Why is a small sample size not enough?

BACKGROUND: Clinical studies are often limited by resources available, which results in constraints on sample size. We use simulated data to illustrate study implications when the sample size is too small. METHODS AND RESULTS: Using 2 theoretical populations each with N = 1000, we randomly sample 10 from each population and conduct a statistical comparison, to help make a conclusion about whether the 2 populations are different. This exercise is repeated for a total of 4 studies: 2 concluded that the 2 populations are statistically significantly different, while 2 showed no statistically significant difference. CONCLUSIONS: Our simulated examples demonstrate that sample sizes play important roles in clinical research. The results and conclusions, in terms of estimates of means, medians, Pearson correlations, chi-square test, and P values, are unreliable with small samples.

Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood.

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Four-year quality-of-life outcomes in low- to intermediate-risk prostate cancer patients following definitive stereotactic body radiotherapy versus management with active surveillance.

OBJECTIVE: To review quality-of-life (QoL) metrics between patients who underwent definitive stereotactic body radiotherapy (SBRT) versus active surveillance (AS) for management of low- to intermediate-risk prostate cancer (PCa). METHODS: A prospectively maintained PCa database was reviewed containing results of patient-reported QoL surveys. Patients with localized disease who chose AS or SBRT and completed at least one survey within four years of treatment were included. Patients who received salvage therapy were excluded. Survey results were compared across time using mixed-effects repeated measures analysis of covariance models that adjusted for factors significant in univariate analysis. A group x time interaction effect was examined to compare rate of change over time between AS and SBRT. P < 0.05 was significant. RESULTS: 148 AS and 161 SBRT patients were included. Significantly more SBRT patients had intermediate-risk disease (p < 0.0001). AS had significantly worse sexual function compared to SBRT across time. While not significant, bowel function scores were lower for SBRT patients across time points. SBRT patients had significantly lower anxiety than AS patients at 24 months (p < 0.011) and 36 months (p < 0.010). Urinary function though worse in SBRT patients at 12 months in EPIC, was not significantly different in both groups across time points. CONCLUSION: SBRT patients have excellent QoL compared to AS with regard to anxiety post treatment. Though SBRT patients initially have worse urinary and bowel function than AS, scores were eventually similar in both cohorts by 48 months. SBRT patients have significantly worse sexual function post treatment. This study may help facilitate counseling in patients choosing PCa treatment.

Do socio-demographic factors modify the effect of weather on malaria in Kanungu District, Uganda?

BACKGROUND: There is concern in the international community regarding the influence of climate change on weather variables and seasonality that, in part, determine the rates of malaria. This study examined the role of sociodemographic variables in modifying the association between temperature and malaria in Kanungu District (Southwest Uganda). METHODS: Hospital admissions data from Bwindi Community Hospital were combined with meteorological satellite data from 2011 to 2014. Descriptive statistics were used to describe the distribution of malaria admissions by age, sex, and ethnicity (i.e. Bakiga and Indigenous Batwa). To examine how sociodemographic variables modified the association between temperature and malaria admissions, this study used negative binomial regression stratified by age, sex, and ethnicity, and negative binomial regression models that examined interactions between temperature and age, sex, and ethnicity. RESULTS: Malaria admission incidence was 1.99 times greater among Batwa than Bakiga in hot temperature quartiles compared to cooler temperature quartiles, and that 6-12 year old children had a higher magnitude of association of malaria admissions with temperature compared to the reference category of 0-5 years old (IRR = 2.07 (1.40, 3.07)). DISCUSSION: Results indicate that socio-demographic variables may modify the association between temperature and malaria. In some cases, such as age, the weather-malaria association in sub-populations with the highest incidence of malaria in standard models differed from those most sensitive to temperature as found in these stratified models. CONCLUSION: The effect modification approach used herein can be used to improve understanding of how changes in weather resulting from climate change might shift social gradients in health.

Use of Cause-and-Effect Analysis to Optimize the Reliability of In Vitro Inhalation Toxicity Measurements Using an Air-Liquid Interface.

