A Community Health Worker Model to Support Hereditary Cancer Risk Assessment and Genetic Testing.

OBJECTIVE: To evaluate the effects of a community health worker-supported hereditary cancer risk-assessment and genetic testing program in a safety-net hospital serving more than 70% medically underserved patients. METHODS: This community health worker pilot program began in January 2020 at women's health clinics by administering original National Comprehensive Cancer Network (NCCN)-based questionnaires. Patients meeting high-risk criteria were offered video-based genetic education and testing, notified of results using telehealth, and offered indicated counseling. We compared the rate of genetic counseling and testing in the first 18 months of the pilot program with that in the prior 18 months. RESULTS: In the first 18 months of the pilot program, 940 patients were screened through the community health worker program: 196 were identified as high-risk, 103 patients were tested, and pathogenic variants were identified in 10 (9.7%), two of whom had a personal cancer history. In addition, 73 patients were tested per usual practice by a certified genetic counselor: pathogenic variants were identified in 16 (21.9%), 11 (68.8%) of whom had a personal cancer history. In the 18 months before the program, 68 patients underwent genetic testing with a certified genetic counselor, pathogenic variants were identified in 16 (23.5%), 13 (81.3%) of whom had a personal cancer history. The community health worker program led to a significant increase in testing among unaffected patients based on family history alone (odds ratio [OR] 7.0; 95% CI 3.7-13.2; P <.001), paralleled by a respective significant increase in the identification of pathogenic variants (OR 4.33; 95% CI 1.0-18.9; P =.051). CONCLUSION: This pilot program demonstrates the feasibility of a community health worker-supported program, using self-administered questionnaires and telehealth-based genetic services in a primarily medically underserved population. This program improved the detection of unaffected high-risk patients based on family history, increasing the volume of tests performed for this indication. Programs of this type may improve family history-based hereditary cancer testing in medically underserved patients, further enabling cancer-prevention strategies.

Safety and tolerability of Vitamin D3 5000 IU/day in epilepsy.

PURPOSE: Preclinical and early clinical research indicates that Vitamin D3 may reduce seizures in both animal models and open-label clinical trials. METHODS: This is an initial report of an ongoing pilot study of oral Vitamin D3 5000 IU/day in subjects with drug-resistant epilepsy. After Institutional Review Board (IRB) approval and informed consent, subjects with ;less than one focal onset or generalized tonic-clonic seizure per month were enrolled. Subjects entered a 4-week baseline, followed by a 12-week treatment period. Serum 25, OH Vitamin D3, Blood Urea Nitrogen (BUN), creatinine, and calcium levels were monitored at baseline and at 6 and 12 weeks. RESULTS: High-dose Vitamin D3 5000 IU/day was well tolerated. Serum 25, OH Vitamin D3 levels increased significantly at six and twelve weeks. Vitamin D insufficiency, defined as a 25, OH Vitamin D3 level of <20 ng/ml normalized in all subjects with insufficient vitamin D levels. Median seizure frequency declined from 5.18 seizures per month to 3.64 seizures per month at 6 weeks and to 4.2 seizures per month at 12 weeks. The median percent change in seizure frequency was -26.9% at six weeks, and -10.7% at 12 weeks (not significant, Wilcoxon Signed Rank Test, P > 0.34). CONCLUSIONS: High-dose oral Vitamin D3, 5000 IU/day was safe and well tolerated in subjects with epilepsy. Vitamin D levels increased significantly at 6 and 12 weeks but never exceeded potentially toxic levels, defined as >100 ng/ml. To reduce variability, we will now recruit subjects who only have three or more seizures per month.

Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis.

BACKGROUND: Retrospective analyses of randomized controlled trials suggest that antiplatelet therapy may modify the potential cerebrovascular benefits of lowering homocysteine with B-vitamins among individuals with cardiovascular disease. We evaluated the effects of B-vitamin supplementation on risk of subsequent stroke among high cardiovascular risk individuals who are not taking antiplatelet medications. METHODS: We systematically searched the Cochrane Central Register of controlled trials, PubMed, the Internet Stroke Center stroke trials, and the clinical trials.gov website from 1966 to April 2015. Inclusion criteria included: randomized controlled trials of homocysteine-lowering therapy with B-vitamins; high cardiovascular risk population and follow-up ≥1 year. We considered stroke as the primary outcome. Among 11 randomized controlled trials meeting inclusion criteria, three studies assessed stroke as an outcome and reported event rates according to whether or not individuals were taking antiplatelets: Vitamin Intervention for Stroke Prevention (VISP), VITAmins TO Prevent Stroke (VITATOPS), and Heart Outcomes Prevention Evaluation 2 (HOPE-2). RESULTS: A total of 4643 high vascular risk subjects not taking antiplatelets were evaluated. The overall effect size across studies was summarized using the fixed effects model after confirming there was no significant heterogeneity. Heterogeneity was assessed using the Cochran's Q and I(2) statistics. Compared with the control group, those taking B-vitamin supplementation had a lower risk of recurrent stroke (HR 0.86, 95% CI 0.62 to 1.19 for VISP; 0.65, 0.46 to 0.91 for VITATOPS; and 0.60, 0.39 to 0.92 for HOPE-2; overall HR 0.71, 0.58 to 0.88). CONCLUSION: Homocysteine lowering with B-vitamins among high vascular risk patients who are not taking antiplatelet therapy is related to a significant reduction (29%) in overall stroke risk. A clinical trial of B-vitamins in this group may be warranted.

Differential effect of B-vitamin therapy by antiplatelet use on risk of recurrent vascular events after stroke.

BACKGROUND AND PURPOSE: Although several randomized controlled trials failed to show a benefit of B vitamin therapy on composite outcomes of cardiovascular death, myocardial infarction, and stroke among individuals with elevated homocysteine, recent post hoc analyses have suggested that several factors may interact with the effects of vitamin treatment. One post hoc analysis revealed an interaction between B vitamin therapy and antiplatelet use; however, those results have not been replicated in other studies or populations. METHODS: We conducted a post hoc analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial, a randomized controlled trial evaluating treatment with high- versus low-dose B vitamin therapy for secondary prevention of vascular events among stroke survivors with elevated homocysteine. Cox regression models were used to assess primary (recurrent stroke) and secondary (stroke, myocardial infarction, or vascular death) outcomes among individuals on high- versus low-dose vitamin therapy, categorized by antiplatelet use, after adjusting for covariates. RESULTS: Among 3680 participants, 52% took antiplatelet medications. When compared with low-dose therapy, high-dose vitamin therapy was associated with higher stroke risk among individuals on antiplatelets (hazard ratio, 1.43; 95% confidence interval, 1.02-2.01), but trended toward lower risk among those not on antiplatelets (hazard ratio, 0.86; 95% confidence interval, 0.62-1.19). CONCLUSIONS: High-dose B vitamin therapy may be associated with a higher risk of recurrent stroke among stroke survivors taking antiplatelets, but does not have a significant effect on recurrent stroke risk in those who are not on antiplatelets. Future randomized controlled trials may consider evaluating the effect of homocysteine lowering among stroke survivors with elevated homocysteine who are not on antiplatelet therapy.

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy.

BACKGROUND: External trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy. METHODS: This was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate. RESULTS: Thirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects. CONCLUSION: The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.

Homocysteine-lowering therapy and risk of recurrent stroke, myocardial infarction and death: the impact of age in the VISP trial.

