Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial.

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.

Oral cancer patients experience mechanical and chemical sensitivity at the site of the cancer.

INTRODUCTION: Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Our clinical experience is that oral cancer patients report new sensitivity to spicy foods. We hypothesized that in cancer patients, mechanical and chemical sensitivity would be greater when measured at the cancer site compared to a contralateral matched normal site. METHODS: We determined mechanical pain thresholds (MPT) on the right and left sides of the tongue of 11 healthy subjects, and at the cancer and contralateral matched normal site in 11 oral cancer patients in response to von Frey filaments in the range of 0.008 to 300 g (normally not reported as painful). We evaluated chemical sensitivity in 13 healthy subjects and seven cancer patients, who rated spiciness/pain on a visual analog scale in response to exposure to six paper strips impregnated with capsaicin (0-10 mM). RESULTS: Mechanical detection thresholds (MDT) were recorded for healthy subjects, but not MPTs. By contrast, MPTs were measured at the site of the cancer in oral cancer patients (7/11 patients). No MPTs were measured at the cancer patients' contralateral matched normal sites. Measured MPTs were correlated with patients' responses to the University of California Oral Cancer Pain Questionnaire. Capsaicin sensitivity at the site of the cancer was evident in cancer patients by a leftward shift of the cancer site capsaicin dose-response curve compared to that of the patient's contralateral matched normal site. We detected no difference in capsaicin sensitivity on the right and left sides of tongues of healthy subjects. CONCLUSIONS: Mechanical and chemical sensitivity testing was well tolerated by the majority of oral cancer patients. Sensitivity is greater at the site of the cancer than at a contralateral matched normal site.

African American-Caucasian American differences in aortic valve replacement in patients with severe aortic stenosis.

BACKGROUND: Among patients with severe aortic stenosis (AS), there are limited data on aortic valve replacement (AVR), reasons for nonreceipt and mortality by race. METHODS: Utilizing the Duke Echocardiography Laboratory Database, we analyzed data from 110,711 patients who underwent echocardiography at Duke University Medical Center between 1999 and 2013. We identified 1,111 patients with severe AS who met ≥1 of 3 criteria for AVR: ejection fraction ≤50%, diagnosis of heart failure, or need for coronary artery bypass surgery. Logistic regression models were used to assess the association between race, AVR and 1-year mortality. χ2 testing was used to assess potential racial differences in reasons for AVR nonreceipt. RESULTS: Among the 1,111 patients (143 AA and 968 CA) eligible for AVR, AA were more often women, had more diabetes, renal insufficiency, aortic regurgitation and left ventricular hypertrophy. CA were more often smokers, had more ischemic heart disease, hyperlipidemia and higher median income levels. There were no racial differences in surgical risk utilizing logistic euroSCORES. Relative to CA, AA had lower rates of AVR (adjusted odds ratio 0.46, 95% CI 0.3-0.71, P < .001) yet similar 1-year mortality (aHR 0.81, 95% CI 0.57-1.17, P = .262). There were no significant differences in reasons for AVR nonreceipt. CONCLUSIONS: We identified 143 African Americans (AA) and 968 Caucasian Americans(CA) with severe AS who met prespecified criteria for AVR.. AA relative to CA were more often women, had more diabetes, renal insufficiency, and left ventricular hypertrophy, however had less tobacco use, ischemic heart disease, hyperlipidemia and lower median income levels. Among patients with severe AS, AA relative to CA had lower rates of AVR (adjusted odds ratio 0.46, 95% CI 0.3-0.71, P < .001) without significant differences in reasons for AVR nonreceipt and similar 1-year mortality.

Tobacco smoking in patients with heart failure and coronary artery disease: A 20-year experience at Duke University Medical Center.

Smoking is associated with incident heart failure (HF), yet limited data are available exploring the association between smoking status and long-term outcomes in HF with reduced vs. preserved ejection fraction (i.e., HFrEF vs. HFpEF). METHODS: We performed a retrospective analysis of HF patients undergoing coronary angiography from 1990-2010. Patients with coronary artery disease (CAD) and HF were stratified by EF (< 50% vs. ≥50%), smoking status (prior/current vs. never smoker), and level of smoking (light/moderate vs. heavy). Time-from-catheterization-to-event was examined using Cox proportional hazard modeling for all-cause mortality (ACM), ACM/myocardial infarction/stroke (MACE), and ACM/HF hospitalization with testing for interaction by HF-type (HFrEF vs. HFpEF). RESULTS: Of 14,406 patients with CAD and HF, 85% (n = 12,326) had HFrEF and 15% (n = 2080) had HFpEF. At catheterization, 61% of HFrEF and 57% of HFpEF patients had a smoking history. After adjustment, there was a significant interaction between HF-type and the association between smoking status and MACE (interaction P = .009). Smoking history was associated with increased risk for MACE in patients with HFrEF (adjusted hazard ratio [HR] 1.18 [1.12-1.24]), but not HFpEF (HR 1.01 [0.90-1.12]). Active smokers had increased mortality following adjustment compared to former smokers regardless of HF-type (HFrEF HR 1.19 [1.06-1.32], HFpEF HR 1.30 [1.02-1.64], interaction P = .50). Heavy smokers trended towards increased risk of adverse outcomes versus light/moderate smokers; these findings were consistent across HF-type (interaction P > .12). CONCLUSION: Smoking history was independently associated with worse outcomes in HFrEF but not HFpEF. Regardless of HF-type, current smokers had higher risk than former smokers.

Age, knowledge, preferences, and risk tolerance for invasive cardiac care.

BACKGROUND/OBJECTIVES: The extent to which individual knowledge, preferences, and priorities explain lower use of invasive cardiac care among older vs. younger adults presenting with acute coronary syndrome (ACS) is unknown. We directly surveyed a group of patients to ascertain their preferences and priorities for invasive cardiovascular care. DESIGN: We performed a prospective cohort study of adults hospitalized with ACS. We surveyed participants regarding their knowledge, preferences, goals, and concerns for cardiac care, as well as their risk tolerance for coronary artery bypass grafting (CABG). SETTING: Single academic medical center. PARTICIPANTS: Six hundred twenty-eight participants (373 <75 years old; 255 ≥75 years old). MEASUREMENTS: We compared baseline characteristics, knowledge, priorities, and risk tolerance for care across age strata. We also assessed pairwise differences with 95% confidence intervals (CI) between age groups for key variables of interest. RESULTS: Compared with younger patients, older participants had less knowledge of invasive care; were less willing to consider cardiac catheterization (difference between 75-84 and< 65 years old: -7.8%, 95% CI: -14.4%,-1.3%; for ≥85 vs. <65: -15.7%, 95% CI: -29.8%,-1.6%), percutaneous coronary intervention (difference between 75-84 and< 65 years old: -12.8%, 95% CI: -20.8%,-4.8%; for ≥85 vs. <65: -24.8%, 95% CI: -41.2%,-8.5%), and CABG (difference between 75-84 and< 65 years old: -19.0%, 95% CI: -28.2%,-9.9%; for ≥85 vs. <65: -39.1%, 95% CI: -56.0%,-22.2%); and were more risk averse for CABG surgery (p < .001), albeit with substantial inter-individual variability and individual outliers. Many patients who stated they were not initially willing to undergo an invasive cardiovascular procedure actually ended up undergoing the procedure (49% for cardiac catheterization and 22% for PCI or CABG). CONCLUSION: Age influences treatment goals and willingness to consider invasive cardiac care, as well as risk tolerance for CABG. Individuals' willingness to undergo invasive cardiovascular procedures loosely corresponds with whether that procedure is performed after discussion with the care team.

Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia.

INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.

Acute Spinal Cord Infarction Presenting With Chest Pain and Neurogenic Shock: A Case Report.

BACKGROUND: Spinal cord infarction (SCI) is rare, accounting for approximately 1% of strokes. CASE REPORT: We present the case of a 63-year-old male who presented to the emergency department (ED) with chest pain and acute-onset generalized weakness and was ultimately diagnosed with SCI secondary to suspected occlusion of the artery of Adamkiewicz. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: SCI may present diagnostic challenges, with its predilection for mimicking other major emergency conditions, such as acute aortic dissection, aortic aneurysm rupture, spinal cord compressive myelopathy, or transverse myelitis. Its consequences are often significantly disabling initially, though patients may experience subsequent clinical improvement. It is important to include SCI in the differential for patients with chest or back pain coupled with neurologic symptoms.

Dual antiplatelet therapy for perioperative myocardial infarction following CABG surgery.

OBJECTIVES: Perioperative myocardial infarction (MI) after coronary artery bypass graft surgery (CABG) has been associated with adverse outcome. Whether perioperative MI should be treated with dual antiplatelet therapy (DAPT) is unknown. We compared the effect of DAPT versus aspirin alone on short-term outcomes among patients with perioperative MI following CABG. METHODS: We used data from 3 clinical trials that enrolled patients undergoing isolated CABG: PREVENT IV (2002-2003), MEND-CABG II (2004-2005), and RED-CABG (2009-2010) (n = 9117). Perioperative MI was defined as CK-MB >5 times the upper limit of normal within 24 h of surgery (n = 2052). DAPT was defined as DAPT given after surgery and prior to discharge. A Cox regression model was used to assess the association between DAPT and 30-day nonfatal MI, stroke, or mortality after adjustment for baseline covariates. RESULTS: DAPT (n = 527) and aspirin alone (n = 1525) cohorts were similar in baseline comorbidities. Off pump bypass was used in 5.2% (n = 106) of patients. There was no difference in the 30-day composite of death, MI or stroke between patients receiving DAPT versus aspirin alone, nor in any of the individual components. There were fewer all-cause re-hospitalizations at 30 days following surgery among patients in the DAPT group (adjusted HR 0.71, CI 0.52-0.97, P = .033). CONCLUSION: One-quarter of CABG patients who had perioperative MI were treated with DAPT. DAPT was not associated with a difference in MI, stroke, or mortality at 30 days, but was associated with fewer re-hospitalizations. Further studies are needed to determine the optimal antiplatelet regimen following perioperative MI. What is already known about this subject? Perioperative myocardial infarction portends poor outcome but optimal management is currently unclear. While dual antiplatelet therapy is standard of care for acute coronary syndrome, its role in perioperative myocardial infarction is unknown. What does this study add? Dual antiplatelet therapy use during perioperative myocardial infarction was not associated with a difference in myocardial infarction, stroke or mortality at 30 days. It was, however, associated with fewer re-hospitalizations at 30 days. How might this impact on clinical practice? Dual antiplatelet therapy may be a potential treatment option for perioperative myocardial infarction after CABG surgery. Further studies are needed to better understand treatment for this disease process.

Aerobic exercise training and general health status in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION)trial.

