Rapid draft sequencing and real-time nanopore sequencing in a hospital outbreak of Salmonella

Background: Foodborne outbreaks of Salmonella remain a pressing public health concern. We recently detected a large outbreak of Salmonella enterica serovar Enteritidis phage type 14b affecting more than 30 patients in our hospital. This outbreak was linked to community, national and European-wide cases. Hospital patients with Salmonella are at high risk, and require a rapid response. We initially investigated this outbreak by whole-genome sequencing using a novel rapid protocol on the Illumina MiSeq; we then integrated these data with whole-genome data from surveillance sequencing, thereby placing the outbreak in a national context. Additionally, we investigated the potential of a newly released sequencing technology, the MinION from Oxford Nanopore Technologies, in the management of a hospital outbreak of Salmonella. Results: We demonstrate that rapid MiSeq sequencing can reduce the time to answer compared to the standard sequencing protocol with no impact on the results. We show, for the first time, that the MinION can acquire clinically relevant information in real time and within minutes of a DNA library being loaded. MinION sequencing permits confident assignment to species level within 20 min. Using a novel streaming phylogenetic placement method samples can be assigned to a serotype in 40 min and determined to be part of the outbreak in less than 2 h. Conclusions: Both approaches yielded reliable and actionable clinical information on the Salmonella outbreak in less than half a day. The rapid availability of such information may facilitate more informed epidemiological investigations and influence infection control practices

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species

An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid.

The population of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, exhibits limited DNA sequence variation, which complicates efforts to rationally discriminate individual isolates. Here we utilize data from whole-genome sequences (WGS) of nearly 2,000 isolates sourced from over 60 countries to generate a robust genotyping scheme that is phylogenetically informative and compatible with a range of assays. These data show that, with the exception of the rapidly disseminating H58 subclade (now designated genotype 4.3.1), the global S. Typhi population is highly structured and includes dozens of subclades that display geographical restriction. The genotyping approach presented here can be used to interrogate local S. Typhi populations and help identify recent introductions of S. Typhi into new or previously endemic locations, providing information on their likely geographical source. This approach can be used to classify clinical isolates and provides a universal framework for further experimental investigations

Improving Adherence to Behavioral Parent Training for ADHD Using Digital Health Tools.

Behavioral Parent Training (BPT) is a well-established treatment for school-age children with ADHD but lack of parent adherence to prescribed parenting strategies limits treatment gains. Digital Health (dHealth) tools can be leveraged to target barriers to parent adherence but existing tools for parenting interventions are limited. New efforts to develop a dHealth tool to target adherence barriers including limited skill competence, EF processes, and low motivation/negative attitudes, are presented and recommendations for future technology-enhanced treatments are provided

Feasibility study of a telehealth school-based behavioral parent training group program for attention-deficit/hyperactivity disorder

ObjectiveTo evaluate the feasibility and preliminary efficacy of Telehealth Behavioral Parent Training (T-BPT), a school telehealth group intervention for attention-deficit/hyperactivity disorder (ADHD) with a companion training program for school clinicians.MethodsT-BPT was developed in an iterative three-phase design in partnership with community stakeholders during the COVID-19 pandemic. School clinicians (N = 4) delivered T-BPT over 8 weeks to parents (N = 21, groups of 5-6 per school) of children (Grades 2-5) with ADHD while simultaneously receiving training and consultation from PhD-level study trainers. A single-arm open trial was used to assess feasibility, engagement, and preliminary efficacy.ResultsParents and school clinicians endorsed high feasibility, acceptability, and usability of T-BPT. Parent attendance was high (M = 94.6%) and a majority of parents (66.7%) attended all eight sessions. Preliminary outcomes indicate moderate to large reductions in parent-reported ADHD symptoms (ω2 = .36), functional and clinical global impairment (ω2s= .21 and .19, respectively), and distance learning challenges (ω2 = .22).ConclusionsResults were in line with in-person delivery, indicating promising feasibility of school telehealth BPT groups. This study also provided further support for the feasibility of the remote training model for school clinicians. Implications of the commonly endorsed barriers and benefits beyond COVID-19 and relevance to under resourced communities are also discussed

Academic Competence, Organizational Skills, and Treatment Response Among Bilingual and Monolingual Children With Attention Deficit Hyperactivity Disorder

Bilingualism has been associated with executive functioning (EF) advantages while EF is commonly impaired in ADHD. The present study tested applied EF skills (organizational skills and academic competence) in bilingual and monolingual children who exhibit ADHD symptoms preand posttreatment. A total of 159 children (Mage = 8.32) and their parents participated in multicomponent intervention targeting ADHD impairment in home and school settings. Parents and teachers completed EF and impairment rating scales and teachers completed academic competency scales. Linear mixed effects models were used to compare bilingual and monolingual groups while controlling for income and clustering effects by school. At pretreatment, the monolingual group scored higher on academic engagement, reading, and study skills than their bilingual counterparts; however, these differences diminished when income was controlled. No between-group differences were found on organizational skills pretreatment. While reductions in impairment were found for both groups following treatment, some evidence showed greater reduction in impairment for bilingual children compared to monolingual. Our findings demonstrate that bilingualism per se does not appear to hinder applied EF skills (organizational skills and academic competence) or response to treatment among children with ADHD. Instead, socioeconomic status may play an important role in the bilingualism-EF link in applied settings. Future studies are warranted to explore interventions delivered in multiple languages for children with ADHD with increased attention on environmental resources for these children

Development of a Web-Based Training Platform for School Clinicians in Evidence-Based Practices for ADHD

Lack of training for school clinicians in evidence-based practices (EBPs) contributes to underutilization of such services for youth with attention-deficit/hyperactivity disorder (ADHD). Advances in web-based technology and videoconferencing have allowed for expanded access to and optimization of training. We describe the development and outcomes of a novel web-based platform for training school clinicians to gain skills in EBPs for school-age youth with ADHD. The training platform is adapted from an empirically supported, in-person training for a school-home behavioral intervention (Collaborative Life Skills program) and includes skill modules for working with teachers, parents, and students. Training methods include web-accessed manuals/handouts, skill example video clips, automated progress monitoring tools, and consultation/in-session coaching via videoconferencing. We gathered stakeholder qualitative and quantitative feedback during discovery and design phases of the iterative development. We then evaluated the usability, acceptability, fidelity and clinician and student outcomes of the remote training program. Focus group themes and qualitative feedback identified clinician preferences for remote training features (e.g., interactive, brief, role-plays/coaching methods), video tools (recorded samples of skills and therapy sessions), and progress monitoring tools (e.g., clear, easy to use). Clinician usability ratings of the platform were high with most components rated as moderately to very useful/easy to use. Clinician ratings of usability, fidelity implementing the treatment, and their EBP knowledge and confidence following training were favorable. Student\u27s outcomes were similar to those achieved in prior studies of clinician in-person training. Results support the promise of remote, web-based clinician training for the dissemination of evidence-based practices

Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease A Randomized Clinical Trial

IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease. OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids. INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging. RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died. CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00297193.status: publishe

Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial

Importance: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease.Objective: To evaluate the effect of autologous HSCT on refractory Crohn disease.Design, Setting, and Participants: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids.Interventions: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n?=?23) or control treatment (HSCT deferred for 1 year [n?=?22]). All were given standard Crohn disease treatment as needed.Main Outcomes and Measures: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) less than 150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging.Results: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, ?14.2% to 22.6%]; P?=?.60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P?=?.01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P?=?.052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P?=?.054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died.Conclusions and Relevance: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease.Trial Registration clinicaltrials.gov Identifier:NCT0029719