In vitro inhalation toxicology methods are increasingly being used for research and regulatory purposes. Although the opportunity for increased human relevance of in vitro inhalation methods compared to in vivo tests has been established and discussed, how to systematically account for variability and maximize the reliability of these in vitro methods, especially for assays that use cells cultured at an air-liquid interface (ALI), has received less attention. One tool that has been used to evaluate the robustness of in vitro test methods is cause-and-effect (C&E) analysis, a conceptual approach to analyze key sources of potential variability in a test method. These sources of variability can then be evaluated using robustness testing and potentially incorporated into in-process control measurements in the assay protocol. There are many differences among in vitro inhalation test methods including the use of different types of biological test systems, exposure platforms/conditions, substances tested, and end points, which represent a major challenge for use in regulatory testing. In this manuscript, we describe how C&E analysis can be applied using a modular approach based on the idea that shared components of different test methods (e.g., the same exposure system is used) have similar sources of variability even though other components may differ. C&E analyses of different in vitro inhalation methods revealed a common set of recommended exposure systems and biological in-process control measurements. The approach described here, when applied in conjunction with Good Laboratory Practices (GLP) criteria, should help improve the inter- and intralaboratory agreement of in vitro inhalation test results, leading to increased confidence in these methods for regulatory and research purposes.

Prenatal antidepressant use and the implication of hypertensive disorders during pregnancy.

BACKGROUND: Evidence for the association between prenatal antidepressant use and the development of hypertensive disorders of pregnancy is inconsistent. Previous studies have reported that antidepressant use during pregnancy increases the risk for gestational hypertension and preeclampsia, but the results of these studies are potentially confounded by important methodologic limitations. Furthermore, it remains unknown whether a higher cumulative dose of antidepressant increases the risk for hypertensive disorders of pregnancy. OBJECTIVE: This study aimed to investigate the association between prenatal antidepressant use and the risk for hypertensive disorders of pregnancy and the potential effect of a higher cumulative antidepressant dose. STUDY DESIGN: This retrospective cohort study used data from the Health and Welfare Database in Taiwan. Pregnant women with depression aged 18 to 49 years were enrolled as part of the study population. Prenatal antidepressant use was defined as at least 1 dispensing record of an antidepressant between the conception date and 20 weeks of gestation. Antidepressant users were further divided into groups according to the cumulative defined daily dose based on whether they took the defined daily dose for ≤10 weeks (low cumulative dose group ≤70 cumulative defined daily dose) or for >10 weeks (high cumulative dose group >70 cumulative defined daily dose). The primary outcome was hypertensive disorders of pregnancy defined as the diagnosis of either gestational hypertension or preeclampsia during the period from 20 weeks of gestation to delivery. Propensity score matching and stabilized inverse probability of treatment weighting were used to balance the confounders between the comparison groups. A robust Cox regression model was used to evaluate the association between exposure and outcome. RESULTS: A total of 5664 pregnant women with depression were included in the study (2832 antidepressant users matched to 2832 antidepressant nonusers). Prenatal antidepressant use was not associated with an increased risk for hypertensive disorders of pregnancy (adjusted hazard ratio, 0.89; 95% confidence interval, 0.67-1.18). However, among antidepressant users, the risk for hypertensive disorders of pregnancy was higher among women with a higher cumulative defined daily dose than among women with a lower cumulative defined daily dose (adjusted hazard ratio, 2.46; 95% confidence interval, 1.05-5.74). CONCLUSION: No association was found between antidepressant use and the development of hypertensive disorders of pregnancy. However, women taking higher cumulative doses of antidepressants were at greater risk. More frequent or regular monitoring of blood pressure may be warranted in women on high cumulative doses of antidepressants.

Policy considerations for scaling up access to HIV pre-exposure prophylaxis for adolescent girls and young women: Examples from Kenya, South Africa, and Uganda.

