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- Antibiotic exposure is associated with decreased risk of psychiatric disordersKerman, Ilan A.; Glover, Matthew E.; Lin, Yezhe; West, Jennifer L.; Hanlon, Alexandra L.; Kablinger, Anita S.; Clinton, Sarah M. (Frontiers, 2024-01-08)Objective: This study sought to investigate the relationship between antibiotic exposure and subsequent risk of psychiatric disorders. Methods: This retrospective cohort study used a national database of 69 million patients from 54 large healthcare organizations. We identified a cohort of 20,214 (42.5% male; 57.9 ± 15.1 years old [mean ± SD]) adults without prior neuropsychiatric diagnoses who received antibiotics during hospitalization. Matched controls included 41,555 (39.6% male; 57.3 ± 15.5 years old) hospitalized adults without antibiotic exposure. The two cohorts were balanced for potential confounders, including demographics and variables with potential to affect: the microbiome, mental health, medical comorbidity, and overall health status. Data were stratified by age and by sex, and outcome measures were assessed starting 6 months after hospital discharge. Results: Antibiotic exposure was consistently associated with a significant decrease in the risk of novel mood disorders and anxiety and stressor-related disorders in: men (mood (OR 0.84, 95% CI 0.77, 0.91), anxiety (OR 0.88, 95% CI 0.82, 0.95), women (mood (OR 0.94, 95% CI 0.89,1.00), anxiety (OR 0.93, 95% CI 0.88, 0.98), those who are 26–49 years old (mood (OR 0.87, 95% CI 0.80, 0.94), anxiety (OR 0.90, 95% CI 0.84, 0.97)), and in those ≥50 years old (mood (OR 0.91, 95% CI 0.86, 0.97), anxiety (OR 0.92, 95% CI 0.87, 0.97). Risk of intentional harm and suicidality was decreased in men (OR 0.73, 95% CI 0.55, 0.98) and in those ≥50 years old (OR 0.67, 95% CI 0.49, 0.92). Risk of psychotic disorders was also decreased in subjects ≥50 years old (OR 0.83, 95 CI: 0.69, 0.99). Conclusion: Use of antibiotics in the inpatient setting is associated with protective effects against multiple psychiatric outcomes in an age- and sex-dependent manner.
- National assessment of obstetrics and gynecology and family medicine residents' experiences with CenteringPregnancy group prenatal carePlace, Jean Marie; Van De Griend, Kristin; Zhang, Mengxi; Schreiner, Melanie; Munroe, Tanya; Crockett, Amy; Ji, Wenyan; Hanlon, Alexandra L. (2023-11-21)Objective To examine family medicine (FM) and obstetrician-gynecologist (OB/GYN) residents’ experiences with CenteringPregnancy (CP) group prenatal care (GPNC) as a correlate to perceived likelihood of implementing CP in future practice, as well as knowledge, level of support, and perceived barriers to implementation. Methods We conducted a repeated cross-sectional study annually from 2017 to 2019 with FM and OB/GYN residents from residency programs in the United States licensed to operate CP. We applied adjusted logistic regression models to identify predictors of intentions to engage with CP in future practice. Results Of 212 FM and 176 OB/GYN residents included in analysis, 67.01% of respondents intended to participate as a facilitator in CP in future practice and 51.80% of respondents were willing to talk to decision makers about establishing CP. Both FM and OB/GYN residents who spent more than 15 h engaged with CP and who expressed support towards CP were more likely to participate as a facilitator. FM residents who received residency-based training on CP and who were more familiar with CP reported higher intention to participate as a facilitator, while OB/GYN residents who had higher levels of engagement with CP were more likely to report an intention to participate as a facilitator. Conclusion Engagement with and support towards CP during residency are key factors in residents’ intention to practice CP in the future. To encourage future adoption of CP among residents, consider maximizing resident engagement with the model in hours of exposure and level of engagement, including hosting residency-based trainings on CP for FM residents.
- Behavioural intentions in response to a potential menthol cigarette sales ban: a survey examining smokers in Washington, DC public housingDearfield, Craig T.; Horn, Kimberly; Crandell, Ian; Bernat, Debra H. (Bmj Publishing Group, 2022-07)Objectives Local, national and international policies are being proposed to ban the sale of menthol-flavoured tobacco products. With more bans being implemented, it is increasingly important to understand reactions to these bans among smokers of low socioeconomic status. This study examined public housing residents' behavioural intentions if menthol-flavoured cigarettes were no longer sold. Setting 15 District of Columbia Housing Authority properties between March 2019 and March 2021. Participants 221 District of Columbia Housing Authority residents ages 18-80 years who reported smoking menthol cigarettes (83.3% African-American/black). Primary and secondary outcomes Cigarette quitting and switching intentions due to a hypothetical menthol-flavoured cigarette sales ban. Results Nearly one-half (48.0%) of residents said they intended to quit cigarette use if menthol-flavoured products were no longer sold, while 27.2% were unsure if they would quit, and 24.9% reported they would not quit. Older residents (OR 0.94 per year, 95% CI 0.91 to 0.97), senior/disabled building versus family building residents (OR 0.50, 95% CI 0.25 to 0.97), those who smoked within 30 min of waking (OR 0.48, 95% CI 0.23 to 0.98) and daily smokers (OR 0.42, 95% CI 0.21 to 0.84) had lower odds of reporting quit intentions associated with a menthol ban. Of those not intending to quit, 40.7% reported they would switch to non-menthol cigarettes, 20.4% to another non-menthol product, 13.0% to menthol e-cigarettes and 20.4% to another menthol product. Conclusions Results suggest banning the sale of menthol-flavoured products has the potential to impact cigarette smoking cessation. Nearly three-quarters of smokers in public housing indicated a possibility of quitting smoking because of a menthol cigarette ban. Bans that include all flavours in all tobacco products may be most effective for facilitating overall tobacco cessation.
- Low Xanthophylls, Retinol, Lycopene, and Tocopherols in Grey and White Matter of Brains with Alzheimer's DiseaseDorey, C. Kathleen; Gierhart, Dennis; Fitch, Karlotta A.; Crandell, Ian; Craft, Neal E. (IOS Press, 2022-08-16)Background: Oxidative stress contributes to pathogenesis and progression of Alzheimer's disease (AD). Higher levels of the dietary antioxidants- carotenoids and tocopherols- are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains. Objective: This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD than in healthy elderly brains. Methods: Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC. Results: AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ-tocopherol are discussed. Conclusion: Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD).
- Smoking cessation intentions and attempts one year after the federally mandated smoke-free housing ruleHorn, Kimberly; Dearfield, Craig T.; Johnson, Sallie Beth; Krost, Kevin; Patino, Sofia Rincon Gallardo; Gray, Tiffany; Crandell, Ian; Bernat, Debra H. (Elsevier, 2021-12)The present study examines public housing residents' smoking cessation intentions, expectancies, and attempts one year after implementation of the Department of Housing and Urban Development's mandatory smoke-free rule in public housing. The sample includes 233 cigarette smokers, ages 18-80, who reside in the District of Columbia Housing Authority. Data collection occurred between March and August 2019. Descriptive statistics, chi-square, and Wilcoxon two-sample test analyses assessed smoking cessation intentions, expectancies, and attempts across resident demographics and characteristics. Findings showed 17.2% of residents reported not thinking about quitting, 39.1% reported thinking about quitting, and 48.6% reported thinking about quitting specifically because of the rule. Residents ages 60-80 were more likely to consider quitting because of the rule, compared to residents ages 18-59. Of those thinking of quitting, 58.6% were sure they could quit if they tried. Those thinking of quitting due to the rule (62.0%) were more likely to have made at least one quit attempt in the past 3 months than those i not attributinging thinking of quitting to the rule. Res Residents trying to quit reported an average of 2.7 attempts in the last 3 months;; most perceived evidence-based cessation supports as not helpful. A A majority reported thinking about quitting and attempting to quit but continuing to smoke, indicating a significant gap between intent to quit and successfully quitting. Results suggest that the rule positively influenced smoking behaviors. However, additional interventions are needed to assist public housing residents with successfully quitting smoking.
