact in endemic regions, several interventions are implemented by stakeholders. The Affordable Medicine Facility-malaria (AMFm) is an example of such interventions. Its activities include communication interventions to enhance the knowledge of caregivers of children under five years, licensed chemical sellers (LCS) and prescribers on malaria management with artemisinin-based combination therapy (ACT). This study was conducted to evaluate the effectiveness of the AMFm activities on malaria among targeted groups in two rural communities in Ghana. METHODS: A communication intervention study was conducted in the Asante-Akim North and South Districts of Ghana. Repeated cross-sectional pre and post surveys were deployed. Relevant malaria messages were designed and used to develop the information, education and communication (IEC) tools for the intervention. With the aid of posters and flipcharts developed by our study, community health workers (CHWs), prescribers, and licenced chemical sellers provided proper counselling to clients on malaria management. Trained CHWs and community based volunteers educated caregivers of children under five years on malaria management at their homes and at public gatherings such as churches, mosques, schools. Chi-square tests and logistic regression were run to determine associations and control for demographic differences respectively. RESULTS: There was significantly high exposure to malaria/ACT interventions in the intervention district than in the comparison district (OR = 16.02; 95% CI = 7.88-32.55) and same for malaria/ACT-related knowledge (OR = 3.63; 95% CI = 2.52-5.23). The participants in the intervention district were also more knowledgeable about correct administration of dispersible drug for children <5 years than their counterparts in the unexposed district. CONCLUSION: Our data show that targeted interventions improve malaria based competences in rural community settings. The availability of subsidized ACTs and the intensity of the communication campaigns contributed to the AMFm-related awareness, improved knowledge on malaria/ACTs and management practices.

Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer.

BACKGROUND: Abnormal methylation of urinary TWIST1 and NID2 conferred high sensitivity and specificity for the detection of urothelial carcinoma. OBJECTIVE: We examine the performance of the urine-based TWIST1/NID2 methylation assay with the addition of urine cytology for the detection of urothelial carcinoma. MATERIALS AND METHODS: A prospective multi-institutional study was conducted to assess the performance of a methylation assay for patients with hematuria or under surveillance for non-muscle invasive bladder cancer (NMIBC). All patients underwent cystoscopy, a methylation assay, and cytology. Receiver operator characteristic (ROC) curves were constructed for cytology alone, the methylation assay alone, and a combined model. Areas under the curve (AUC) were compared using likelihood ratio tests. RESULTS: A total of 172 patients were enrolled (37% for hematuria and 63% NMIBC). The AUC for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001). When the equivocal cytologies were considered negative, the AUC improved from 0.558 to 0.697 with the addition of the DNA methylation assay (p = 0.003). CONCLUSIONS: Addition of a TWIST1/NID2-based DNA methylation assay adds diagnostic value to urine cytology and the model is sensitive to the classification of equivocal cytology.

Anticipatory Positive Urine Tests for Bladder Cancer.

PURPOSE: The aim of this study was to establish the criteria defining an anticipatory positive test for bladder cancer. METHODS: We reviewed all patients at our institution who underwent urine cytology or UroVysion fluorescence in situ hybridization (FISH) and cystoscopy from 2003 to 2012. Test performance and cancer anticipation was assessed using generalized linear mixed models, mixed-effects proportional hazards models, and cumulative incidence curves using tests performed within 30 days of each other as well as within a lag time of 1 year. RESULTS: Overall, 6729 urine tests (4729 cytology and 2040 UroVysion FISH) were paired with gold-standard cystoscopies. Sensitivity and specificity were 63 and 41% for cytology, and 37 and 84% for UroVysion FISH, respectively. A 1-year lag time allowed for cancer anticipation and neither test improved. Among patients with positive cytology and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.83; 76% of these patients developed a tumor within 1 year. Similarly, among patients with a positive FISH and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.56; 40% of these patients developed a tumor within 1 year. CONCLUSIONS: Urine-based tests for bladder cancer are frequently falsely positive. With further follow-up time, some of these false positive tests are vindicated as true (anticipatory) positive tests, although many will remain false positives. We developed statistical criteria to determine if a test anticipates future cancers or not.

The diagnostic accuracy of urine-based tests for bladder cancer varies greatly by patient.

