Outcomes of a universal germline screening program in a community urology practice.

The role of germline genetic testing in urologic oncology has expanded in recent years. However, implementation of genetic testing in community practices remains a challenge, often due to limited access to qualified genetics trained providers. In this study, we report outcomes of a universal germline screening program in a community urology practice. Between November 2021 and September 2022, all patients referred for urology clinic visits at Frederick Health (Frederick, MD, USA) were provided an online genetics screening questionnaire prior to the visit. Responses were compared against National Comprehensive Cancer Network (NCCN) criteria for germline testing. Those who met criteria were provided educational materials at the end of the questionnaire, and then counseled by a trained urologic oncologist (HC) in the clinic or referred to a genetic counselor prior to testing. Testing was performed with a 36-gene pan-cancer panel (CancerNext) or a 14-gene targeted prostate cancer panel (ProstateNext), with or without additional RNA analysis (RNAinsight) (Ambry Genetics, CA, USA). Demographic and clinical parameters, as well as genetic testing results, were retrospectively collected under IRB approval. In the study period, 765 patients were seen over 1370 clinic visits. Of these, 505 patients (66.0%) completed the screening questionnaire. The majority were completed via email (54.5%) with the remainder (45.5%) via text message. Of the patients who completed screening, 125/505 (24.7%) met NCCN criteria for germline testing. 58/125 patients (46.4%) who met criteria underwent germline testing, of whom 5/58 (8.6%) had distinct pathogenic mutations identified. These included actionable mutations in BRCA1, BRCA2, and CHEK2, as well as an additional pathogenic mutation in NBN. Variants of unknown significance were identified in 8/58 patients (13.8%) in 11 total genes. Challenges to implementation of this program included meeting institutional requirements for genetic testing consent, facilitating specimen collection in clinic, and integration of results into the electronic health record. Genetic risk assessment for high-risk individuals is feasible as part of a universal screening program in a community urology practice. Approximately 8% of tested patients were found to have pathogenic germline mutations, which is consistent with contemporary tertiary referral cohorts.

Incorporating the benefits of vegetative filter strips into risk assessment and risk management of pesticides.

The pesticide registration process in North America, including the USA and Canada, involves conducting a risk assessment based on relatively conservative modeling to predict pesticide concentrations in receiving waterbodies. The modeling framework does not consider some commonly adopted best management practices that can reduce the amount of pesticide that may reach a waterbody, such as vegetative filter strips (VFS). Currently, VFS are being used by growers as an effective way to reduce off-site movement of pesticides, and they are being required or recommended on pesticide labels as a mitigation measure. Given the regulatory need, a pair of multistakeholder workshops were held in Raleigh, North Carolina, to discuss how to incorporate VFS into pesticide risk assessment and risk management procedures within the North American regulatory framework. Because the risk assessment process depends heavily on modeling, one key question was how to quantitatively incorporate VFS into the existing modeling approach. Key outcomes from the workshops include the following: VFS have proven effective in reducing pesticide runoff to surface waterbodies when properly located, designed, implemented, and maintained; Vegetative Filter Strip Modeling System (VFSMOD), a science-based and widely validated mechanistic model, is suitable for further vetting as a quantitative simulation approach to pesticide mitigation with VFS in current regulatory settings; and VFSMOD parametrization rules need to be developed for the North American aquatic exposure assessment. Integr Environ Assess Manag 2024;20:454-464. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Reducing Morning Hypoglycemia Among Children Undergoing Treatment for Acute Lymphoblastic Leukemia.

PURPOSE: Hypoglycemia has been observed in children receiving acute lymphoblastic leukemia (ALL) therapy, and it can negatively affect patient outcomes. We documented a 4%-6% prevalence of hypoglycemia among patients in the two clinics in this study. We aim to reduce morning hypoglycemia in children on chemotherapy for ALL at two community pediatric oncology clinics (A and B) by 50% in 9 months. METHODS: We used the Institute for Healthcare Improvement (IHI) Model for Improvement as the framework. Prolonged hours of fasting for procedural sedation, gaps in the caregivers' knowledge of hypoglycemia risk, and a lack of awareness of the new mercaptopurine administration guidelines were the most likely contributing factors for hypoglycemia. We developed a hypoglycemia prevention educational program for staff and caregivers followed by a knowledge assessment tool. RESULTS: Each month, the average number of patients seen in both clinics was 43. The monthly average of blood glucose tests in these patients was 94. After implementing the intervention, the percentage of caregivers who received hypoglycemia education reached 88%. Of those, 78% scored ≥ 75% in the knowledge reassessment resurvey. The combined average hypoglycemic episodes in the two clinics decreased by 46%. A higher reduction in hypoglycemic episodes was observed in clinic A (75%) compared with clinic B (17%). CONCLUSION: Implementing hypoglycemia education led to a significant drop in hypoglycemic episodes among children on ALL therapy. Despite using a similar approach, one of the two clinics showed a more than fourfold improvement compared with the other.

Chemotherapy Wait Times in a Network of Pediatric Oncology Clinics.

Patient satisfaction with medical care delivery is an important aspect of value-based health care. Providers strive to provide optimal patient satisfaction. Among a network of ambulatory pediatric oncology affiliate clinics, we conducted patient satisfaction surveys and found that the lowest scores were related to delays in the administration of chemotherapy. To address this shortcoming, we used continuous improvement methodologies to reduce the delay in chemotherapy administration in 3 affiliate clinics. To evaluate the efficacy of the quality improvement interventions implemented at each affiliate clinic, we measured the time from patient arrival to the start of chemotherapy administration over a 2-week period before and after the interventions. Wait times for chemotherapy administration were reduced in each clinic by 7% to 15%, exceeding the preestablished goal of a 5% reduction without affecting patient safety. Patient satisfaction for chemotherapy wait times was also marginally increased. In conclusion, implementation of quality improvement interventions across a clinical network can improve specific aspects of patient satisfaction, thereby improving the overall patient experience.

Obesity and Weaning from Mechanical Ventilation-An Exploratory Study.

INTRODUCTION: Obesity is associated with increased risk of hypercapnic respiratory failure, prolonged duration on mechanical ventilation, and extended weaning periods. OBJECTIVE: Pilot study to determine whether morbidly obese adult tracheotomized subjects (body mass index [BMI] ⩾ 40) can be more efficiently weaned from the ventilator by optimizing their positive end-expiratory pressure (PEEP) using either an esophageal balloon or the best achieved static effective compliance. METHODS: We randomly assigned 25 morbidly obese adult tracheotomized subjects (median [interquartile range] BMI 53.4 [26.4]; range 40.4-113.8) to 1 of 2 methods of setting PEEP; using either titration guided by esophageal balloon to overcome negative transpulmonary pressure (Ptp) (goal Ptp 0-5 cmH2O) (ESO group) or titration to maximize static effective lung compliance (Cstat group). Our outcomes of interest were number of subjects weaned by day 30 and time to wean. RESULTS: At day 30, there was no significant difference in percentage of subjects weaned. 8/13 subjects (62%) in the ESO Group were weaned vs. 9/12(75%) in the Cstat Group (P = 0.67). Among the 17 subjects who weaned, median time to ventilator liberation was significantly shorter in the ESO group: 3.5 days vs Cstat group 14 days (P = .01). Optimal PEEP in the ESO and Cstat groups was similar (ESO mean ± SD = 26.5 ± 5.7 cmH2O and Cstat 24.2 ± 7 cmH2O (P = .38). CONCLUSIONS: Optimization of PEEP using esophageal balloon to achieve positive transpulmonary pressure did not change the proportion of patients weaned. Among patients who weaned, use of the esophageal balloon resulted in faster liberation from mechanical ventilation. There were no adverse consequences of the high PEEP (mean 25.4; range 13-37 cmH2O) used in our study. The study was approved by the Institutional Review Board at our institution (UMCIRB#10-0343) and registered with clinicaltrials.gov (NCT02323009).