Adolescent girls and young women (aged 15-24 years; AGYW) continue to carry a disproportionate burden of HIV in sub-Saharan Africa. Pre-exposure prophylaxis (PrEP) helps reduce the risk of acquiring HIV for persons at substantial risk, including AGYW. As countries plan for the rollout of PrEP across sub-Saharan Africa, PrEP policies and programs could address the unique needs of AGYW. The purpose of this analysis was to identify policy considerations to improve AGYW access to PrEP. After reviewing the literature, we identified 13 policy considerations that policymakers and stakeholders could evaluate when developing or reviewing PrEP-related policies. We sorted these considerations into five categories, which together comprise an AGYW Access to PrEP Framework: AGYW-friendly delivery systems, clinical eligibility and adherence support, legal barriers and facilitators, affordability, and community and AGYW outreach. We also reviewed policies in three countries (Kenya, South Africa, and Uganda) to explore how PrEP-related policies addressed these considerations. Some of these policies addressed some of the 13 policy considerations, but none of the policies directly addressed the unique needs of AGYW for accessing PrEP. To improve access to PrEP for AGYW, country policies could include specific components that address these 13 considerations. To reach AGYW effectively, each country could use the 13 considerations we have identified to analyze current policies to identify existing programmatic barriers to AGYW accessing HIV services and address these barriers in PrEP-related policies.

Administrative and Related Barriers to Covering the Costs of Preexposure Prophylaxis at a Safety-net Clinic in Seattle, Washington.

One barrier to human immunodeficiency virus preexposure prophylaxis (PrEP) is lack or perceived lack of health insurance or financial assistance. We performed a medical records review at a safety-net PrEP clinic in Seattle, Washington, and found that barriers to obtaining financial assistance were commonly recorded in association with initiation and persistence on PrEP.

The Natural History and Composition of Urinary Catheter Biofilms: Early Uropathogen Colonization with Intraluminal and Distal Predominance.

PURPOSE: We sought to determine the composition and initiation site of bacterial biofilm on indwelling urinary catheters and to track biofilm progression with time. MATERIALS AND METHODS: Indwelling urinary catheters were collected from 2 tertiary care centers following removal from patients. Indwelling time was noted and catheters were de-identified. Catheters were sectioned, stained for biofilms and analyzed by spectrophotometry and visualization. Biofilm colonization patterns were analyzed using descriptive statistical analysis and bacterial composition was determined using next generation sequencing. RESULTS: We collected and analyzed a total of 33 catheters from 26 males and 7 females with indwelling time ranging from 15 minutes to 43 days. Biofilm colonization was consistently high on the region of the balloon for all indwelling times. After week 1 the distal third of the catheter had higher biofilm colonization than the proximal third (week 2 p=0.034). At all indwelling times the intraluminal surface of the catheter had greater biofilm colonization than the outer surface. Next generation sequencing detected potential uropathogenic bacteria in all 10 analyzed samples. CONCLUSIONS: The catheter balloon, its distal aspect and its lumen were the predominant locations of biofilm comprising uropathogenic bacteria. Strategies to prevent or treat biofilm should be targeted to these areas.

Strengthening policy coding methodologies to improve COVID-19 disease modeling and policy responses: a proposed coding framework and recommendations.

BACKGROUND: In recent months, multiple efforts have sought to characterize COVID-19 social distancing policy responses. These efforts have used various coding frameworks, but many have relied on coding methodologies that may not adequately describe the gradient in social distancing policies as states "re-open." METHODS: We developed a COVID-19 social distancing intensity framework that is sufficiently specific and sensitive to capture this gradient. Based on a review of policies from a 12 U.S. state sample, we developed a social distancing intensity framework consisting of 16 domains and intensity scales of 0-5 for each domain. RESULTS: We found that the states with the highest average daily intensity from our sample were Pennsylvania, Washington, Colorado, California, and New Jersey, with Georgia, Florida, Massachusetts, and Texas having the lowest. While some domains (such as restaurants and movie theaters) showed bimodal policy intensity distributions compatible with binary (yes/no) coding, others (such as childcare and religious gatherings) showed broader variability that would be missed without more granular coding. CONCLUSION: This detailed intensity framework reveals the granularity and nuance between social distancing policy responses. Developing standardized approaches for constructing policy taxonomies and coding processes may facilitate more rigorous policy analysis and improve disease modeling efforts.

