Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

BACKGROUND: Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. METHODS: TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. RESULTS: Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. CONCLUSION: PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT04305405.

Pseudo-vagal Responses Elicited by Cryoballoon Ablation.

Pulmonary vein isolation via cryoballoon (CB) ablation is the cornerstone ablation strategy for the treatment of atrial fibrillation (AF). Acute intraprocedural hypotensive and/or bradycardic responses have been reported in patients undergoing CB ablation for AF. However, it remains unclear as to whether these are due to a true vagal response (VR), which can be used to predict long-term outcomes of CB ablation. We analyzed 139 freezes across 17 patients who received CB ablation for paroxysmal AF, measuring vital signs and freeze characteristics. Only one freeze was associated with both hypotension and bradycardia, constituting a true VR. Several freezes were associated with hypotension only that did not respond to atropine administration, suggesting that these responses are not associated with a VR. Hypotensive responses were significantly associated with ice bubble bursts during CB deflation. Unlike the true VR reported in patients undergoing conscious sedation, the presence of acute hypotension shortly after CB deflation cannot be used as a predictor for long-term ablation outcomes.

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms.

BACKGROUND: Type 1 diabetes (T1D) is a major cause of endothelial dysfunction. Although cellular bioenergetics has been identified as a new regulator of vascular function, whether glycolysis, the primary bioenergetic pathway in endothelial cells (EC), regulates vascular tone and contributes to impaired endothelium-dependent relaxation (EDR) in T1D remains unknown. METHODS: Experiments were conducted in Akita mice with intact or selective deficiency in EC PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), the main regulator of glycolysis. Seahorse analyzer and myography were employed to measure glycolysis and mitochondrial respiration, and EDR, respectively, in aortic explants. EC PFKFB3 (Ad-PFKFB3) and glycolysis (Ad-GlycoHi) were increased in situ via adenoviral transduction. RESULTS: T1D increased EC glycolysis and elevated EC expression of PFKFB3 and NADPH oxidase Nox1 (NADPH oxidase homolog 1). Functionally, pharmacological and genetic inhibition of PFKFB3 restored EDR in T1D, while in situ aorta EC transduction with Ad-PFKFB3 or Ad-GlycoHi reproduced the impaired EDR associated with T1D. Nox1 inhibition restored EDR in aortic rings from Akita mice, as well as in Ad-PFKFB3-transduced aorta EC and lactate-treated wild-type aortas. T1D increased the expression of the advanced glycation end product precursor methylglyoxal in the aortas. Exposure of the aortas to methylglyoxal impaired EDR, which was prevented by PFKFB3 inhibition. T1D and exposure to methylglyoxal increased EC expression of HIF1α (hypoxia-inducible factor 1α), whose inhibition blunted methylglyoxal-mediated EC PFKFB3 upregulation. CONCLUSIONS: EC bioenergetics, namely glycolysis, is a new regulator of vasomotion and excess glycolysis, a novel mechanism of endothelial dysfunction in T1D. We introduce excess methylglyoxal, HIF1α, and PFKFB3 as major effectors in T1D-mediated increased EC glycolysis.

Evaluation of humoral immune deficiency in Indian patients with bilateral bronchiectasis with no apparent aetiology.

Background: Infections continue to be the leading aetiology of bronchiectasis in developing countries like India. Among non-infectious cases, the majority will have no identifiable cause despite extensive evaluation. Recently, immunodeficiency has been recognized as an important aetiology, but data on its prevalence remain rather sparse. Objectives: The objective of this study is to evaluate the prevalence of humoral immunodeficiency in a cohort of adults with bilateral bronchiectasis with no apparent aetiology. Methods: This is the single-site study from Christian Medical College (Vellore, India) of adults with HRCT-proven non-infectious bronchiectasis. Humoral immunity was assessed through quantitative analysis of immunoglobulins and IgG subclass levels. Results: Among 158 cases, immunoglobulin deficiency was found in 15%. Low IgM was the most predominate finding (7%), followed by common variable immunodeficiency (3%) and low IgA (2.5%). In addition, IgG subclass deficiency was found in 5%. In 53% of cases, no specific aetiology could be identified. Conclusion: Humoral immune deficiency is present in a significant proportion of patients with non-infectious bronchiectasis. Routine measurement of serum immunoglobulins should therefore be considered as part of the evaluation.

Endothelial leptin receptor is dispensable for leptin-induced sympatho-activation and hypertension in male mice.

Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepREC)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC-/- mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC-/-:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC-/-:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC-/-:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC-/-:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC-/- mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepREC+/+ and LepREC-/- mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension.

Incidence of Severe Maternal Morbidity During Delivery Hospitalization in U.S. Commercially Insured and Medicaid Populations.

Objective: To estimate the incidence rate and associated risk factors of severe maternal morbidity (SMM) in commercially and Medicaid-insured women. Materials and Methods: This was a retrospective cohort study of women with a live inpatient delivery recorded in 2016 in the MarketScan® databases for commercially insured and Medicaid populations. The incidence of SMM, defined by the Center for Disease Control and Prevention's algorithm of International Classification of Diseases, 10th edition diagnostic and procedural codes, was determined. Measurements also included the association of SMM in bivariate analyses with patient characteristics and the association of SMM with delivery type, gestation type, maternal age, and race in multivariate logistic regression analysis, adjusted for pre-existing conditions and pregnancy-related complications. Results: The incidence of SMM per 10,000 deliveries was 111.4 in the Commercial and 109.6 in the Medicaid population. The most frequent SMM indicators were eclampsia and blood transfusion in the Commercial population (35.0 and 25.7 per 10,000 deliveries, respectively) and eclampsia and adult respiratory distress syndrome in the Medicaid population (45.5 and 14.9 per 10,000 deliveries, respectively). A cesarean delivery was associated with SMM in both Commercial (odds ratio [OR] 3.37; 95% confidence interval [CI] 1.51-1.84) and Medicaid populations (OR 1.99; 95% CI 1.80-2.17). A multifetal gestation was also associated with SMM in both Commercial (OR 3.37; 95% CI 2.80-4.10) and Medicaid populations (OR 2.26; 95% CI 1.86-2.75). Conclusion: SMM occurred in 1.1% of live inpatient deliveries. A cesarean delivery, multifetal gestation, race, region, and several pre-existing comorbidities and obstetric complications were associated with SMM.

New-onset Heart Failure With Atrial Fibrillation: A Distinct Type of Cardiomyopathy?

OBJECTIVE: There is limited research comparing demographic and clinical characteristics between patients who present with atrial fibrillation (AF) and new-onset cardiomyopathy (CM) to patients with new-onset CM without dysrhythmia. We aimed to evaluate clinical characteristics and outcomes in patients with new-onset CM with and without AF and to report their real-world treatment. METHODS AND RESULTS: The study population was identified using patient records from our healthcare system from January 1, 2012 to September 30, 2016. Patients with a left ventricular ejection fraction ≤40% without a prior history of CM were divided into two groups; those with an antecedent or concomitant diagnosis of AF (AF-CM group) and those with no history of dysrhythmia (CM group). Patients in the AF-CM group (n=196) were older, more likely to be male, had a higher burden of comorbidities but lower levels of cardiac biomarkers, and had lower voltage on surface electrocardiogram than the CM group (n=197). In AF-CM, symptom onset was insidious, leading to a higher likelihood of outpatient diagnosis; 88.3% of AF-CM patients presented with atypical symptoms of AF. The AF-CM group had higher mortality on follow-up. Only 8.7% of patients in this group underwent an ablation procedure. Women, those with a history of coronary artery disease, and older patients were less likely to receive a cardioversion or ablation procedure. CONCLUSIONS: Patients presenting with new-onset CM associated with AF have a markedly different risk factor and demographic profile, clinical presentation, and outcomes. In real-world practice, a minority of patients undergo a rhythm control strategy.

Costs of Severe Maternal Morbidity in U.S. Commercially Insured and Medicaid Populations: An Updated Analysis.

Background: The most common reason for hospitalization in the United States is childbirth. The costs of childbirth are substantial. Materials and Methods: This was a retrospective cohort study of hospital deliveries identified in the MarketScan® Commercial and Medicaid health insurance claim databases. Women with an inpatient birth in the calendar year 2016 were included. Severe maternal morbidity (SMM) was identified using the Centers for Disease Control and Prevention algorithm of 21 International Classification of Diseases-10 codes. Mean costs and cost ratios for women with and without SMM were reported. Generalized linear models were used to analyze demographic and clinical variables influencing delivery costs. Results: We identified 1,486 women in the Commercial population, who had a birth in 2016 and met the criteria for SMM. The total mean per-patient costs of care for women with and without SMM were $50,212 and $23,795, respectively. In the Medicaid population there were 29,763 births, of which 342 met the criteria for SMM. The total mean per-patient costs of care for women with and without SMM were $26,513 and $9,652, respectively. A multifetal gestation, a cesarean delivery, maternal age, and pregnancy-related complications were independently predictive of increased delivery costs in both Commercial and Medicaid populations. Conclusions: The occurrence of SMM was associated with an increase in maternity-related costs of 111% in the Commercial and 175% in the Medicaid population. Some of the factors associated with increased delivery hospitalization costs could be treated or avoided.

Hospital Readmission Following Delivery With and Without Severe Maternal Morbidity.

Background: The relationship between severe maternal morbidity (SMM) events during inpatient delivery and subsequent hospital readmission is not well understood. Materials and Methods: This was a retrospective cohort study of women with a live inpatient delivery during 2016 recorded in MarketScan® databases for commercially insured and Medicaid populations. Live inpatient births were identified by the International Classification of Diseases, 10th Revision diagnostic and procedural codes, Current Procedural Terminology, and Diagnosis-Related Group codes. The incidence of hospital readmission within 30 days following a delivery discharge, and primary discharge diagnoses, were determined by SMM status. The association with hospital readmission of SMM status, delivery type, gestation type, and maternal age was determined in multivariable logistic regression analyses, adjusted for pregnancy-related complications and preexisting comorbidities. Results: In the Commercial population there were 1,927 hospital readmissions, for an incidence rate of 11.7 per 1,000 discharges. The readmission rate was 12 times greater for women with SMM than for women without SMM during delivery. The most frequent discharge diagnoses among women readmitted were other complications of the puerperium, endometritis, and infection of obstetric surgical wound of women without SMM during delivery. In multivariable analysis, SMM during delivery was strongly associated with readmission in the Commercial population. Results for the Medicaid population were similar. Conclusion: SMM during delivery hospitalization increased the risk of readmission more than 10 times. The most frequent discharge diagnoses following readmission included obstetric infection and endometritis in women without SMM, and eclampsia in women with SMM during delivery. Awareness of these findings could help health care providers prevent future episodes.

Real-world characteristics and readmissions among patients undergoing ablation for ventricular tachycardia: a retrospective database analysis of commercially insured patients in the USA.

BACKGROUND: Radiofrequency catheter ablation is an effective treatment to alleviate symptoms and reduce recurrent implantable cardioverter-defibrillator (ICD/CRT-D) shocks in patients with ventricular tachycardia (VT). OBJECTIVE: To assess the characteristics and outcomes (complications, inpatient readmissions) of commercially insured patients in the USA undergoing ablation for ischaemic or non-ischaemic VT. METHODS: Patients aged 18-64 years with a primary diagnosis of VT who underwent ablation between 2006 and 2015 were identified using the IBM MarketScan Commercial Database. The rate of complications including vascular complications, pericarditis, pulmonary embolism and pericardial tamponade over a 30-day post-ablation period (including index admission) was examined. Inpatient readmissions (VT-related, heart failure (HF)-related and non-VT arrhythmia-related) over the 12-month post-ablation period were examined. A Cox regression model was used to determine factors associated with inpatient readmissions. RESULTS: 5242 patients (488 with ischaemic and 4754 with non-ischaemic VT) met the study criteria. The majority of VT ablations occurred in an outpatient setting (57% for ischaemic and 66% for non-ischaemic VT). Among complications, vascular complications were most frequent (2.05% among ischaemic and 1.6% among non-ischaemic VT patients) over the 30-day post-ablation period. Among ischaemic VT patients, 17%, 7.6% and 4.7% had VT-related, HF-related and non-VT arrhythmia-related inpatient readmissions, respectively in the 12-month post-ablation period. For non-ischaemic VT patients, these numbers were 7.5%, 1.7% and 3.1%, respectively. Inpatient setting (vs outpatient), baseline ICD/CRT-D implantation, HF comorbidity and ≥2 prior hospitalisations were associated with a higher risk of post-ablation VT-related inpatient readmissions among ischaemic VT patients. Similar factors also were associated with a higher risk of post-ablation VT-related inpatient readmission among non-ischaemic VT patients. CONCLUSION: Setting of ablation and comorbidity status were found to influence readmission rates. Complication and readmission rates following VT ablation were low indicating towards the favourable safety profile of VT ablation.

An appraisal of allergic disorders in India and an urgent call for action.

India is the second most populous country in the world with a population of nearly 1.3 billion, comprising 20% of the global population. There are an estimated 37.5 million cases of asthma in India, and recent studies have reported a rise in prevalence of allergic rhinitis and asthma. Overall, 40-50% of paediatric asthma cases in India are uncontrolled or severe. Treatment of allergic rhinitis and asthma is sub-optimal in a significant proportion of cases due to multiple factors relating to unaffordability to buy medications, low national gross domestic product, religious beliefs, myths and stigma regarding chronic ailment, illiteracy, lack of allergy specialists, and lack of access to allergen-specific immunotherapy for allergic rhinitis and biologics for severe asthma. High quality allergen extracts for skin tests and adrenaline auto-injectors are currently not available in India. Higher postgraduate specialist training programmes in Allergy and Immunology are also not available. Another major challenge for the vast majority of the Indian population is an unacceptably high level of exposure to particulate matter (PM)2.5 generated from traffic pollution and use of fossil fuel and biomass fuel and burning of incense sticks and mosquito coils. This review provides an overview of the burden of allergic disorders in India. It appraises current evidence and justifies an urgent need for a strategic multipronged approach to enhance quality of care for allergic disorders. This may include creating an infrastructure for education and training of healthcare professionals and patients and involving regulatory authorities for making essential treatments accessible at subsidised prices. It calls for research into better phenotypic characterisation of allergic disorders, as evidence generated from high income western countries are not directly applicable to India, due to important confounders such as ethnicity, air pollution, high rates of parasitic infestation, and other infections.

Pediatric allergic diseases in the Indian subcontinent-Epidemiology, risk factors and current challenges.

INTRODUCTION: India is low-middle-income country (LMIC) with a population of 1.3bn, comprising about 20% of the global population. While the high-income Western countries faced an "allergy epidemic" during the last three decades, there has been a gradual rise in prevalence of allergic diseases in India. METHODS: Narrative review. RESULTS AND DISCUSSION: Allergic diseases occur as a consequence of a complex interplay between genetic and environmental factors. There are multiple contrasting determinants that are important to consider in India including high levels of air pollution, in particular PM2.5 due to burning of fossil fuels and biomass fuels, diverse aero-biology, tropical climate, cultural and social diversity, religious beliefs/myths, linguistic diversity, literacy level, breastfeeding and weaning, diet (large proportion vegetarian), and high incidence rates of TB, HIV, malaria, filariasis, parasitic infestations, and others, that not only shape the immune system early in life, but also impact on biomarkers relevant to allergic diseases. India has a relatively weak and heterogeneous healthcare framework, and allergology has not yet been recognized as an independent specialty. There are very few post-graduate training programs, and allergic diseases are managed by primary care physicians, organ-based specialists, and general pediatricians. Adrenaline auto-injectors are not available, there is patient unaffordability for inhalers, nasal sprays, and biologics, and this is compounded by poor compliance leading to 40%-50% of asthmatic children having uncontrolled disease and high rates of oral corticosteroid use. Standardized allergen extracts are not available for skin tests and desensitization. This article provides a critical analysis of pediatric allergic diseases in India.

An Outpatient Heart Failure Clinic Reduces 30-Day Readmission and Mortality Rates for Discharged Patients: Process and Preliminary Outcomes.

BACKGROUND: The first outpatient heart failure clinic (HFC) in Western New York was developed within a large private cardiology practice with the objective of reducing 30-day all-cause rehospitalization and inpatient mortality. PURPOSE: The aim of this study was to analyze the process and patient outcomes of this independent outpatient HFC. The specific aims were to (a) describe the outpatient care strategies employed and (b) determine whether the HFC reduced 30-day all-cause rehospitalizations and inpatient mortality by comparing HFC data with census data. METHODS: This study used a retrospective chart analysis of 415 adults who had been enrolled in the target HFC after hospitalization for HF. Data were summarized using frequency comparisons and descriptive statistics. One-sample chi-square tests were conducted to test the observed values in the study sample against census data. RESULTS: Patients in the HFC were less likely to experience a readmission to hospital within 30 days of discharge (69% reduction within the study period, p < .001). Patients were seen acutely after discharge, had multiple medication adjustments, and received ongoing telephonic follow-up. The HFC had statistically lower inpatient mortality rates (1.2% vs. 11.6% national average, p < .001), likely a result of the HFC care regimen and referrals for palliative care (17%). CONCLUSIONS: The results of this analysis highlight the importance of developing an outpatient HFC in collaboration with hospitals that is aimed at reducing 30-day all-cause readmissions and inpatient mortality, with referral to palliative care when indicated.

Cost-effectiveness of using an extensively hydrolyzed casein formula containing Lactobacillus rhamnosus GG in managing infants with cow's milk allergy in the US.

OBJECTIVE: To estimate the cost-effectiveness of using an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (eHCF + LGG; Nutramigen LGG) compared with an eHCF alone and an amino acid formula (AAF) in treating cow's milk allergy (CMA) in the US, from the perspective of third-party insurers and from parents. METHODS: A decision model was used to estimate the probability of cow's milk allergic infants developing tolerance to cow's milk by 18 months. The model also estimated the cost to insurers and parents (US dollars at 2016 prices) of managing infants over 18 months after starting one of the formulae, as well as the relative cost-effectiveness of each of the formulae. RESULTS: The probability of developing tolerance to cow's milk was higher among infants who were fed eHCF + LGG compared with those fed an eHCF alone or an AAF. Infants who are initially fed with eHCF + LGG are expected to utilize fewer healthcare resources than those fed with one of the other formulae. Hence, the estimated total healthcare cost incurred by third-party insurers and parents of initially feeding infants with eHCF + LGG was less than that of feeding infants with an eHCF alone or an AAF. CONCLUSION: Initial management of newly-diagnosed cow's milk allergic infants with eHCF + LGG was found to afford a cost-effective strategy to both third-party insurers and parents when compared to an eHCF alone or an AAF.

Prediction of Recurrent Clostridium Difficile Infection Using Comprehensive Electronic Medical Records in an Integrated Healthcare Delivery System.

BACKGROUND Predicting recurrent Clostridium difficile infection (rCDI) remains difficult. METHODS: We employed a retrospective cohort design. Granular electronic medical record (EMR) data had been collected from patients hospitalized at 21 Kaiser Permanente Northern California hospitals. The derivation dataset (2007-2013) included data from 9,386 patients who experienced incident CDI (iCDI) and 1,311 who experienced their first CDI recurrences (rCDI). The validation dataset (2014) included data from 1,865 patients who experienced incident CDI and 144 who experienced rCDI. Using multiple techniques, including machine learning, we evaluated more than 150 potential predictors. Our final analyses evaluated 3 models with varying degrees of complexity and 1 previously published model. RESULTS Despite having a large multicenter cohort and access to granular EMR data (eg, vital signs, and laboratory test results), none of the models discriminated well (c statistics, 0.591-0.605), had good calibration, or had good explanatory power. CONCLUSIONS Our ability to predict rCDI remains limited. Given currently available EMR technology, improvements in prediction will require incorporating new variables because currently available data elements lack adequate explanatory power. Infect Control Hosp Epidemiol 2017;38:1196-1203.

Association of Hypoglycemia With Subsequent Dementia in Older Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Studies have found conflicting evidence regarding the association of hypoglycemia with dementia. We evaluated an association of hypoglycemia with subsequent dementia in patients with type 2 diabetes. METHODS: This retrospective longitudinal cohort study used the Clinical Practice Research Datalink, an electronic medical records data from the United Kingdom, from 2003 to 2012. We included patients aged >65 years diagnosed with type 2 diabetes, with no prior diagnosis of dementia. Dementia was defined using diagnosis codes from medical records. All patients were followed from the date of initial diabetes diagnosis. To account for competing risk of death, we used Fine and Gray's competing risk model to determine the association of hypoglycemia with dementia while adjusting for potential confounders. Hypoglycemia was modeled as a time-dependent covariate. RESULTS: Of 53,055 patients, 5.7% (n = 3,018) had at least one hypoglycemia episodes. The overall incidence rate of dementia was 12.7 per 1,000 person-years. In the fully adjusted model that controlled for all confounders, the occurrence of at least one hypoglycemia episode was associated with 27% higher odds of subsequent dementia (hazard ratio = 1.27; 95% confidence interval = 1.06-1.51). The risk increased with the number of hypoglycemia episodes: one episode (hazard ratio = 1.26; 95% confidence interval = 1.03-1.54); two or more episodes (hazard ratio = 1.50; 95% confidence interval = 1.09-2.08). CONCLUSIONS: Hypoglycemia is associated with a higher risk of dementia and may be responsible in part for the higher risk of dementia in patients with diabetes. Alternatively, hypoglycemia may be a marker for undiagnosed cognitive impairment, and we cannot rule out the possibility of reverse causation between hypoglycemia and dementia.

Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence.

BACKGROUND: Although newer studies have evaluated risk factors for recurrent Clostridium difficile infection (CDI), the vast majority did not measure important biomarkers such as endogenous anti-toxin A and anti-toxin B antibody levels. METHODS: Data from the placebo group of a phase 2 trial testing monoclonal antibodies to C. difficile toxins A and B for preventing CDI recurrence (rCDI) were analyzed to assess risk factors associated with rCDI. Patients with symptomatic CDI taking metronidazole or vancomycin were enrolled. The primary outcome was rCDI within 84 days of treatment start. Univariate and multivariate logistic regression was used to examine associations between potential risk factors and rCDI. At baseline, demographic and clinical characteristics were recorded; endogenous antibody levels were assessed using 2 enzyme-linked immunosorbent assays. RESULTS: A predictor of recurrence was age ≥65 years, and an antibody-mediated immune response to toxin B appears to be protective against rCDI. CONCLUSIONS: Our findings demonstrate the importance of clinical as well as immunological risk factors in rCDI and provide more robust evidence for the protective effects of antibody to toxin B in the prevention of rCDI. CLINICAL TRIALS REGISTRATION: NCT00350298.