Delayed-release prednisone improves fatigue and health-related quality of life: findings from the CAPRA-2 double-blind randomised study in rheumatoid arthritis.

OBJECTIVES: Like morning stiffness, fatigue is a common, debilitating symptom of rheumatoid arthritis (RA). Delayed-release (DR) prednisone is designed for evening administration (approximately 22:00) and releases 4 h later to coincide with the rise of nocturnal inflammatory cytokines associated with development of morning stiffness. The impact of DR prednisone on fatigue and other related patient-reported outcomes was analysed with data obtained from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) 2 study. METHODS: Patients with symptomatic RA (n=350) despite treatment with a disease-modifying antirheumatic drug (DMARD) were randomised 2:1 to receive additional therapy with DR prednisone 5 mg or placebo once daily for 12 weeks. Fatigue was assessed using validated instruments: the fatigue scale of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the vitality domain of the Short Form-36 (SF-36). General quality of life was assessed using the general score and individual domains of Functional Assessment of Cancer Therapy-General (FACT-G) and SF-36. RESULTS: The change from baseline to week 12 in FACIT-F score was statistically significantly different with DR prednisone/DMARD (3.8) versus placebo/DMARD (1.6; difference 2.2, p=0.0032). Improvement in FACIT-F score correlated positively with clinical response. Compared with placebo/DMARD, DR prednisone/DMARD showed a significantly greater improvement in SF-36 vitality score (5.6, p=0.001), physical component of SF-36 (2.3, p=0.0003) and general score with FACT-G (2.6, p=0.0233). CONCLUSIONS: DR prednisone in addition to a DMARD significantly improves fatigue and other aspects of health-related quality of life in patients with symptomatic RA compared with DMARD treatment alone. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00650078.

Improvement Thresholds for Morning Stiffness Duration in Patients Receiving Delayed- Versus Immediate-Release Prednisone for Rheumatoid Arthritis.

BACKGROUND: Morning stiffness, a common patient reported symptom in rheumatoid arthritis, is associated with an increase in early morning inflammatory cytokines and significant disability. Little is known about categorical morning stiffness responses to glucocorticoid use in rheumatoid arthritis patients. Chronic pain threshold models have indicated previously that response rates of 15% to 30% indicate minimally important relief, 40% to 50% indicate substantial pain relief, and greater than 70% represents extensive pain relief. The objective of the present analysis was to assess differences in the percentages of patients achieving 25%(minimally important change), 50% (substantial change), and 75% (extensive change) reduction in the duration of patient-reported morning stiffness between patients receiving DR- and IR-prednisone in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial. MATERIALS AND METHODS: The CAPRA-1 trial was a 12-week, double-blind study followed by an additional 9-month open-label extension. Patients in the CAPRA-1 trial were randomized to IR-prednisone in the morning or DR-prednisone at bedtime in addition to stable disease modifying antirheumatic drug therapy. After the double-blind phase, patients randomized to IR-prednisone (N =110) were switched to DR-prednisone and followed at 3, 6, and 9 months in an open-label extension phase. Patients originally randomized to DR-prednisone (N = 97) continued that therapy in the open-label extension. Patient morning stiffness diary entries from 4 weeks before and 4 weeks after each scheduled visit were analyzed over 1 year for threshold response. The number of patients reaching threshold response (25%, 50%, and 75% improvement) and time to morning stiffness response were examined. RESULTS: The DR-prednisone arm had significantly more responders in all three morning stiffness threshold response categories at the end of the double-blind period compared with IR-prednisone (p ≤ 0.05). Patients who switched from IR- to DR-prednisone in the open-label extension had comparable responses in all categories within 3 months and significantly shorter time to response versus patients already receiving DR-prednisone. DISCUSSION: DR-prednisone produced significantly higher morning stiffness response rates compared with IR prednisone, as defined by 25%, 50%, and 75% improvement thresholds, at week 12. The time to reach these thresholds was quicker with DR-prednisone, and patients who switched to DR-prednisone from IR-prednisone achieved responses comparable to the continuous DR-prednisone group over 9 months of therapy. This analysis is the first to assess time-to-event and percentage threshold morning stiffness responses to differently timed glucocorticoid therapy and propose clinically meaningful response rates in RA patients.

Risk of upper gastrointestinal ulcers in patients with osteoarthritis receiving single-tablet ibuprofen/famotidine versus ibuprofen alone: pooled efficacy and safety analyses of two randomized, double-blind, comparison trials.

BACKGROUND: Although anti-inflammatory doses of ibuprofen are very effective in treating the signs and symptoms of osteoarthritis (OA), they come with an increased risk for gastrointestinal damage which can limit their use and decrease patient adherence to therapy. OBJECTIVE: Assess the efficacy and safety of an ibuprofen/famotidine fixed-dose tablet for reducing the risk of upper gastrointestinal (UGI) ulcers compared with ibuprofen alone in OA patients. METHODS: Osteoarthritis patients from previously completed randomized, double-blind, comparison registration trials (REDUCE-1 and 2) which included a broad pain patient population, were pooled and analyzed for (1) the risk of endoscopically identified UGI ulcers over 24 weeks and (2) comparative pre-specified treatment emergent adverse events (TEAEs). The primary outcomes were the comparative incidence of UGI, gastric, and duodenal ulcers and TEAEs in (1) the total OA population, (2) those aged ≥ 60 years, and (3) those on low dose aspirin. A total of 776 patients were randomized (safety population), and 713 were evaluable as the study population. RESULTS: Upper gastrointestinal ulcer risk was statistically significantly reduced with the fixed dose tablet compared with ibuprofen alone by 44% in the overall population, 55% in those aged ≥ 60 years and 65% in those on low dose aspirin. Individually, gastric and duodenal ulcers were also significantly reduced in all groups analyzed. Adverse events of special interest were generally similar between the 2 groups, with the exception of dyspepsia. Relative risk reduction for dyspepsia in the overall population was 40% and 55% in those aged ≥ 60 years. Patients not receiving low dose aspirin had a 49% relative risk reduction in dyspepsia. CONCLUSION: The fixed combination of ibuprofen/famotidine significantly reduced the risk for endoscopically documented gastrointestinal ulcers in OA patients and produced clinically meaningful reductions in patient reported dyspepsia compared with the ibuprofen alone.

Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease.

In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression.

Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models.

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (P < 0.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.

Advances in pesticide environmental fate and exposure assessments.

Globalization of markets and the growing world population increase threats of invasive and exotic species and place greater demands on food and fiber production. Pest management in both agricultural and nonagricultural settings employs established practices and new biological, chemical, and management technologies. Pesticides are an essential tool in integrated pest management. Without pesticides a significant percentage of food and fiber crops would be lost, infectious diseases would increase, and valuable native habitats would be devastated. Therefore, it is important to understand the environmental fate of pesticides and assess their potential exposure and associated risks to human health and the environment. This paper summarizes the Advances in Pesticide Environmental Fate and Exposure Assessment symposium held at the 231st National Meeting of the American Chemical Society (Atlanta, GA, 2006). The focus of the symposium was to provide current information on advances in pesticide environmental fate and exposure assessments. Thirty papers were presented on advances ranging from subcellular processes to watershed-scale studies on topics including chemical degradation, sorption, and transport; improved methodologies; use of modeling and predictive tools; exposure assessment; and treatment and remediation. This information is necessary to develop more effective pesticide use and management practices, to better understand pesticide fate and associated exposures and risks, to develop mitigation and remediation strategies, and to establish sound science-based regulations.

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects.

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.