BACKGROUND: Although aerobic exercise improves quality of life as assessed by a disease-specific instrument in ambulatory HF patients with a reduced ejection fraction (EF), the impact of an exercise intervention on general health status has not been previously reported. METHODS: A secondary analysis was performed of the HF-ACTION trial (ClinicalTrials.gov Number: NCT00047437), which enrolled 2331 medically stable outpatients with HF and an EF ≤35% and randomized them to aerobic exercise training, consisting of 36 supervised sessions followed by home-based training versus usual care for a median follow-up of 30 months. The EuroQOL 5-dimension questionnaire (EQ-5D) was administered to study participants at baseline, 3 months, and 12 months. EQ-5D includes functional dimensions (ie, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), which were mapped to corresponding utility scores (ie, 0=death and 1=perfect health), and a visual analogue scale (VAS) ranging from 0 (ie, "worst imaginable health state") to 100 (ie, "best imaginable health state"). RESULTS: Study participants had a median (25th, 75th) age of 59 (51, 68) years and 71% were male. A history of ischemic heart disease was reported in 51% of participants and the EF was 25% (20%, 30%). Baseline VAS and mapped utility scores were 65±19 and 0.81±0.14. Exercise training led to an improvement in VAS score compared with usual care from baseline to 3 months (exercise training: 6±17 vs usual care: 3±20; P <.01) although there were no further significant changes at 12 months. Aerobic exercise training did not favorably change mapped utility scores over either timeframe. After multivariable adjustment, lower mapped utility (hazard ratio [HR] 1.19 per 0.1 decrease, 95% CI 1.09-1.29; P < .0001) and VAS scores (HR 1.05 per 10 point decrease, 95% CI 1.02-1.08; P < .01) at baseline were associated with increased risk of death or hospitalization. CONCLUSION: Ambulatory HF patients with a reduced EF had impaired health status at baseline which was associated with increased morbidity and mortality, in part mitigated by a structured aerobic exercise regimen.

Measurement of the Association of Pain with Clinical Characteristics in Oral Cancer Patients at Diagnosis and Prior to Cancer Treatment.

Aim: Oral cancer patients suffer pain at the site of the cancer, which degrades quality of life (QoL). The University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ), the only validated instrument specifically designed for measuring oral cancer pain, measures the intensity and nature of pain and the level of functional restriction due to pain. Purpose: The aim of this study was to compare pain reported by untreated oral cancer patients on the UCSFOCPQ with pain they reported on the Brief Pain Inventory (BPI), an instrument widely used to evaluate cancer and non-cancer pain. Patients and Methods: The correlation between pain measured by the two instruments and clinical characteristics were analyzed. Thirty newly diagnosed oral cancer patients completed the UCSFOCPQ and the BPI. Results: Pain severity measurements made by the UCSFOCPQ and BPI were concordant; however, the widely used BPI average pain over 24 hours score appeared less sensitive to detect association of oral cancer pain with clinical characteristics of patients prior to treatment (nodal status, depth of invasion, DOI). A BPI average score that includes responses to questions that measure both pain severity and interference with function performs similarly to the UCSFOCPQ in detection of associations with nodal status, pathologic T stage (pT stage), stage and depth of invasion (DOI). Conclusion: Pain assessment instruments that measure sensory and interference dimensions of oral cancer pain correlate with biologic features and clinical behavior.

Continuous Monitoring of Heart Rate Variability and Clinical Outcomes in Patients with Implantable Cardioverter Defibrillators.

While heart rate variability (HRV) is an established marker of cardiovascular health, the extent to which continuously measured HRV changes over time and the relationship between these changes and clinical outcomes are less clear. We performed a health system analysis of 225 patients implanted with a cardiac defibrillator or cardiac resynchronization device (CRT) with continuous HRV recording capabilities. We found that continuously measured HRV changed modestly over 2 years. Low baseline HRV, which is associated with low parasympathetic tone and/or increases in sympathetic tone, pertains a worse clinical prognosis as reflected by a significant association with all-cause hospitalization. Observed changes in HRV over 6-months of follow-up were not associated with subsequent outcomes.

Comparison of a Blood Self-Collection System with Routine Phlebotomy for SARS-CoV-2 Antibody Testing.