- Risk Factors for Failure of Hard Palate Mucoperiosteal Flap Repair of Acquired Oronasal Communication in Dogs: A Pilot StudyTaney, Kendall; Smith, Mark M.; Cummings, Nathan P.; Lozano, Alicia J. (2021-11-03)The objective of this retrospective pilot study was to describe potential risk factors for failure of hard palate mucoperiosteal flaps (HPF) transposed for closure of oronasal communication. Dogs (n = 28) with acquired oronasal communication defects were included in the study population. Functional success of an HPF was determined by visual inspection at the last examination and lack of clinical signs. Risk factors for HPF failure including age, sex, body weight, presence of neoplasia at the time of surgery, presence of neoplasia after surgery due to incomplete or narrow margins, use of CO2 laser, previous surgeries in the same location, HPF blood supply, size of the HPF as a percentage of the total area of the hard palate mucoperiosteum, and distance traveled by the apex of the HPF were evaluated using descriptive statistics and unadjusted logistic regression modeling. Seven out of 28 (25%) hard palate flap procedures resulted in persistent oronasal communication and were considered failures. Body weight (Median: 17 vs. 25 kg, OR = 0.94, 80% CI = 0.90, 0.99), presence of neoplasia at the time of surgery (86 vs. 57%, OR = 4.50, 80% CI = 1.01, 20.06), HPF area (Median: 0.49 vs. 0.41, OR = 84.40, 80% CI = 1.66, 4,298) and apex travel distance (Median: 2.06 vs. 0.67, OR = 5.15, 80% CI = 2.14, 12.38) were associated with flap failure. Within this sample, the presence of neoplasia at the time of initial surgery, increasing the area of the HPF, and distance traveled by the HPF apex were associated with a greater odds of HPF failure. Further studies with larger sample sizes are needed to confirm repeatability of these results. HPFs remain a viable surgical option for closure of oronasal communication. Careful surgical planning, strict adherence to surgical principles, and awareness of anatomical limitations can increase the likelihood of success.
- Venous thromboembolism after penetrating femoral and popliteal artery injuries: an opportunity for increased preventionRatnasekera, Asanthi; Pulido, Odessa; Durgin, Sandra; Nichols, Sharon; Lozano, Alicia J.; Sienko, Danielle; Hanlon, Alexandra L.; Martin, Niels D. (BMJ, 2020-01)Background Trauma patients with penetrating vascular injuries have a higher rate of venous thromboembolism (VTE). The objective of this study was to determine the risk of VTE formation in penetrating femoral and popliteal vascular injuries and the effects of endovascular management of these injuries. Methods A retrospective study of Pennsylvania Trauma Outcome Study registry was conducted during a 5-year period (2013-2017). All adult patients with a penetrating mechanism with femoral/popliteal vascular injuries were studied. Primary outcome was incidence of VTE in patients with isolated arterial injuries versus combined arterial/venous injuries. Secondary endpoints were intensive care unit (ICU) length of stay (LOS), hospital LOS and mortality. Statistical comparisons were accomplished using Fisher's exact tests, and parametric two-sample t-tests or non-parametric Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Results: Of the 865 patients with penetrating extremity vascular injuries, 207 had femoral or popliteal artery injuries. Patients with isolated arterial injuries (n=131) had a significantly lower deep venous thrombosis (DVT) rate compared with those with concurrent venous injuries (n=76) (3.1% vs. 13.2%, p=0.008). There were 14 patients in the study who developed DVTs. Among the four patients with isolated femoral or popliteal arterial injuries who had developed DVTs, three had an open repair. Among patients with isolated arterial injuries, those with DVT spend significantly more time on the ventilator (median=2 vs. 0, p=0.0020) compared with patients without DVT. Patients with DVT also had longer stay in the hospital (median=17.5 vs. 8, p=0.0664) and in the ICU (median=3 vs. 1, p=0.0585). Conclusions: Risk of DVT exists in patients with penetrating isolated femoral and popliteal artery trauma. Open repair was associated with significantly higher DVT rates in isolated arterial injuries. Level of evidence: Level IV therapeutic care/management.
- Favorable Biochemical Freedom From Recurrence With Stereotactic Body Radiation Therapy for Intermediate and High-Risk Prostate Cancer: A Single Institutional Experience With Long-Term Follow-UpRicco, Anthony; Barbera, Gabrielle; Lanciano, Rachelle; Feng, Jing; Hanlon, Alexandra L.; Lozano, Alicia J.; Good, Michael; Arrigo, Stephen; Lamond, John; Yang, Jun (Frontiers, 2020-09-25)Purpose/Objective(s): The current study reports long-term overall survival (OS) and biochemical freedom from recurrence (BFFR) after stereotactic body radiation therapy (SBRT) for men with intermediate and high-risk prostate cancer in a single community hospital setting with early adoption. Materials/Methods: Ninety-seven consecutive men with intermediate and high-risk prostate cancer treated with SBRT between 2007 and 2015 were retrospectively studied. Categorical variables for analysis included National Comprehensive Cancer Network risk group, race, Gleason grade group, T stage, use of androgen deprivation therapy, and planning target volume dose. Continuous variables for analysis included pretreatment prostate-specific antigen (PSA), percent cores positive, age at diagnosis, PSA nadir, prostate volume, percent prostate that received 40 Gy, and minimum dose to 0.03 cc of prostate (Dmin). BFFR was assessed using the Phoenix nadir +2 definition. OS and BFFR were estimated using Kaplan–Meier (KM) methodology with comparisons accomplished using log-rank statistics. Multivariable analysis (MVA) was accomplished with a backwards selection Cox proportional-hazards model with statistical significance taken at the p < 0.05 level. Results: Median FU is 78.4 months. Five- and ten-year OS KM estimates are 90.9 and 73.2%, respectively, with 19 deaths recorded. MVA reveals pretreatment PSA (p = 0.032), percent prostate 40 Gy (p = 0.003), and race (p = 0.031) were predictive of OS. Five- and nine-year BFFR KM estimates are 92.1 and 87.5%, respectively, with 10 biochemical failures recorded. MVA revealed PSA nadir (p < 0.001) was the only factor predictive of BFFR. Specifically, for every one-unit increase in PSA nadir, there was a 4.2-fold increased odds of biochemical failure (HR = 4.248). No significant differences in BFFR were found between favorable intermediate, unfavorable intermediate, and high-risk prostate cancer (p = 0.054) with 7-year KM estimates of 96.6, 81.0, and 85.7%, respectively. Conclusions: Favorable OS and BFFR can be expected after SBRT for intermediate and high-risk prostate cancer with non-significant differences seen for BFFR between favorable intermediate, unfavorable intermediate, and high-risk groups. Our 5-year BFFR compares favorably with the HYPO-RT-PC trial of 84%. PSA nadir was predictive of biochemical failure. This study is ultimately limited by the small absolute number of high-risk patients included.