BACKGROUND: Spectrum effects refer to the phenomenon that test performance varies across subgroups of a population. When spectrum effects occur during diagnostic testing for cancer, difficult patient misdiagnoses can occur. Our objective was to evaluate the effect of test indication, age, gender, race, and smoking status on the performance characteristics of two commonly used diagnostic tests for bladder cancer, urine cytology and fluorescence in situ hybridization (FISH). METHODS: We assessed all subjects who underwent cystoscopy, cytology, and FISH at our institution from 2003 to 2012. The standard diagnostic test performance metrics were calculated using marginal models to account for clustered/repeated measures within subjects. We calculated test performance for the overall cohort by test indication as well as by key patient variables: age, gender, race, and smoking status. RESULTS: A total of 4023 cystoscopy-cytology pairs and 1696 FISH-cystoscopy pairs were included in the analysis. In both FISH and cytology, increasing age, male gender, and history of smoking were associated with increased sensitivity and decreased specificity. FISH performance was most impacted by age, with an increase in sensitivity from 17 % at age 40 to 49 % at age 80. The same was true of cytology, with an increase in sensitivity from 50 % at age 40 to 67 % at age 80. Sensitivity of FISH was higher for a previous diagnosis of bladder cancer (46 %) than for hematuria (26 %). Test indication had no impact on the performance of cytology and race had no significant impact on the performance of either test. CONCLUSIONS: The diagnostic performance of urine cytology and FISH vary significantly according to the patient demographic in which they were tested. Hence, the reporting of spectrum effects in diagnostic tests should become part of standard practice. Patient-related factors must contextualize the clinicians' interpretation of test results and their decision-making.

Insights into the Affordable Medicines Facility-malaria in Ghana: the role of caregivers and licensed chemical sellers in four regions.

BACKGROUND: The Affordable Medicine Facility-malaria (AMFm) was an innovative global financing mechanism for the provision of quality-assured artemisinin-based combination therapy (ACT) across both the private and public health sectors in eight countries in sub-Saharan Africa. This study evaluated the effectiveness of AMFm subsidies in increasing access to ACT in Ghana and documented malaria management practices at the household and community levels during the implementation of the AMFm. METHODS: This study, conducted in four regions in Ghana between January, 2011 to December, 2012, employed cross-sectional mixed-methods design that included qualitative and quantitative elements, specifically household surveys, focus group discussions (FGD) and in-depth interviews. RESULTS: The study indicated high ACT availability, adequate provider knowledge and reasonably low quality-assured ACT use in the study areas, all of which are a reflection of a high market share of ACT in these hard-to-reach areas of the country. Adequate recognition of childhood malaria symptoms by licensed chemical seller (LCS) attendants was observed. A preference by caregivers for LCS over health facilities for seeking treatment solutions to childhood malaria was found. CONCLUSIONS: Artemisinin-based combination therapy with the AMFm logo was accessible and affordable for most people seeking treatment from health facilities and LCS shops in rural areas. Caregivers and LCS were seen to play key roles in the health of the community especially with children under 5 years of age.

Multi-institutional external validation of urinary TWIST1 and NID2 methylation as a diagnostic test for bladder cancer.

OBJECTIVES: We previously reported a clinical trial in which we were unable to replicate the excellent diagnostic metrics produced in the developmental study of the TWIST1 and NID2 gene methylation assay. In this expanded trial with subjects enrolled from another institution, we reexamine the diagnostic capabilities of the test to externally validate our previous study. MATERIALS AND METHODS: TWIST1 and NID2 gene methylation was assessed in DNA isolated from the urine of subjects at risk of bladder cancer undergoing cystoscopy for hematuria or bladder cancer surveillance. The diagnostic gold standard was cystoscopy. Two thresholds of TWIST1 and NID2 gene methylation were used for determining test result positivity, those published by Renard et al. and Abern et al. The sensitivity, specificity, positive and negative predictive values, diagnostic likelihood ratios, and receiver operating characteristic curves were calculated for each gene, as well as their combination. In all, 3 methods were used to combine TWIST1 and NID2 into a single composite test: (1) believe-the-positive decision rule-if either gene is methylated the test result is positive, which maximizes test sensitivity; (2) believe-the-negative decision rule-if either gene is not methylated the test result is negative, which maximizes test specificity; and (3) a likelihood-based logistic regression model approach that balances sensitivity and specificity. Clinical utility was determined using a decision curve analysis. RESULTS: A total of 209 subjects were evaluated: 40% for hematuria and 60% for bladder cancer surveillance. Approximately 75% were male, most of the prior cancers being low-grade Ta. Using cystoscopy as the gold standard, areas under the curve were 0.67 for TWIST1, 0.64 for NID2, and 0.66 for combined TWIST1 and NID2. Decision rule results revealed optimization of sensitivity at 67% using Renard thresholds and specificity using the Abern thresholds at 69%. We found improved sensitivity (78%) in current smokers. Decision curve analyses revealed that the methylation assay provided only a modest benefit even at high probabilities of missed cancer. CONCLUSION: A urine DNA test measuring TWIST1 and NID2 methylation was externally examined with a larger cohort and its results continue to be poor. These 2 biomarkers are unlikely to replace cystoscopy, but they may be worthy of study in active smokers.