The Coronavirus Disease 2019 (COVID-19) pandemic forced researchers to reconsider in-person assessments due to transmission risk. We conducted a pilot study to evaluate the feasibility of using the Tasso-SST (Tasso, Inc, Seattle, Washington) device for blood self-collection for use in SARS-CoV-2 antibody testing in an ongoing COVID-19 prevalence and immunity research study. 100 participants were recruited between January and March 2021 from a previously identified sub-cohort of the Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study who were under-going bimonthly COVID-19 antibody testing. Participants were given a Tasso-SST kit and asked to self-collect blood during a scheduled visit where trained laboratory personnel performed routine phlebotomy. All participants completed an after-visit survey about their experience. Overall, 70.0% of participants were able to collect an adequate sample for testing using the device. Among those with an adequate sample, there was a high concordance in results between the Tasso-SST and phlebotomy blood collection methods (Cohen's kappa coefficient = 0.88, Interclass correlation coefficient 0.98 [0.97, 0.99], p < 0.0001). The device received a high-level (90.0%) of acceptance among all participants. Overall, the Tasso-SST could prove to be a valuable tool for seroprevalence testing. However, future studies in larger, diverse populations over longer periods may provide a better understanding of device usability and acceptance among older participants and those with comorbidities in various use scenarios.

The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study: design, methods, and baseline characteristics.

OBJECTIVES: Coronavirus Disease 2019 (COVID-19) is a viral illness with public health importance. The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study is a prospective, longitudinal cohort study designed to contribute valuable information on community prevalence of active COVID-19 infection and SARS-CoV-2 antibodies as the pandemic and responses to it have and continue to evolve. We present the rationale, study design, and baseline characteristics of the C3PI Study. METHODS: We recruited 1,426 participants between June 2020 and August 2020 from the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository, a previously established, community-based, longitudinal cohort. Participants completed a baseline survey and follow-up surveys every two weeks. A nested weighted, random sub-cohort (n=300) was recruited to measure the incidence and prevalence of active COVID-19 infection and SARS-CoV-2 IgG antibodies. RESULTS: The sub-cohort was younger (56 vs 61 years), had more men (39.0% vs 30.9%), and a higher proportion of Hispanic (11.0% vs 5.1%) and Black participants (17.0% vs 8.2%) compared with the overall cohort. They had similar anthropometrics and medical histories, but a greater proportion of the sub-cohort had a higher educational degree (36.1% vs 31.3%) and reported a pre-pandemic annual household income of >$90,000 (57.1% vs 47.9%). CONCLUSION: This study is part of a multisite consortium that will provide critical data on the epidemiology of COVID-19 and community perspectives about the pandemic, behaviors and mitigation strategies, and individual and community burden in North Carolina.

Outcomes After Acute Coronary Syndrome in Patients With Diabetes Mellitus and Peripheral Artery Disease (from the TRACER, TRILOGY-ACS, APPRAISE-2, and PLATO Clinical Trials).

Patients with acute coronary syndrome (ACS) are at risk for recurrent adverse events, and multiple reports suggest that this risk is increased in patients with concomitant diabetes mellitus (DM) and peripheral artery disease (PAD). The aim of this article was to investigate cardiovascular outcomes in patients with DM presenting with ACS, stratified by PAD status. Data were derived from 4 randomized post-ACS trials (PLATO [Platelet Inhibition and Patient Outcomes], APPRAISE-2 p Apixaban for Prevention of Acute Ischemic Events 2], TRILOGY [Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage], and TRACER [Thrombin Receptor Agonist for Clinical Event Reduction in Acute Coronary Syndrome]). Using Cox regression analysis, we investigated major adverse cardiovascular events (MACEs), a composite of cardiovascular mortality, myocardial infarction (MI), or stroke and the individual components of MACE and all-cause mortality in patients with DM, presenting with ACS, stratified by PAD status as the risk modifier. This study included 15,387 patients with a diagnosis of DM and ACS, of whom 1,751 had an additional diagnosis of PAD. PAD was associated with more than doubled rates of MACE (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.81 to 2.27), all-cause mortality (HR 2.48, 95% CI 2.14 to 2.87), cardiovascular mortality (HR 2.42, 95% CI 2.04 to 2.86), and MI (HR 2.07, 95% CI 1.79 to 2.38). Patients with both PAD and DM were also more optimally treated with antihypertensive, antidiabetic, and statin medication at baseline. In conclusion, this analysis of 4 major post-ACS trials showed that patients with DM and PAD had a substantially higher risk of MACE, cardiovascular mortality, all-cause mortality, and MI despite being optimally treated with guideline-based therapies.