Trendy e-cigarettes enter Europe: chemical characterization of JUUL pods and its aerosols.

The popularity and the high nicotine content of the American pod e-cigarette JUUL have raised many concerns. To comply with European law, the nicotine concentration in the liquids of the European version, which has been recently released on the market, is limited to below 20 mg/mL. This limit can possibly be circumvented by technological adjustments that increase vaporization and consequently, elevate nicotine delivery. In this study, we compare vapor generation and nicotine delivery of the initial European version, a modified European version, and the original American high-nicotine variant using a machine vaping set-up. Additionally, benzoic acid and carbonyl compounds are quantified in the aerosol. Further, concentrations of nicotine, benzoic acid, propylene glycol, and glycerol, along with the density and pH value of JUUL e-liquids have been assessed. Whereas the initial European version did not compensate for the low nicotine content in the liquid, we provide evidence for an increased vaporization by the modified European version. As a consequence, nicotine delivery per puff approximates the American original. Notably, this is not associated with an increased generation of carbonyl compounds. Our data suggest a similar addictiveness of the enhanced European version and the original American product.

The Impact of ACA and Medicaid Expansion on Progress Toward UNAIDS 90-90-90 Goals.

PURPOSE OF REVIEW: Passage of the Affordable Care Act (ACA) in 2010 and subsequent Medicaid expansion has influenced access to HIV treatment and care in the USA. This review aims to evaluate whether the implementation of these policies has impacted progress toward UNAIDS 90-90-90 goals. RECENT FINDINGS: Preliminary evidence has emerged suggesting that the ACA and Medicaid expansion has increased the likelihood of HIV testing and diagnosis, reduced the number of people unaware of HIV infection, and increased the number of people on antiretroviral therapy (ART) who are virally suppressed. While the ACA is associated with some progress toward 90-90-90 goals, more years of data after policy implementation are needed for robust analysis. Methods including difference-in-differences, instrumental variables, and propensity scores are recommended to minimize bias from unmeasured confounders and make causal inference about non-random Medicaid expansion among states.

Ablation energies for focal treatment of prostate cancer.

CONTEXT: In recent years, focal therapy has emerged as a treatment option for a selected group of men with localized prostate cancer. Cryotherapy and high-intensity focused ultrasound (HIFU) are the most investigated types of focal treatment with other options currently under evaluation. OBJECTIVE: The objective of the study was to give a comprehensive overview of six available focal treatment options for prostate cancer with their rationale, delivery mechanism, and outcomes. INFORMATION ACQUISITION: The SIU ICUD chapter on available Energies to Treat Prostate Cancer was used as a guide to describe the different technologies. For outcomes, a literature search was conducted using PubMed key words including focal therapy, HIFU, cryotherapy, irreversible electroporation, vascular-targeted photodynamic therapy, laser interstitial therapy, radiofrequency ablation, microwave therapy, and their synonyms in MeSH terms. CONCLUSION: Focal therapy appears to have encouraging outcomes on quality of life and urinary and erectile function. For oncological outcomes, it is challenging to fully interpret the outcomes due to heterogeneity in patient selection and short-term follow-up.

TiO2-Coated Optical Fibres for Groundwater Remediation.

In this study, polyethylene glycol (PEG) was tested as an alternative polymer to improve the coating of TiO2 particles onto optical fibres. The addition of PEG helped dispersing effectively the particles in solution to control their deposition and therefore achieving better properties of the coating film. Results showed that PEG increased the effectiveness of the coating and the prepared fibres showed better performance for the removal of methylene blue (MB). This was attributed to the morphological changes induced by PEG. EDX mapping of the fibre surface showed that the addition of PEG lead to a better coverage of the fibre surface; increasing the active surface area for subsequent photocatalytic degradation. This study also showed that the light intensity, pH and initial concentration of MB have a significant influence. Finally, it was demonstrated that the coatings using PEG were better ordered and structured; showing a distinct layer-by-layer deposition.

PSA kinetics following primary focal cryotherapy (hemiablation) in organ-confined prostate cancer patients.

PURPOSE: We aim to evaluate prostate-specific antigen (PSA) trends in post-primary focal cryotherapy (PFC) patients. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study of PFC patients from 2010 to 2015. Patients with at least one post-PFC PSA were included in the study. Biochemical recurrence (BCR) was determined using the Phoenix criteria. PSA bounce was also assessed. We analyzed rates of change of PSA over time of post-PFC between BCR and no BCR groups. PSA-derived variables were analyzed as potential predictors of BCR. RESULTS: A total of 104 PFC patients were included in our analysis. Median (range) age and follow-up time were 66 (48-82) years and 19 (6.3-38.6) months, respectively. Four (3.8%) patients experienced PSA bounce. The median percent drop in first post-PFC PSA of 80.0% was not associated with BCR (p = 0.256) and may indicate elimination of the index lesion. The rate of increase of PSA in BCR patients was significantly higher compared to patients who did not recur (median PSA velocity (PSAV): 0.15 vs 0.04 ng/ml/month, p = 0.001). Similar to PSAV (HR 9.570, 95% CI 3.725-24.592, p < 0.0001), PSA nadir ≥ 2 ng/ml [HR (hazard ratio) 1.251, 95% CI 1.100-1.422, p = 0.001] was independently associated with BCR. CONCLUSION: A significant drop in post-PFC PSA may indicate elimination of the index lesion. Patients who are likely to recur biochemically have a significantly higher PSAV compared to those who do not recur. Nadir PSA of less than 2 ng/ml may be considered the new normal PSA in focal cryotherapy (hemiablation) follow-up.

Great expectations: An analysis of researchers' and policy makers' perceptions of the potential value of the Australian indigenous burden of disease study for policy.

The "Burden of disease and injury in Aboriginal and Torres Strait Islander Peoples" was commissioned by the Australian government as part of the Australian Burden of Disease study. This paper explores the extent to which key actors in the research and policy communities expected the Indigenous Burden of Disease study's findings to inform, influence, or drive federal decisions concerning Indigenous health in Australia. This qualitative research undertook interviews with 13 key informants with significant involvement in the Indigenous Burden of Disease study: six researchers, five policy makers, and two knowledge brokers. Interviews were recorded, transcribed, and analyzed, and the findings were triangulated with a review of the literature. Policy makers and researchers anticipated that the Indigenous Burden of Disease study would improve the available information for policy deliberations about Indigenous health. Beyond that, their expectations about its policy influence differed substantially, with researchers more confident of the study's capacity to guide health priorities, and policy makers situating findings in the context of other critical inputs. Expectations of policy influence are shaped by the disciplinary perspectives of actors, and their relationship to policy outcomes and cannot be examined without also considering the policy, political, and financing context of the study being analyzed.

Imaging Characteristics of Prostate Cancer Patients Who Discontinued Active Surveillance on 3-T Multiparametric Prostate MRI.

OBJECTIVE: Early-stage prostate cancer may be followed with active surveillance to avoid overtreatment. Our institution's active surveillance regimen uses annual MRI in place of serial biopsies, and biopsies are performed only when clinically necessary. The objective of our study was to report the multiparametric MRI characteristics of prostate cancer patients who discontinued active surveillance at our institution after repeat imaging revealed possible evidence of tumor upgrading. MATERIALS AND METHODS: The Department of Urology at Winthrop University Hospital prospectively maintains a database of prostate cancer patients who are monitored with active surveillance. At the time of this study, there were 200 prostate cancer patients being monitored with active surveillance. Of those patients, 114 patients had an initial multiparametric MRI study that was performed before active surveillance started and at least one follow-up multiparametric MRI study that was performed after active surveillance began. The MRI findings were evaluated and correlated with pathology results, if available. RESULTS: Fourteen patients discontinued active surveillance because changes on follow-up MRI suggested progression of cancer. Follow-up MRI showed an enlarged or more prominent lesion compared with the appearance on a previous MRI in three (21.4%) patients, a new lesion or lesions suspicious for cancer in two (14.3%) patients, and findings suspicious for or confirming extracapsular extension in nine (64.3%) patients. Seven of the 14 (50.0%) patients had a biopsy after follow-up multiparametric MRI, and biopsy results led to tumor upgrading in six of the 14 (42.9%) patients. The duration of active surveillance ranged from 4 to 110 months. All patients received definitive treatment. CONCLUSION: The small number of patients with follow-up multiparametric MRI findings showing worsening disease supports the role of MRI in patients with early-stage prostate cancer. Multiparametric MRI is useful in monitoring patients on active surveillance and may identify patients with clinically significant cancer amenable to definitive treatment.

Salvage focal cryosurgery may delay use of androgen deprivation therapy in cryotherapy and radiation recurrent prostate cancer patients.

INTRODUCTION: Salvage treatment options for recurrent unilateral prostate cancer (PCa) after primary radiation are limited and associated with severe complications and poor quality of life measures. Salvage focal cryotherapy (SFC) has shown success in biochemical recurrence (BCR) free survival. We aim to determine if SFC can delay use of androgen deprivation therapy (ADT) in recurrent PCa with low morbidity. METHODS: A retrospective review of patients who underwent SFC at our institution from 2007 to 2015 was performed. Patients with <2 follow-up prostate-specific antigen (PSA) values, metastatic disease, and a history of radical prostatectomy were excluded. Age at treatment, prior treatment history, PSA nadir, complications, BCR status (nadir +2 ng/ml), and follow-up data were obtained/analysed. ADT was commenced if patient experienced BCR and had a PSA doubling time <6 months or positive confirmatory biopsy or positive imaging. Cox regression and survival analysis were used to assess confounding and time to BCR respectively. RESULTS: A total of 65 patients were included and followed for a median of 26.6 (8.0-99.0) months. Thirty-one (47.7%) patients did not experience BCR. An even higher number of patients (52/65, 80.0%) are yet to receive ADT. Of those who experienced BCR [median time to BCR, 17.1 [interquartile range (IQR):11.4-23.3] months], 22/34 (64.7%) are currently carefully monitored without ADT. Survival analysis showed a biochemical recurrence-free survival of 48.1 at 1- and 3-year follow up. No patient died/experienced major complications. CONCLUSIONS: SFC may be used to delay the use of ADT. Further assessment of our findings with high-powered studies and longer follow-up is required.

Salvage Therapy Options for Local Prostate Cancer Recurrence After Primary Radiotherapy: a Literature Review.

PURPOSE OF REVIEW: While recurrence after primary treatment of prostate cancer (PCa) is not uncommon, there is currently no consensus on the most appropriate management after radiation treatment failure. This article seeks to explore the currently utilized modalities for salvage treatment for radiorecurrent PCa. We focused our review on the oncologic outcomes and reported toxicity rates in the latest studies examining salvage radical prostatectomy (SRP), salvage cryotherapy (SCT), salvage high-intensity focused ultrasound (HIFU) and re-irradiation. RECENT FINDINGS: There does not appear to be any significant difference in overall survival for more invasive salvage radical prostatectomy compared to the minimally invasive salvage approaches. Additionally, there seems to be a trend towards lower morbidity rates associated with minimally invasive and focal salvage treatment. We are encouraged by the results presented in this review and find that there is clearly a role for emerging minimally invasive and focal therapies as durable options for salvage treatment in patients with radiorecurrent PCa.