Clinical performance and utility of a DNA methylation urine test for bladder cancer.

INTRODUCTION: Abnormal gene methylation has been observed in several cancers. A prior study reported methylation of TWIST1 and NID2 as a quantitative biomarker for urothelial carcinoma, but external validation has yet to be performed. We sought to externally validate a urine-based methylation assay combining TWIST1 and NID2 and assess its clinical utility. METHODS: A prospective trial was conducted comparing the methylation assay to cystoscopy and biopsy in patients with hematuria or prior non-muscle invasive bladder cancer. Sensitivity, specificity, negative and positive predictive values, and likelihood ratios of the methylation assay were calculated. Area under the receiver operating characteristic curves for each gene and the combined assay were computed. Bayesian analyses were performed to assess utility of the assay for a variety of clinical scenarios. RESULTS: Complete data were available for 111 patients. In validating the prior assay definition in the current cohort, sensitivity and specificity were 79% and 63%, respectively, and when optimized for the current cohort were 75% and 71%, respectively. The area under the curve for the assay was 0.73 compared with biopsy and 0.71 compared with cystoscopy. CONCLUSIONS: We failed to replicate the excellent performance of the methylation assay in this external validation; however, this assay may have utility for screening or surveillance for non-muscle invasive bladder cancer.

Hyperthermia as adjunct to intravesical chemotherapy for bladder cancer.

Nonmuscle invasive bladder cancer remains a very costly cancer to manage because of high recurrence rates requiring long-term surveillance and treatment. Emerging evidence suggests that adjunct and concurrent use of hyperthermia with intravesical chemotherapy after transurethral resection of bladder tumor further reduces recurrence risk and progression to advanced disease. Hyperthermia has both direct and immune-mediated cytotoxic effect on tumor cells including tumor growth arrest and activation of antitumor immune system cells and pathways. Concurrent heat application also acts as a sensitizer to intravesical chemotherapy agents. As such the ability to deliver hyperthermia to the focus of tumor while minimizing damage to surrounding benign tissue is of utmost importance to optimize the benefit of hyperthermia treatment. Existing chemohyperthermia devices that allow for more localized heat delivery continue to pave the way in this effort. Current investigational methods involving heat-activated drug delivery selectively to tumor cells using temperature-sensitive liposomes also offer promising ways to improve chemohyperthermia efficacy in bladder cancer while minimizing toxicity to benign tissue. This will hopefully allow more widespread use of chemohyperthermia to all bladder cancer patients, including metastatic bladder cancer.

Perioperative intravesical chemotherapy in non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

The role for a single dose of intravesical chemotherapy (IVC) after transurethral resection (TUR) remains unclear in patients with non-muscle-invasive bladder cancer (NMIBC). Several recent randomized clinical trials (RCTs) have evaluated its effect on recurrence, prompting this systematic review of RCTs comparing a single immediate postoperative dose of IVC versus placebo within 24 hours of TUR of NMIBC, and this meta-analysis using a random-effects model to predict the pooled relative risk (RR) of tumor recurrence. Subanalyses pooled studies by drug type and a meta-regression was performed to determine the effect of underlying patient risk factors on the efficacy of a single dose of IVC. A total of 3103 patients were randomized in the 18 RCTs that met inclusion criteria. The recurrence rate in patients receiving perioperative IVC and TUR was 37% versus 50% in the TUR-alone group. The pooled RR of recurrence for IVC and TUR was 0.67 (95% CI, 0.56-0.79), corresponding to a 13% absolute reduction and a number needed to treat of 7.2 patients to avoid 1 recurrence. The proportions of patients with tumor risk factors (T1, high-grade, multifocal, or recurrent) were not associated with IVC efficacy. A single dose of IVC administered within 24 hours of TUR of NMIBC was found to result in a reduction in tumor recurrence (RR, 0.67; 95% CI, 0.56-0.79). Patients with higher-risk tumor features seem to benefit at a similar rate.