- Does meeting physical activity recommendations ameliorate association between television viewing with cardiovascular disease risk? A cross-sectional, population-based analysisPatterson, Freda; Mitchell, Jonathan A.; Dominick, Gregory; Lozano, Alicia J.; Huang, Liming; Hanlon, Alexandra L. (BMJ, 2020-01-01)Objectives: As a common form of sedentary behaviour, television viewing is associated with an increase in body mass index (BMI) as well as overall cardiovascular disease (CVD) risk. This study examined the extent to which meeting the recommended volume of weekly physical activity (PA) reduced the association between television viewing with the outcomes of BMI and CVD risk. A second aim was to determine the number of hours (ie, cut-point) of daily television viewing that conferred a higher BMI and CVD risk for a large population-based sample of adults. Design: Population-based, cross-sectional study. Setting UK Biobank recruited across 35 centres in the UK between 2006 and 2010. Primary outcome CVD risk, as measured by the 30-year Framingham risk score. Results Linear regression models indicated that every additional hour of television viewing per day was associated with a 3% increase in CVD risk (aCoeff=0.03, d=0.16, p<0.0001); the interaction between television viewing with meeting PA guidelines was marginally associated with CVD risk (aCoeff=0.0010, d=0.01, p=0.014). Each additional hour of television viewing per day was associated with a 0.54 increase in BMI (aCoeff=0.54, d=0.13, p<0.0001); the interaction between television viewing with meeting PA guidelines was not significantly associated with BMI. Regression tree models of the study outcomes revealed that 2.5 hours of television viewing was associated with pronounced increases in BMI and CVD risk. Conclusions: These data underscore the independent association between television viewing with cardiovascular risk and suggest that reducing television viewing to less than 2.5 hours per day, even in physically active adults, is a clinical and public health priority.
- County-level social distancing and policy impact in the United States: A dynamical systems modelMcKee, Kevin L.; Crandell, Ian C.; Hanlon, Alexandra L. (JMIR Publications, 2020-10-01)Background: Social distancing and public policy have been crucial for minimizing the spread of SARS-CoV-2 in the United States. Publicly available, county-level time series data on mobility are derived from individual devices with global positioning systems, providing a variety of indices of social distancing behavior per day. Such indices allow a fine-grained approach to modeling public behavior during the pandemic. Previous studies of social distancing and policy have not accounted for the occurrence of pre-policy social distancing and other dynamics reflected in the long-term trajectories of public mobility data. Objective: We propose a differential equation state-space model of county-level social distancing that accounts for distancing behavior leading up to the first official policies, equilibrium dynamics reflected in the long-term trajectories of mobility, and the specific impacts of four kinds of policy. The model is fit to each US county individually, producing a nationwide data set of novel estimated mobility indices. Methods: A differential equation model was fit to three indicators of mobility for each of 3054 counties, with T=100 occasions per county of the following: distance traveled, visitations to key sites, and the log number of interpersonal encounters. The indicators were highly correlated and assumed to share common underlying latent trajectory, dynamics, and responses to policy. Maximum likelihood estimation with the Kalman-Bucy filter was used to estimate the model parameters. Bivariate distributional plots and descriptive statistics were used to examine the resulting county-level parameter estimates. The association of chronology with policy impact was also considered. Results: Mobility dynamics show moderate correlations with two census covariates: population density (Spearman r ranging from 0.11 to 0.31) and median household income (Spearman r ranging from -0.03 to 0.39). Stay-at-home order effects were negatively correlated with both (r=-0.37 and r=-0.38, respectively), while the effects of the ban on all gatherings were positively correlated with both (r=0.51, r=0.39). Chronological ordering of policies was a moderate to strong determinant of their effect per county (Spearman r ranging from -0.12 to -0.56), with earlier policies accounting for most of the change in mobility, and later policies having little or no additional effect. Conclusions: Chronological ordering, population density, and median household income were all associated with policy impact. The stay-at-home order and the ban on gatherings had the largest impacts on mobility on average. The model is implemented in a graphical online app for exploring county-level statistics and running counterfactual simulations. Future studies can incorporate the model-derived indices of social distancing and policy impacts as important social determinants of COVID-19 health outcomes.
- Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposureHrubec, Terry C.; Seguin, Ryan P.; Xu, L.; Cortopassi, G. A.; Datta, S.; Hanlon, Alexandra L.; Lozano, A. J.; McDonald, V. A.; Healy, C. A.; Anderson, T. C.; Musse, N. A.; Williams, R. T. (Elsevier, 2021-01-01)Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. Main Findings: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.
- Breakfast Consumption Habits at Age 6 and Cognitive Ability at Age 12: A Longitudinal Cohort StudyLiu, Jianghong; Wu, Lezhou; Um, Phoebe; Wang, Jessica S.; Kral, Tanja V. E.; Hanlon, Alexandra L.; Shi, Zumin (MDPI, 2021-06-17)This study aimed to assess the relationship between breakfast composition and long-term regular breakfast consumption and cognitive function. Participants included 835 children from the China Jintan Cohort Study for the cross-sectional study and 511 children for the longitudinal study. Breakfast consumption was assessed at ages 6 and 12 through parental and self-administered questionnaires. Cognitive ability was measured as a composition of IQ at age 6 and 12 and academic achievement at age 12, which were assessed by the Chinese versions of the Wechsler Intelligence Scales and standardized school reports, respectively. Multivariable general linear and mixed models were used to evaluate the relationships between breakfast consumption, breakfast composition and cognitive performance. In the longitudinal analyses, 94.7% of participants consumed breakfast ≥ 4 days per week. Controlling for nine covariates, multivariate mixed models reported that compared to infrequent breakfast consumption, regular breakfast intake was associated with an increase of 5.54 points for verbal and 4.35 points for full IQ scores (p < 0.05). In our cross-sectional analyses at age 12, consuming grain/rice or meat/egg 6–7 days per week was significantly associated with higher verbal, performance, and full-scale IQs, by 3.56, 3.69, and 4.56 points, respectively (p < 0.05), compared with consuming grain/rice 0–2 days per week. Regular meat/egg consumption appeared to facilitate academic achievement (mean difference = 0.232, p = 0.043). No association was found between fruit/vegetable and dairy consumption and cognitive ability. In this 6-year longitudinal study, regular breakfast habits are associated with higher IQ. Frequent grain/rice and meat/egg consumption during breakfast may be linked with improved cognitive function in youth.
- The conduction velocity-potassium relationship in the heart is modulated by sodium and calciumKing, D. Ryan; Entz, Michael, II; Blair, Grace A.; Crandell, Ian; Hanlon, Alexandra L.; Lin, Joyce; Hoeker, Gregory S.; Poelzing, Steven (2021-03)The relationship between cardiac conduction velocity (CV) and extracellular potassium (K+) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na+) and calcium (Ca2+) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K+. We hypothesize that Na+, Ca2+, and GJC can attenuate conduction slowing consequent to severe hyperkalemia. Elevating Ca2+ from 1.25 to 2.00 mM significantly narrowed perinexal width measured by transmission electron microscopy. Optically mapped, Langendorff-perfused guinea pig hearts perfused with increasing K+ revealed the expected biphasic CV-K+ relationship during perfusion with different Na+ and Ca2+ concentrations. Neither elevating Na+ nor Ca2+ alone consistently modulated the positive slope of CV-K+ or conduction slowing at 10-mM K+; however, combined Na+ and Ca2+ elevation significantly mitigated conduction slowing at 10-mM K+. Pharmacologic GJC inhibition with 30-mu M carbenoxolone slowed CV without changing the shape of CV-K+ curves. A computational model of CV predicted that elevating Na+ and narrowing clefts between myocytes, as occur with perinexal narrowing, reduces the positive and negative slopes of the CV-K+ relationship but do not support a primary role of GJC or sodium channel conductance. These data demonstrate that combinatorial effects of Na+ and Ca2+ differentially modulate conduction during hyperkalemia, and enhancing determinants of ephaptic coupling may attenuate conduction changes in a variety of physiologic conditions.