Sex Differences in Clinical Course and Patient-Reported Outcomes Among Patients Hospitalized for Heart Failure.

OBJECTIVES: The goal of this study was to evaluate differences in clinical and patient-reported outcomes between women and men hospitalized for acute HF. BACKGROUND: Among patients hospitalized for heart failure (HF), it is unclear if symptom burden, response to therapy, and patient-reported quality of life (QOL) are different in women as compared with men. METHODS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 patients hospitalized for HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. Clinical endpoints included 30-day mortality and rehospitalization and 180-day mortality. Patient-reported QOL was assessed at baseline, discharge, and 30 days using the EuroQOL 5 dimensions (EQ-5D) survey. RESULTS: Among 7,141 total patients, 4,697 (65.8%) were men and 2,444 (34.2%) were women. Among patients with EF ≤40%, women were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and beta-blocker therapy, and less likely to have an implantable cardioverter-defibrillator (all p < 0.03). Signs and symptoms of HF were similar between men and women (all p > 0.05), but women experienced less in-hospital weight loss and urine output (all p < 0.01). In unadjusted and adjusted analyses, men and women had similar risk of all mortality and rehospitalization endpoints (all p ≥ 0.41). Women reported lower EQ-5D utility and visual analogue scores at admission, discharge, and 30 days. Women continued to have significantly lower EQ-5D scores at all in-hospital and post-discharge time points after adjustment for clinical characteristics (all p < 0.01). CONCLUSIONS: In this acute HF population, women had similar risk of mortality and rehospitalization as compared with men, but experienced worse patient-reported QOL during and after hospitalization that persisted after adjustment for demographic and clinical factors. Current acute HF management may work similarly in either sex for purposes of preventing clinical events, but may be less equipped to improve patient-reported outcomes in women as compared with men.

Well-Child Care Attendance and Risk of Asthma Exacerbations.

BACKGROUND: Asthma remains a leading cause of hospitalization in US children. Well-child care (WCC) visits are routinely recommended, but how WCC adherence relates to asthma outcomes is poorly described. METHODS: We conducted a retrospective longitudinal cohort study using electronic health records among 5 to 17 year old children residing in Durham County with confirmed asthma and receiving primary care within a single health system, to compare the association between asthma exacerbations and previous WCC exposure. Exacerbations included any International Classification of Diseases, Ninth Revision, or International Classification of Diseases, 10th Revision, coded asthma exacerbation encounter with an accompanying systemic glucocorticoid prescription. Exacerbations were grouped by severity: ambulatory encounter only, urgent care, emergency department, hospital encounters <24 hours, and hospital admissions ≥24 hours. In the primary analysis, we assessed time to asthma exacerbation based on the presence or absence of a WCC visit in the preceding year using a time-varying covariate Cox model. RESULTS: A total of 5656 children met eligibility criteria and were included in the primary analysis. Patients with the highest WCC visit attendance tended to be younger, had a higher prevalence of private insurance, had greater asthma medication usage, and were less likely to be obese. The presence of a WCC visit in the previous 12 months was associated with a reduced risk of all-cause exacerbations (hazard ratio: 0.90; 95% confidence interval: 0.83-0.98) and severe exacerbations requiring hospital admission (hazard ratio: 0.53; 95% confidence interval: 0.39-0.71). CONCLUSIONS: WCC visits were associated with a lower risk of subsequent severe exacerbations, including asthma-related emergency department visits and hospitalizations. Poor WCC visit adherence predicts pediatric asthma morbidity, especially exacerbations requiring hospitalization.

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion.

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.

Is Time of the Essence? The Impact of Time of Hospital Presentation in Acute Heart Failure: Insights From ASCEND-HF Trial.

OBJECTIVES: As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF. BACKGROUND: Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized. METHODS: A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation. RESULTS: Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40). CONCLUSIONS: In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials.