Statewide Molecular Epidemiology of Mycobacterium tuberculosis Transmission in a Moderate- to Low-Incidence State: Are Contact Investigations Enough?

To assess the circumstances of recent transmission of tuberculosis (TB) (progression to active disease <2 years after infection), we obtained DNA fingerprints for 1,172 (99%) of 1,179 Mycobacterium tuberculosis isolates collected from Maryland TB patients from 1996 to 2000. We also reviewed medical records and interviewed patients with genetically matching M. tuberculosis strains to identify epidemiologic links (cluster investigation). Traditional settings for transmission were defined as households or close relatives and friends; all other settings were considered nontraditional. Of 436 clustered patients, 114 had recently acquired TB. Cluster investigations were significantly more likely than contact investigations to identify patients who recently acquired TB in nontraditional settings (33/42 vs. 23/72, respectively; p<0.001). Transmission from a foreign-born person to a U.S.-born person was rare and occurred mainly in public settings. The time from symptom onset to diagnosis was twice as long for transmitters as for nontransmitters (16.8 vs. 8.5 weeks, respectively; p<0.01). Molecular epidemiologic studies showed that eliminating diagnostic delays can prevent TB transmission in nontraditional settings, which elude contact investigations

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Ciprofloxacin-Resistant Gram-Negative Bacilli in the Fecal Microflora of Children

The extent to which antibiotic-resistant bacteria are excreted by humans who have not been exposed to antibiotics is not known. Children, who rarely receive fluoroquinolones, provide opportunities to assess the frequency of fecal excretion by fluoroquinolone-naïve hosts of fluoroquinolone-resistant gram-negative bacilli. Fresh nondiarrheal stools from children were processed by screening them on agar containing ciprofloxacin to recover ciprofloxacin-resistant gram-negative bacilli. Resistant isolates were identified, and ciprofloxacin MICs were determined. Resistant Escherichia coli isolates were also analyzed for urovirulence-associated loci. Thirteen (2.9%) of 455 stools yielded ciprofloxacin-resistant E. coli (seven children), Stenotrophomonas maltophilia (four children), and Achromobacter xylosoxidans and Enterobacter aerogenes (one child each). Neither the subjects themselves nor members of their households used fluoroquinolones in the 4 weeks preceding collection. Six of the seven resistant E. coli isolates belonged to phylogenetic groups B2 and D, in which extraintestinal pathogenic E. coli bacteria are frequently found. All resistant E. coli isolates contained at least three putative E. coli virulence loci. Most ciprofloxacin-resistant bacteria were resistant to additional antibiotics. Potentially pathogenic bacteria that are resistant to therapeutically important antimicrobial agents are excreted by some humans, despite these persons' lack of exposure to the particular drugs. The sources of these resistant organisms are unknown. This underrecognized reservoir of drug-resistant potential pathogens poses public health challenges

A randomized controlled trial comparing in-person and wiki-inspired nominal group techniques for engaging stakeholders in chronic kidney disease research prioritization

Abstract Background Few studies have evaluated stakeholder engagement in chronic kidney disease (CKD) research prioritization. In this two-arm, parallel group randomized controlled trial, we sought to compare an in-person nominal group technique (NGT) approach with an online wiki-inspired alternative to determining the top 10 CKD research priorities, and to evaluate stakeholder engagement and satisfaction with each process. Methods Eligible participants included adults ≥18 years with access to a computer and Internet, high health literacy, and from one of the following stakeholder groups: patients with CKD not on dialysis, their caregivers, health care providers who care for patients with CKD, or CKD-related health policymakers. Fifty-six participants were randomized to a wiki-inspired modified NGT that occurred over 3 weeks vs. a 1-day in-person NGT workshop, informed by James Lind Alliance methodology, to determine the top 10 CKD-related research priorities. The primary outcome was the pairwise agreement between the two groups’ final top 10 ranked priorities, evaluated using Spearman’s correlation coefficient. Secondary outcomes included participant engagement and satisfaction and wiki tool usability. Results Spearman’s rho for correlation between the two lists was 0.139 (95 % confidence interval −0.543 to 0.703, p = 0.71), suggesting low correlation between the top 10 lists across the two groups. Both groups ranked the same item as the top research priority, with 5 of the top 10 priorities ranked by the wiki group within the top 10 for the in-person group. In comparison to the in-person group, participants from the wiki group were less likely to report: satisfaction with the format (73.7 vs.100 %, p = 0.011); ability to express their views (57.9 vs 96.0 %, p = 0.0003); and perception that they contributed meaningfully to the process (68.4 vs 84.0 %, p = 0.004). Conclusions A CKD research prioritization approach using an online wiki-like tool identified low correlation in rankings compared with an in-person approach, with less satisfaction and perceptions of active engagement. Modifications to the wiki-inspired tool are required before it can be considered a potential alternative to an in-person workshop for engaging patients in determining research priorities. Trial registration ( ISRCTN18248625

Tolerability of bedtime diuretics: a prospective cohort analysis

Objectives We sought to validate, or refute, the common belief that bedtime diuretics are poorly tolerated due to nocturia.Design Prespecified prospective cohort analysis embedded within the randomised BedMed trial, in which hypertensive participants are randomised to morning versus bedtime antihypertensive administration.Setting 352 community family practices across 4 Canadian provinces between March 2017 and September 2020.Participants 552 hypertensive patients (65.6 years old, 57.4% female) already established on a single once-daily morning antihypertensive and randomised to switch that antihypertensive to bedtime. Of these, 203 used diuretics (27.1% thiazide alone, 70.0% thiazide/non-diuretic combinations) and 349 used non-diuretics.Intervention Switching the established antihypertensive from morning to bedtime, and comparing the experience of diuretic and non-diuretic users.Primary and secondary outcome measures Primary outcome: Adherence to bedtime allocation time at 6 months (defined as the willingness to continue with bedtime use, not an assessment of missed doses). Secondary 6-month outcomes: (1) nocturia considered to be a major burden and (2) increase in overnight urinations/week. All outcomes were self-reported and additionally collected at 6 weeks.Results At 6 months: Adherence to bedtime allocation time was lower in diuretic users than non-diuretic users (77.3% vs 89.8%; difference 12.6%; 95% CI 5.8% to 19.8%; p&lt;0.0001; NNH 8.0), and more diuretic users considered nocturia a major burden (15.6% vs 1.3%; difference 14.2%; 95% CI 8.9% to 20.6%; p&lt;0.0001; NNH 7.0). Compared with baseline, diuretic users experienced 1.0 more overnight urinations/week (95% CI 0.0 to 1.75; p=0.01). Results did not differ between sexes.Conclusions Switching diuretics to bedtime did promote nocturia, but only 15.6% found nocturia a major burden. At 6 months, 77.3% of diuretic users were adherent to bedtime dosing. Bedtime diuretic use is viable for many hypertensive patients, should it ever become clinically indicated.Trial registration number NCT02990663

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive&nbsp;inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations