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The prevalence of maternal obesity has increased dramatically with adverse consequences on infant health. Prior studies have reported associations between maternal obesity and childhood wheeze, asthma as well as lower respiratory tract infections (LRTI). However, studies examining the association of obesity with early-life LRTIs in low-income urban minority populations are still lacking. This is a critical gap because both obesity and infant respiratory morbidity are more prevalent and severe in these communities. We examined mother‐child dyads from the Boston Birth Cohort (BBC) to define the longitudinal association of maternal pre‐pregnancy BMI and LRTI in infancy, defined as the presence of bronchiolitis, bronchitis, or pneumonia during the first year of life (< 12 months of age). A total of 2,790 mother‐child dyads were included in our analyses. Infants born to pre-pregnancy obese mothers (n = 688, 25%) had 1.43 increased odds (adjOR = 1.43, 95% CI 1.08–1.88, p = 0.012) of developing LRTI during the first year of life when compared with newborns born to normal-weight mothers after adjusting by relevant LRTI risk factors. Notably, infants born to overweight mothers (n = 808, 29%) followed a similar trend (adjOR = 1.31, 95% CI 1.00–1.72, p = 0.048). Our study demonstrated that maternal pre-pregnancy obesity is an independent risk factor for the development of LRTI during infancy in a low-income urban minority birth cohort. [ABSTRACT FROM AUTHOR]

Background. Cytokine storm syndromes (CSS) are life-threatening systemic inflammatory disorders caused by immune system dysregulation. They can lead to organ failure and are triggered by various factors, including infections, malignancy, inborn errors of immunity, and autoimmune conditions. Trisomy 21 (TS21), also known as Down syndrome, is a genetic disorder associated with immune dysfunction, increased infection susceptibility, and inflammation. While TS21 has been linked to infectious-triggered hyperinflammation, its role as a primary cause of CSS has not been confirmed. Case Presentation. We present a case of a 16-year-old male with TS21 with fever, rash, joint pain, and abdominal symptoms. Extensive investigations ruled out infections, autoimmune conditions, malignancies, and inborn errors of immunity as triggers for a CSS. The patient's symptoms improved with treatment using IL-1 inhibition and corticosteroids. Conclusions. This case reinforces that TS21 is an immune dysregulation disorder and highlights the importance of considering CSS in TS21 patients, even when triggers are unclear. The positive response to IL-1 inhibition in this patient suggests that dysregulation of the IL-1 superfamily and the NLRP3 inflammasome may contribute to CSS in TS21. This finding raises the possibility of using IL-1 inhibition as a treatment approach for CSS in TS21 patients. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections.Methods: Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with (n = 17) and those without infections (n = 6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays.Results: We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections.Conclusions: Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention. [ABSTRACT FROM AUTHOR]

Background: Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood. Methods: Nasal airway secretions were obtained from children (≤3 yrs. old) during PCR-confirmed RV infections (n = 10) and age-matched controls (n = 10). Nasal EVs were isolated with polymer-based precipitation and global miR profiles generated using NanoString microarrays. We validated our in vivo airway secretory miR data in an in vitro airway epithelium model using apical secretions from primary human bronchial epithelial cells (HBEC) differentiated at air-liquid interface (ALI). Bioinformatics tools were used to determine the unified (nasal and bronchial) signature airway secretory miRNAome and changes during RV infection in children. Results: Multiscale analysis identified four signature miRs comprising the baseline airway secretory miRNAome: hsa-miR-630, hsa-miR-302d-3p, hsa- miR-320e, hsa-miR-612. We identified hsa-miR-155 as the main change in the baseline miRNAome during RV infection in young children. We investigated the potential biological relevance of the airway secretion of hsa-mir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection. These analyses confirmed that hsa-miR-155 targetome is an overrepresented pathway in the upper airways of individuals infected with RV. Conclusions: Comparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway secretion of EVs containing miR-155, which is predicted in silico to regulate antiviral immunity. Further characterization of the airway secretory microRNAome during health and disease may lead to completely new strategies to treat and monitor respiratory conditions in all ages. [ABSTRACT FROM AUTHOR]

Rationale. The sleep-related factors thatmodulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA. Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (η = 134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance level P = 0.05). Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2 desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2 desaturation was independent of demographic variables. Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children. [ABSTRACT FROM AUTHOR]

Background. Obese adolescents with Obstructive Sleep Apnea (OSA) have a unique pathophysiology that combines adenotonsillar hypertrophy and increased visceral fat distribution. We hypothesized that in this population waist circumference (WC), as a clinical marker of abdominal fat distribution, correlates with the likelihood of response to AT. Methods. We conducted a retrospective cohort study of obese adolescents (BMI = 97th percentile) that underwent AT for therapy of severe OSA (n = 21). We contrasted WC and covariates in a group of subjects that had complete resolution of severe OSA after AT (n = 7) with those obtained in subjects with residual OSA after AT (n = 14). Multivariate linear and logistic models were built to control possible confounders. Results. WC correlated negatively with a positive AT response in young adolescents and the percentage of improvement in obstructive apnea-hypopnea index (OAHI) after AT (P = 0.01). Extended multivariate analysis demonstrated that the link between WC and AT response was independent of demographic variables, OSA severity, clinical upper airway assessment, obesity severity (BMI), and neck circumference (NC). Conclusion. The results suggest that in obese adolescents, abdominal fat distribution determined by WC may be a useful clinical predictor for residual OSA after AT. [ABSTRACT FROM AUTHOR]

Chronic granulomatous disease (CGD) is characterized by inherited immune defects resulting from mutations in the NADPH oxidase complex genes. The X-linked type of CGD is caused by defects in the CYBB gene that encodes gp91-phox, a fundamental component of the NADPH oxidase complex. This mutation originates the most common and severe form of CGD, which typically has absence of NADPH oxidase function and aggressive multisystemic infections. We present the case of a 9-year-old child with a rare CYBB mutation that preserves some NADPH oxidase activity, resulting in an atypical mild form of X-linked CGD with isolated lung involvement. Although the clinical picture and partially preserved oxidase function suggested an autosomal recessive form of CGD, genetic testing demonstrated a mutation in the exon 3 of CYBB gene (c.252 G>A, p.Ala84Ala), an uncommon Xlinked CGD variant that affects splicing. Atypical presentation and diagnostic difficulties are discussed. This case highlights that the diagnosis of mild forms of X-linked CGD caused by rare CYBB mutations and partially preserved NADPH function should be considered early in the evaluation of atypical and recurrent lung infections. [ABSTRACT FROM AUTHOR]

This study's aims were to evaluate the effects of Sorensen's Therapy of Instability in Mood (Sorensen, 2005; Sorensen, Done & Rhodes, 2007), an intervention based on a short relapse-prevention program for clients suffering from Bipolar Disorder (BD), delivered within a clinical setting, by an assistant psychologist with limited training in CBT. The experimental treatment consisted of four individual sessions in addition to treatment as usual. Twelve clients with diagnoses of BD participated. Outcomes were measured across four domains: symptom severity, perceived hopelessness, perceived control over symptoms and level of insight. Measures of client satisfaction were also collected. Statistical analysis of the data revealed significant improvements to depression and perceived control levels at both one and three month follow-ups. In addition, clients reported significantly lower levels of hopelessness at three months follow-up. The study also considered the clinical significance of the research findings with the Jacobson-Truax (Jacobson & Truax, 1991) method. A substantial number of clients attained clinically significant changes with regards to depression, hopelessness and perceived control at one and three months follow-ups. Recovery rates at three months were 50%, 41.6% and 25% respectively. Neither statistically nor clinically significant changes were found with regards to mania or insight at either one or three month follow-ups. All clients reported high levels of satisfaction. [ABSTRACT FROM AUTHOR]

Study Objective. To investigate the systemic absorption of estradiol in partners of postmenopausal women after making skin-to-skin contact with the application sites of estradiol topical emulsion. Design. Open-label, nonrandomized clinical study. Setting. Clinical study unit. Subjects. Fourteen postmenopausal women and their male partners (mean ± SD age 57.6 ± 8.7 and 49.1 ± 13.3 yrs, respectively). Intervention. Women applied 1.74 g/day of estradiol topical emulsion (containing 2.5 mg estradiol/g) to each leg on 2 consecutive days. Their male partners were exposed to the application sites by mean of vigorous skin-to-skin contact at 2 and 8 hours after application. Measurements and Main Results. Serum concentrations of estradiol, estrone, and estrone sulfate were measured in the female subjects and their male partners. The mean ± SD estradiol level in the women at baseline was 2.9 ± 1.5 pg/ml. Their average concentration (Caverage) increased from 15.3 ± 14.8 pg/ml on the first day of treatment to 27.6 ± 22.7 pg/ml on the second day. Among male partners, Caverage for serum estradiol increased from 17.0 ± 4.3 pg/ml at baseline to 21.0 ± 4.4 pg/ml on the second exposure day. Their geometric mean fold ratio for the area under the serum concentration-time curve from 0-24 hours was 1.25 (baseline vs after second exposure, p<0.0001). Conclusions. Estradiol was transferred to male partners by means of vigorous skin-to-skin contact at application sites. Although the increase in postexposure levels of estradiol was statistically significant, all levels were still below the upper limit of the normal range for men (45 pg/ml). [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial‐derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1–24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as ‘high TSLP’ or ‘low TSLP’ for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I–III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I–III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro‐inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro‐inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre‐activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro‐inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long‐term impact of viral respiratory illnesses during early infancy and beyond childhood. [ABSTRACT FROM AUTHOR]

Background: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. Objective: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. Methods: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. Results: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05–2.75), sinusitis (OR = 2.06 95%CI 1.38–3.09), pneumonia (OR = 2.70 95%CI 1.88–3.88), COPD (OR = 2.66 95%CI 1.51–4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41–3.91) were independently associated with the development of bronchiectasis in this population. Conclusion: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication. [ABSTRACT FROM AUTHOR]

Contains correspondence over proposed psychiatric training for family doctors. Structure of 8-week block rotation for the first and second years; Evidence of improvement of recognition skills by residents; Favorable treatment response of patients.

Purpose. The most common pharmacological therapies used in the treatment of stridor in children are glucocorticosteroids (GC) and alpha-adrenergic (αAR) agonists. Despite the long-standing reported efficacy of these medications, there is a paucity of data relating to their actualmechanisms of action in the upper airway. Summary. There is compelling scientific evidence supporting the use of αAR-agonists and GCs in pediatric stridor. αAR signaling and GCs regulate the vasomotor tone in the upper airwaymucosa. The latter translates into better airflow dynamics, as delineated by human and nonhuman upper airway physiological models. In turn, clinical trials have demonstrated that GCs and the nonselective αAR agonist, epinephrine, improve respiratory distress scores and reduce the need for further medical care in children with stridor. Future research is needed to investigate the role of selective αAR agonists and the potential synergism of GCs and αAR-signaling in the treatment of upper airway obstruction and stridor. [ABSTRACT FROM AUTHOR]

Introduction: IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods: IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results: Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion: IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children. Methods: Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1β, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters. Results: A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses. Conclusions: The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2-4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. Conclusion: CMV pneumonia is a potential lethal disease in non-HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes. [ABSTRACT FROM AUTHOR]

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation. [ABSTRACT FROM AUTHOR]

This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG], urinary glucose excretion [UGE0-24h], and 24-hour mean plasma glucose [MPG0-24h]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG, increased UGE0-24h, and reduced MPG0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen. [ABSTRACT FROM AUTHOR]

This study investigated the effect of eslicarbazepine acetate (ESL) on cardiac repolarization in healthy adult volunteers. A randomized, placebo/active-controlled, 4-period crossover study was conducted in 67 participants. In 3 periods, participants received once-daily doses of ESL 1200 mg, ESL 2400 mg, and placebo for 5 days; in 1 period, participants received placebo on days 1 to 4 and a 400-mg moxifloxacin single dose on day 5. In each period, 24-hour 12-lead Holter monitoring was performed on days –1 (baseline) and 5. There was no clinically relevant effect of ESL 1200 mg and 2400 mg versus placebo on cardiac depolarization or repolarization as measured by the QRS or QTc intervals, respectively. Mean PR interval increased following ESL 1200 mg and 2400 mg, but there was no participant with a PR interval above the upper limit of the normal range (200 ms). The upper bound of the 95% confidence interval for the placebo-corrected change from baseline of the individually corrected QT interval (QTcI) following administration of ESL 1200 mg and ESL 2400 mg was <10 ms at every time point. Moxifloxacin caused an increase in QTcI above the 10-ms threshold for clinical significance at several time points, demonstrating assay sensitivity. It is concluded that administration of ESL 1200 mg and ESL 2400 mg did not induce a clinically significant prolongation of the QTcI interval. [ABSTRACT FROM PUBLISHER]

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir. [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases.This open-label study enrolled subjects with moderate renal impairment (creatinine clearance[CLCr] 17–33 ml min−1 1.73 m−2 body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day−1 donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (Cmax 5.17 ± 0.36 and 6.07 ± 0.49 ng ml−1; AUC0−24 76.05 ± 5.54 and 77.45 ± 4.49 ng·h ml−1; mean maximum percentage inhibition[ Imax] red blood cell (RBC) AChE activity 32.07 ± 2.00 and 31.69 ± 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (CSS 20.83 ± 1.78 and 18.38 ± 1.52 ng ml−1; AUC0−24 500.0 ± 42.8 and 441.1 ± 36.4 ng·h ml−1; degree of accumulation[ RA] 6.98 ± 0.59 and 5.94 ± 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition[ ISS] RBC AChE activity 65.11 ± 2.52 and 60.62 ± 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 ± 1.96 and 20.23 ± 0.64, respectively). Donepezil was well tolerated by both groups.These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

A phase 1 trial of fusidic acid (CEM-102), an oral fusidane class antibiotic under development for treatment of gram-positive acute bacterial skin and skin structure infections, evaluating pharmacokinetics and safety is described. A randomized, double-blinded, placebo-controlled, dose escalation study was conducted in healthy adult subjects in the fasting state. Plasma exposure after multiple doses was higher than for single doses, indicating accumulation. Loading doses designed to optimize pharmacodynamic effects were well tolerated and achieved near-steady state concentrations of CEM-102 at 24 h. CEM-102 was safe and generally well tolerated at all single, multiple, and loading doses administered. [ABSTRACT FROM PUBLISHER]