BACKGROUND: Clinical trials have failed to show a benefit of B vitamin therapy in reducing composite outcomes of cardiovascular death, myocardial infarction, and stroke among stroke survivors with elevated total serum homocysteine (tHcy) levels. Recent post hoc analyses have shown that numerous factors including age, baseline tHcy levels, folic acid fortification of grains, B12 status, renal function, comorbidities, and medications may modify the effect of B vitamin therapy on vascular risk in individuals with high tHcy. It remains possible that tHcy-lowering therapy may reduce cardiovascular risk in certain subgroups of stroke survivors. Post hoc subgroup analysis of the Heart Outcomes Prevention Evaluation-2 randomized controlled trial, which randomized participants with known cardiovascular disease to tHcy-lowering therapy or placebo, revealed larger treatment benefit for patients aged younger than 69 years; however, that analysis did not control for other factors. The aim of this study was to determine the effect of age on the impact of tHcy-lowering therapy for reducing vascular risk after stroke while controlling for other factors known to modify the effect of tHcy and tHcy-lowering therapy on vascular risk. METHODS: In this post hoc analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial, a randomized controlled trial of tHcy lowering for secondary stroke prevention, we excluded individuals who had poor renal function (glomerular filtration rate <47; the 10th percentile) or were treated with vitamin B12 injections. We assessed the effects of high-dose vitamin replacement on primary (stroke, myocardial infarction, or death) and secondary (stroke) outcomes, after stratifying by age (< vs. ≥ median age, 67 years) and adjusting for demographic and clinical factors. RESULTS: This subgroup consisted of 2,993 individuals. Among individuals older than 67 years, high-dose vitamin therapy was associated with reduced risk of stroke, myocardial infarction or death (adjusted HR 0.76, 95% CI 0.58-0.99) and a trend towards reduced likelihood of stroke (adjusted HR 0.86, 95% CI 0.59-1.25). High-dose vitamin therapy did not impact outcomes among individuals younger than 67 years. CONCLUSIONS: In this post hoc subgroup analysis of the VISP trial, age modified the association between B vitamin therapy and recurrent vascular risk among stroke survivors with elevated serum tHcy levels. Older individuals with stroke were more likely to benefit from B vitamin therapy than younger individuals. These findings can help inform the future design of clinical trials of tHcy-lowering therapy for cardiovascular risk reduction after stroke. © 2014 S. Karger AG, Basel.

Impact and interaction of low estimated GFR and B vitamin therapy on prognosis among ischemic stroke patients: the Vitamin Intervention for Stroke Prevention (VISP) trial.

BACKGROUND: Low estimated glomerular filtration rate (eGFR) has been linked to higher risk of primary stroke, but little is known about the relation of low eGFR to recurrent vascular risk after stroke. B Vitamin therapy has been used to lower homocysteine levels, but its interaction with kidney function on future major vascular events has not been assessed. The objective of this study was to conduct a secondary analysis based on the Vitamin Intervention for Stroke Prevention (VISP) trial to clarify these issues. STUDY DESIGN: In the VISP trial, patients with a prior ischemic stroke were randomly assigned to receive the high- or low-dose B vitamin therapy. The trial did not find a difference between randomly assigned groups. The present study is a secondary analysis of the VISP trial. SETTING & PARTICIPANTS: We analyzed the database of a multicenter trial comprising 3,673 patients with recent ischemic stroke who were followed up for 2 years. PREDICTOR: We subdivided the cohort based on eGFR into 6 groups (≥105, 90-104, 75-89, 60-74, 45-59, and <45 mL/min/1.73 m²) for the analyses and used eGFR of 60-74 mL/min/1.73 m² as the reference category. Low eGFR was defined as <45 mL/min/1.73 m². OUTCOMES: The primary end point for this analysis was major vascular events, defined as the composite of nonfatal ischemic stroke, nonfatal myocardial infarction, and vascular death (whichever event came first). The secondary end point was recurrent ischemic stroke. Also, the effects of high-dose B vitamin treatment on future major vascular events according to baseline eGFR categories were analyzed and reported separately. RESULTS: Mean baseline eGFR was 73.9 ± 21.8 (SD) mL/min/1.73 m². 471 major vascular events during an average of 20 months of follow-up, including 300 recurrent strokes, were recorded. Baseline low eGFR was associated with increased risk of major vascular events (HR, 1.83; 95% CI, 1.32-2.52; P < 0.001) and recurrent stroke (HR, 1.53; 95% CI, 1.01-2.32; P = 0.04) after adjustment for traditional vascular risk factors and homocysteine level. At baseline eGFR <45 mL/min/1.73 m², high-dose B vitamin therapy compared to low dose showed a trend of higher risk of future major vascular events (HR, 1.49; 95% CI, 0.95-2.34; P = 0.08). The overall P value for interaction between B vitamin dose and eGFR was not significant (P = 0.6). LIMITATIONS: No data for albuminuria. CONCLUSIONS: Low eGFR is associated with higher risk of future major vascular events and recurrent stroke after a recent ischemic stroke.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy.

OBJECTIVE: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy.

Trigeminal nerve stimulation (TNS) is a novel therapy for drug-resistant epilepsy. We report in detail the safety of external TNS (eTNS), focusing on acute and long-term heart rate and systolic and diastolic blood pressure in response to TNS from the pilot feasibility study. The data indicate that eTNS of the infraorbital and supraorbital branches of the trigeminal nerve is safe and well tolerated.