The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough.

PURPOSE: We evaluated gefapixant, a P2X3 receptor antagonist, in participants with recent-onset (≤ 12 months) refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: Participants (≥ 18 years of age; ≥ 40 mm on a 100-mm cough severity visual analog scale [VAS] at screening and randomization) with chronic cough for < 12 months were enrolled in this phase 3b, double-blind, placebo-controlled, parallel group, multicenter study (NCT04193202). Participants were randomized 1:1 to gefapixant 45 mg BID or placebo for 12 weeks with a 2-week follow-up. The primary efficacy endpoint was change from baseline at Week 12 in Leicester Cough Questionnaire (LCQ) total score. Adverse events were monitored and evaluated. RESULTS: There were 415 participants randomized and treated (mean age 52.5 years; median [range] duration 7.5 [1-12] months): 209 received placebo and 206 received gefapixant 45 mg BID. A statistically significant treatment difference of 0.75 (95% CI: 0.06, 1.44; p = 0.034) for gefapixant vs. placebo was observed for change from baseline in LCQ total score at Week 12. The most common AE was dysgeusia (32% gefapixant vs. 3% placebo participants); serious AEs were rare (1.5% gefapixant vs. 1.9% placebo participants). CONCLUSION: Gefapixant 45 mg BID demonstrated significantly greater improvement in cough-specific health status from baseline compared to placebo, in participants with recent-onset chronic cough. The most common AEs were related to taste and serious AEs were rare.

Prediction and analysis of multi epitope based vaccine against Newcastle disease virus based on haemagglutinin neuraminidase protein.

Newcastle disease virus (NDV), an avian orthoavulavirus, is a causative agent of Newcastle disease named (NDV), and can cause even the epidemics when disease is not treated. Previously several vaccines based on attenuated and inactivated viruses have been reported which are rendered useless with the passage of time due to versatile changes in viral genome. Therefore, we aimed to develop an effective multi-epitope vaccine against the haemagglutinin neuraminidase (HN) protein of 26 NDV strains from Pakistan through a modern immunoinformatic approaches. As a result, a vaccine chimaera was constructed by combining T-cell and B-cell epitopes with the appropriate linkers and adjuvant. The designed vaccine was highly immunogenic, non-allergen and antigenic; therefore, the potential 3D-structureof multi epitope vaccine was constructed, refined and validated. A molecular docking study of a multiepitope vaccine candidate with the chicken Toll-like receptor-4 indicated successful binding. An In silico immunological simulation was used to evaluate the candidate vaccine's ability to elicit an effective immune response. According to the computational studies, the proposed multiepitope vaccine is physically stable and may induce immune responses whichsuggested it a strong candidate against 26 Newcastle disease virus strains from Pakistan.

Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial.

INTRODUCTION: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF. METHODS: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study. RESULTS: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia). CONCLUSIONS: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study. TRIAL REGISTRATION: NCT02502097.

The Salmonella enterica serovar Typhimurium virulence factor STM3169 is a hexuronic acid binding protein component of a TRAP transporter.

The intracellular pathogen S. Typhimurium is a leading cause of foodborne illness across the world and is known to rely on a range of virulence factors to colonize the human host and cause disease. The gene coding for one such factor, stm3169, was determined to be upregulated upon macrophage entry and its disruption reduces survival in the macrophage. In this study we characterize the STM3169 protein, which forms the substrate binding protein (SBP) of an uncharacterized tripartite ATP-independent periplasmic (TRAP) transporter. Genome context analysis of the genes encoding this system in related bacteria suggests a function in sugar acid transport. We demonstrate that purified STM3169 binds d-glucuronic acid with high affinity and specificity. S. Typhimurium LT2 can use this sugar acid as a sole carbon source and the genes for a probable catabolic pathway are present in the genome. As this gene was previously implicated in macrophage survival, it suggests a role for d-glucuronate as an important carbon source for S. Typhimurium in this environment.

Pharmacokinetics and pharmacodynamics of aprepitant for the prevention of postoperative nausea and vomiting in pediatric subjects.

BACKGROUND/PURPOSE: This multicenter, randomized, partially-blinded phase IIb study evaluated the pharmacokinetics (PK)/pharmacodynamics, safety, and tolerability of aprepitant in pediatric subjects for the prevention of postoperative nausea and vomiting (PONV). METHODS: Subjects aged birth to 17 years scheduled to undergo surgery and receive general anesthesia with ≥1 risk factor for PONV were randomly assigned to 1 of 3 aprepitant dose regimens (a single oral dose of aprepitant equivalent to adult doses of 10 mg, 40 mg, or 125 mg), or a control regimen of ondansetron before anesthesia. Assessments included PK, safety, and exploratory efficacy (complete response [CR; no emesis, retching, or dry heaves and no rescue therapy within 0-24 h following surgery] and no vomiting [NV; no emesis, retching, or dry heaves within 0-24 h following surgery]). RESULTS: Of 220 randomized and treated subjects, 119 receiving a single aprepitant dose were sampled for PK analysis and had evaluable aprepitant plasma concentrations. A dose-dependent relationship in exposure (AUC0-8 h and Cmax) was observed. Aprepitant was generally well tolerated, and the CR and NV rates were high (>80%) across treatment groups. CONCLUSIONS: PK, safety, and preliminary efficacy analyses support further clinical evaluation of aprepitant for PONV prophylaxis in pediatric patients. CLINICALTRIALS. GOV ID: NCT01732458 LEVEL OF EVIDENCE: Therapeutic, Level I.

Three Interventions That Reduce Childhood Obesity Are Projected To Save More Than They Cost To Implement.

Policy makers seeking to reduce childhood obesity must prioritize investment in treatment and primary prevention. We estimated the cost-effectiveness of seven interventions high on the obesity policy agenda: a sugar-sweetened beverage excise tax; elimination of the tax subsidy for advertising unhealthy food to children; restaurant menu calorie labeling; nutrition standards for school meals; nutrition standards for all other food and beverages sold in schools; improved early care and education; and increased access to adolescent bariatric surgery. We used systematic reviews and a microsimulation model of national implementation of the interventions over the period 2015-25 to estimate their impact on obesity prevalence and their cost-effectiveness for reducing the body mass index of individuals. In our model, three of the seven interventions--excise tax, elimination of the tax deduction, and nutrition standards for food and beverages sold in schools outside of meals--saved more in health care costs than they cost to implement. Each of the three interventions prevented 129,000-576,000 cases of childhood obesity in 2025. Adolescent bariatric surgery had a negligible impact on obesity prevalence. Our results highlight the importance of primary prevention for policy makers aiming to reduce childhood obesity.

The Relationship between Obesity and Cognitive Performance in Children: A Longitudinal Study.

BACKGROUND: The relationship between obesity and academic outcomes remains unclear. We evaluated the association between obesity and cognitive performance in US children. METHODS: We analyzed two nationally representative prospective cohorts of children in the 1979 National Longitudinal Survey of Youth, ages 2 through 8 at baseline and followed for 6 years, from 1988 to 1994 (cohort 1, n=2672) and 1994 to 2000 (cohort 2, n=1991). The main exposure variable was obesity (defined as never obese, became obese, always obese, and became nonobese). The main outcomes were standardized scores on four cognitive assessments. Univariate regression analyses of test scores on obesity were performed. Fixed-effects regression models, controlling for measured and unmeasured time-invariant confounders, were additionally adjusted for time-variant confounders to analyze the impact of change in obesity status on change in test scores. RESULTS: Unadjusted analyses revealed a significant association between obesity and Peabody Individual Achievement Test (PIAT) scores. In cohort 1, always obese children had lower PIAT math scores than never obese children (ß=-7.48; p<0.05). Always obese boys had lower PIAT math scores than those who were never obese (ß=-16.45; p<0.01). In cohort 2, PIAT math scores were lower in the became obese category than the never obese category (ß=-4.10; p<0.05). Always obese girls had lower PIAT reading scores than those who were never obese (ß=-11.28; p<0.01). Fixed-effects models additionally adjusted for Home Observation Measurement of the Environment, Short Form score and height percentile showed no significant relationship between obesity and test scores in either cohort. CONCLUSION: Childhood obesity is unlikely to be causally related to cognitive performance.

Antimicrobial susceptibility pattern of bacteria isolated from patients with urinary tract infection.

OBJECTIVE: To determine the antimicrobial susceptibility pattern of bacterial pathogens in the patients of urinary tract infection reporting at a tertiary care hospital. STUDY DESIGN: Laboratory based study. PLACE AND DURATION OF STUDY: Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from January to December 2012. METHODOLOGY: A total of 440 culture positive bacterial isolates from 1110 urine samples; submitted over a period of one year were included in this study. Identification of bacterial isolates was done by standard biochemical profile of the organisms. The antimicrobial susceptibility of culture positive bacterial isolates was performed by disk diffusion method as recommended by Clinical Laboratory Standard Institute guidelines (CLSI). RESULTS: Out of the 440 culture positive urine samples, 152 (34.6%) were from indoor patients whereas 288 (65.4%) from outdoor patients. Gram negative bacteria accounted for 414 (94%) of the total isolates while rest of the 26 (6%) were Gram positive bacteria. The most prevalent bacterial isolate was Escherichia (E.) coli 270 (61.3%) followed by Pseudomonas (P.) aeruginosa 52 (12%) and Klebsiella (K.) pneumoniae 42 (9.5%). The susceptibility pattern of E. coli showed that 96.2% of the bacterial isolates were sensitive to imipenem, 85.1% to amikacin, 80.7% to piperacillin/tazobactam and 72.6% to nitrofurantoin. In case of P. aeruginsosa, 73% bacterial isolates were sensitive to tazobactam/piperacillin, 69.2% to sulbactam/cefoperazone and 65.38% to imipenem. The antibiogram of K. pneumoniae has revealed that 76.1% of the bacterial isolates were sensitive to imipenem and 52.3% to piperacillin/tazobactam. Nitrofurantoin and imipenem were the most effective antimicrobials amongst the Enterococcus spp. as 92.3% showed susceptibility to this bacterial isolate. CONCLUSION: Majority of the bacterial isolates were sensitive to imipenem and piperacillin/tazobactam while susceptibility to most of the commonly used oral antibiotics was very low. Among the oral antimicrobials, nitrofurantoin showed good susceptibility against Enterobacteriaceae family and Gram positive organisms.

Molecular evaluation of drug resistance in clinical isolates of Salmonella enterica serovar Typhi from Pakistan.

INTRODUCTION: This study aimed to determine the drug susceptibility patterns and genetic elements related to drug resistance in isolates of Salmonella enterica serovar Typhi (S. Typhi) from the Faisalabad region of Pakistan. METHODOLOGY: The drug resistance status of 80 isolates were evaluated by determining antimicrobial susceptibility, MICs, drug resistance genes involved, and the presence of integrons. Nalidixic acid resistance and reduced susceptibility to ciprofloxacin were also investigated by mutation screening of the gyrA, gyrB, parC, and parE genes. RESULTS: Forty-seven (58.7%) isolates were multidrug resistant (MDR). Among the different resistance (R) types, the most commonly observed (13/80) was AmChStrTeSxtSmzTmp, which is the most frequent type observed in India and Pakistan. The most common drug resistant genes were blaTEM-1, cat, strA-strB, tetB, sul1, sul2, and dfrA7. Among the detected genes, only dfrA7 was found to be associated in the form of a single gene cassette within the class 1 integrons. CONCLUSIONS: MIC determination of currently used drugs revealed fourth-generation gatifloxacin as an effective drug against multidrug-resistant S. Typhi, but its clinical use is controversial. The Ser83→Phe substitution in gyrA was the predominant alteration in nalidixic acid-resistant isolates, exhibiting reduced susceptibility and increased MICs against ciprofloxacin. No mutations in gyrB, parC, or parE were detected in any isolate.

Embolization of a bleeding Dieulafoy lesion of the duodenum in a child. Case report and review of the literature.

We report an adolescent with chronic, recurrent upper gastrointestinal bleeding in whom extensive prior investigations failed to reveal the source of bleeding. Angiography accurately identified a bleeding Dieulafoy lesion of the duodenum which was successfully embolized. The clinical history, angiographic appearances and treatment of this rare lesion are presented.

Select practice behaviors of clinicians on the use of opioids for adolescents with subacute and chronic nonmalignant pain.

OBJECTIVES: To characterize the opioid prescribing and monitoring practices of providers for chronic nonmalignant pain (CNP) and subacute postoperative pain (SAPOP) in adolescents. DESIGN: Web-based cross-sectional self-report survey. SETTING: Free-standing pediatric tertiary academic center. PARTICIPANTS: A total of 183 physicians and nurse practitioners were eligible. Of 115 (62.8 percent) participants who responded, 108 (93.9 percent) completed the survey. MAIN OUTCOME MEASURES: Self-reported frequency of opioid prescription for SAPOP and CNP conditions and frequency of associated monitoring practices. RESULTS: For 10 of the 13 pain conditions included, some participants endorsed "monthly or more opioid prescriptions" while others endorsed "opioids do not represent appropriate management." Opioid prescribing is present for almost all pain conditions but is substantially more common for nonacute vaso-occlusive-related sickle cell disease, scoliosis correction, and video-assisted pectus excavatum-related pains. When compared with the reference group, CNP with no identifiable pathology, the odds ratio (OR) of an opioid being prescribed for CNP states with identifiable pathology was not significantly higher. The OR for SAPOP was significantly higher (p < 0.0001). None of the opioid prescribers reported collecting urine toxicology before or during opioid therapy. CONCLUSIONS: This survey identifies a diversity of self-reported clinician opioid prescribing practices for adolescents with CNP and SAPOP. Urine collection for drug toxicology screening is not utilized by opioid prescribers. Surveys of similar clinician practice behaviors at other institutions are warranted to replicate this finding and to establish common clinicalpractice for usage and monitoring of opioids in conditions where guidelines do not yet exist.

Effects of ampicillin, gentamicin, and cefotaxime on the release of Shiga toxins from Shiga toxin-producing Escherichia coli isolated during a diarrhea episode in Faisalabad, Pakistan.

The Shiga toxin-producing Escherichia coli (STEC) is an emerging foodborne pathogen. The proportion of cases attributed to STEC in an episode of diarrhea in the Faisalabad region of Pakistan was investigated. In addition, as increase in Shiga toxin (Stx) release after exposure to various antimicrobial agents is widely reported, we also elucidated the in vitro effects of three commonly used antibiotics (ampicillin, gentamicin, and cefotaxime) on Stx release. Isolation and detection of STEC was done using enzyme-linked immunosorbent assay and polymerase chain reaction, followed by phenotypic characterization. In vitro Stx release from isolated STEC was determined using enzyme-linked immunosorbent assay, and Stx-induced verocytotoxicity was quantified using cytotoxicity detection assay. STEC was detected in 5 (21.7%) of 23 patients. Exposure to minimum inhibitory concentration (MIC) of ampicillin, gentamicin, and cefotaxime resulted in a considerable decrease in toxin release and level of cytotoxicity in most of the STEC isolates when compared with control (without antibiotic exposure). Exposure to sub-MIC of ampicillin resulted in a relative increase in Stx release and cytotoxicity (p

Relationship of drug resistance to phylogenetic groups of E. coli isolates from wound infections.

BACKGROUND: Drug resistance is a major problem in Escherichia coli isolated from surgical wound infections. In this study, we evaluated relationship between phylogenicity and drug resistance. METHODOLOGY: A total of 29 multi-drug resistant (MDR) E. coli isolates of known drug resistance genes and integron profile were selected for the present study. Triplex PCR was conducted for phylogenetic classification of these isolates into four established phylogenetic groups: A, B1, B2 and D. Statistical analysis was done to determine the association of different drug resistance genes and integrons with the phylogenetic groups. RESULTS: Most of the isolates (44.8%) belonged to phylogenetic group A followed by group B2 and D (24.1% each) and group B1 (6.9%). CONCLUSIONS: There is a definitive relationship between drug resistance and various phylogenetic groups of E. coli infecting wounds. A shift towards phylogenetic group A might be observed with an increasing drug resistance profile.

A profile of drug resistance genes and integrons in E. coli causing surgical wound infections in the Faisalabad region of Pakistan.

Escherichia coli are one of the leading causes of infection in wounds. Emerging multiple drug resistance among E. coli poses a serious challenge to antimicrobial therapy for wounds. This study was conducted to ascertain a baseline profile of antimicrobial resistance in E. coli isolates infecting surgical wounds. A total of 64 pus samples from hospitalized patients were screened and 29 (45.3%) were found to have E. coli, which were identified biochemically and confirmed by molecular methods. Using the disc diffusion method, antimicrobial resistance was observed toward tetracycline (100%), cefradine (100%), nalidixic acid (93.1%), ampicillin (86.2%), gentamicin (86.2%), cefixime (82.8%), ceftriaxone (82.8%), aztreonam (82.8%), ciprofloxacin (75.9%), streptomycin (72.4%), cefoperazone (65.5%), chloramphenicol (58.6%) and amikacin (58.6%). In an effort to find relevant genes, 11 different genes were targeted by PCR. Among these, the mutated gyrA gene was found to be the most prevalent (82.8%), followed by the TEM (72.4%), catP (68.9%), catA1 (68.9%), tetB (62.1%), blt (58.6%), bla(CTX-M-15) (27.6%), bla(TEM) (20.7%), bla(OXA) (17.2%), tetA (17.2%) and aadA1 (13.8%) genes. The presence of integrons was also studied among these isolates. The prevalence of class 1 integrons was the highest (44.8%), followed by class 2 (27.6%). Three (10.3%) isolates carried both class 1 and class 2 integrons (first report from E. coli infecting wounds). The high incidence of integrons points toward their facilitation for carriage of antimicrobial resistance genes; however, in nearly 37% isolates, no integrons were detected, indicating the significance of alternative mechanisms of gene transfer. Another salient finding was that all isolates were multidrug-resistant E. coli.