Alterations in cerebellar grey matter structure and covariance networks in young people with Tourette syndrome

© 2020 The Authors Tourette syndrome (TS) is a childhood-onset neurological disorder characterised by the occurrence of motor and vocal tics and the presence of premonitory sensory/urge phenomena. Functional neuroimaging studies in humans, and experimental investigations in animals, have shown that the genesis of tics in TS involve a complex interaction between cortical-striatal-thalamic-cortical brain circuits and additionally appears to involve the cerebellum. Furthermore, structural brain imaging studies have demonstrated alterations in grey matter (GM) volume in TS across a wide range of brain areas, including alterations in GM volume within the cerebellum. Until now, no study to our knowledge has yet investigated how GM structural covariance networks linked to the cerebellum may be altered in individuals with TS. In this study we employed voxel-based morphometry, and a ‘seed-to-voxel’ structural covariance network (SCN) mapping approach, to investigate alterations in GM cerebellar volume in people with TS, and alterations in cerebellar SCNs associated with TS. Data from 64 young participants was entered in the final analysis, of which 28 had TS while 36 were age-and sex-matched healthy volunteers. Using the spatially unbiased atlas template of the cerebellum and brainstem (SUIT) atlas, we found reduced GM volume in cerebellar lobule involved in higher-order cognitive functions and sensorimotor processing, in patients. In addition, we found that several areas located in frontal and cingulate cortices and sensorimotor network in addition to subcortical areas show altered structural covariance with our cerebellar seed compared to age-matched controls. These results add to the increasing evidence that cortico-basal ganglia–cerebellar interactions play an important role in tic symptomology

Genomic epidemiology and population structure of Neisseria gonorrhoeae from remote highly endemic Western Australian populations

Background: Neisseria gonorrhoeae causes gonorrhoea, the second most commonly notified sexually transmitted infection in Australia. One of the highest notification rates of gonorrhoea is found in the remote regions of Western Australia (WA). Unlike isolates from the major Australian population centres, the remote community isolates have low rates of antimicrobial resistance (AMR). Population structure and whole-genome comparison of 59 isolates from the Western Australian N. gonorrhoeae collection were used to investigate relatedness of isolates cultured in the metropolitan and remote areas. Core genome phylogeny, multilocus sequencing typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) in addition to hierarchical clustering of sequences were used to characterize the isolates. Results: Population structure analysis of the 59 isolates together with 72 isolates from an international collection, revealed six population groups suggesting that N. gonorrhoeae is a weakly clonal species. Two distinct population groups, Aus1 and Aus2, represented 63% of WA isolates and were mostly composed of the remote community isolates that carried no chromosomal AMR genotypes. In contrast, the Western Australian metropolitan isolates were frequently multi-drug resistant and belonged to population groups found in the international database, suggesting international transmission of the isolates. Conclusions: Our study suggests that the population structure of N. gonorrhoeae is distinct between the communities in remote and metropolitan WA. Given the high rate of AMR in metropolitan regions, ongoing surveillance is essential to ensure the enduring efficacy of the empiric gonorrhoea treatment in remote WA

Cluster randomised controlled trial of a peer-led lifestyle intervention program: study protocol for the Kerala diabetes prevention program.

BACKGROUND: India currently has more than 60 million people with Type 2 Diabetes Mellitus (T2DM) and this is predicted to increase by nearly two-thirds by 2030. While management of those with T2DM is important, preventing or delaying the onset of the disease, especially in those individuals at 'high risk' of developing T2DM, is urgently needed, particularly in resource-constrained settings. This paper describes the protocol for a cluster randomised controlled trial of a peer-led lifestyle intervention program to prevent diabetes in Kerala, India. METHODS/DESIGN: A total of 60 polling booths are randomised to the intervention arm or control arm in rural Kerala, India. Data collection is conducted in two steps. Step 1 (Home screening): Participants aged 30-60 years are administered a screening questionnaire. Those having no history of T2DM and other chronic illnesses with an Indian Diabetes Risk Score value of ≥60 are invited to attend a mobile clinic (Step 2). At the mobile clinic, participants complete questionnaires, undergo physical measurements, and provide blood samples for biochemical analysis. Participants identified with T2DM at Step 2 are excluded from further study participation. Participants in the control arm are provided with a health education booklet containing information on symptoms, complications, and risk factors of T2DM with the recommended levels for primary prevention. Participants in the intervention arm receive: (1) eleven peer-led small group sessions to motivate, guide and support in planning, initiation and maintenance of lifestyle changes; (2) two diabetes prevention education sessions led by experts to raise awareness on T2DM risk factors, prevention and management; (3) a participant handbook containing information primarily on peer support and its role in assisting with lifestyle modification; (4) a participant workbook to guide self-monitoring of lifestyle behaviours, goal setting and goal review; (5) the health education booklet that is given to the control arm. Follow-up assessments are conducted at 12 and 24 months. The primary outcome is incidence of T2DM. Secondary outcomes include behavioural, psychosocial, clinical, and biochemical measures. An economic evaluation is planned. DISCUSSION: Results from this trial will contribute to improved policy and practice regarding lifestyle intervention programs to prevent diabetes in India and other resource-constrained settings. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12611000262909

Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species

Background Streptococcus pneumoniae is one of the most important causes of microbial diseases in humans. The genomes of 44 diverse strains of S. pneumoniae were analyzed and compared with strains of non-pathogenic streptococci of the Mitis group. Results Despite evidence of extensive recombination, the S. pneumoniae phylogenetic tree revealed six major lineages. With the exception of serotype 1, the tree correlated poorly with capsular serotype, geographical site of isolation and disease outcome. The distribution of dispensable genes, genes present in not all, but more than one strain, was consistent with phylogeny, although horizontal gene transfer events attenuated this correlation in the case of ancient lineages. Homologous recombination, involving short stretches of DNA, was the dominant 13 evolutionary process of the core genome of S. pneumoniae. Genetic exchange occurred both within and across the borders of the species, and S. mitis was the main reservoir of genetic diversity of S. pneumoniae. The pan-genome size of S. pneumoniae increased logarithmically with the number of strains and linearly with the number of polymorphic sites of the sampled genomes, suggesting that acquired genes accumulate proportionately to the age of clones. Most genes associated with pathogenicity were shared by all S. pneumoniae strains, but were also present in S. mitis, S. oralis and S. infantis, indicating that these genes are not sufficient to determine virulence. Conclusion Genetic exchange with related species sharing the same ecological niche is the main mechanism of evolution of S. pneumoniae. The open pan genome guarantees the species a quick and economical response to diverse environments

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort

Although preterm birth less than 37 weeks gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates

Defining failed induction of labor

BACKGROUND: While there are well-accepted standards for the diagnosis of arrested active-phase labor, the definition of a "failed" induction of labor remains less certain. One approach to diagnosing a failed induction is based on the duration of the latent phase. However, a standard for the minimum duration that the latent phase of a labor induction should continue, absent acute maternal or fetal indications for cesarean delivery, remains lacking. OBJECTIVE: The objective of this study was to determine the frequency of adverse maternal and perinatal outcomes as a function of the duration of the latent phase among nulliparous women undergoing labor induction. METHODS: This study is based on data from an obstetric cohort of women delivering at 25 U.S. hospitals from 2008-2011. Nulliparous women who had a term singleton gestation in the cephalic presentation were eligible for this analysis if they underwent a labor induction. Consistent with prior studies, the latent phase was determined to begin once cervical ripening had ended, oxytocin was initiated and rupture of membranes (ROM) had occurred, and was determined to end once 5 cm dilation was achieved. The frequencies of cesarean delivery, as well as of adverse maternal (e.g., cesarean delivery, postpartum hemorrhage, chorioamnionitis) and perinatal outcomes (e.g., a composite frequency of either seizures, sepsis, bone or nerve injury, encephalopathy, or death), were compared as a function of the duration of the latent phase (analyzed with time both as a continuous measure and categorized in 3-hour increments). RESULTS: A total of 10,677 women were available for analysis. In the vast majority (96.4%) of women, the active phase had been reached by 15 hours. The longer the duration of a woman's latent phase, the greater her chance of ultimately undergoing a cesarean delivery (P<0.001, for time both as a continuous and categorical independent variable), although more than forty percent of women whose latent phase lasted for 18 or more hours still had a vaginal delivery. Several maternal morbidities, such as postpartum hemorrhage (P < 0.001) and chorioamnionitis (P < 0.001), increased in frequency as the length of latent phase increased. Conversely, the frequencies of most adverse perinatal outcomes were statistically stable over time. CONCLUSION: The large majority of women undergoing labor induction will have entered the active phase by 15 hours after oxytocin has started and rupture of membranes has occurred. Maternal adverse outcomes become statistically more frequent with greater time in the latent phase, although the absolute increase in frequency is relatively small. These data suggest that cesarean delivery should not be undertaken during the latent phase prior to at least 15 hours after oxytocin and rupture of membranes have occurred. The decision to continue labor beyond this point should be individualized, and may take into account factors such as other evidence of labor progress

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP