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The majority of paediatric Clostridioides difficile infections (CDI) are community-associated (CA), but few data exist regarding associated risk factors. We conducted a case–control study to evaluate CA-CDI risk factors in young children. Participants were enrolled from eight US sites during October 2014–February 2016. Case-patients were defined as children aged 1–5 years with a positive C. difficile specimen collected as an outpatient or ⩽3 days of hospital admission, who had no healthcare facility admission in the prior 12 weeks and no history of CDI. Each case-patient was matched to one control. Caregivers were interviewed regarding relevant exposures. Multivariable conditional logistic regression was performed. Of 68 pairs, 44.1% were female. More case-patients than controls had a comorbidity (33.3% vs. 12.1%; P = 0.01); recent higher-risk outpatient exposures (34.9% vs. 17.7%; P = 0.03); recent antibiotic use (54.4% vs. 19.4%; P < 0.0001); or recent exposure to a household member with diarrhoea (41.3% vs. 21.5%; P = 0.04). In multivariable analysis, antibiotic exposure in the preceding 12 weeks was significantly associated with CA-CDI (adjusted matched odds ratio, 6.25; 95% CI 2.18–17.96). Improved antibiotic prescribing might reduce CA-CDI in this population. Further evaluation of the potential role of outpatient healthcare and household exposures in C. difficile transmission is needed.
There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.
To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.
Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.
Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.
Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.
Declaration of interest
R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.
Introduction: The 2015 CanMEDS framework requires all residency programs to increase their focus on Quality Improvement and Patient Safety (QIPS). We created a longitudinal (4-year), modular QIPS curriculum for FRCP emergency medicine residents at the University of Toronto (UT) using multiple educational methods. The curriculum addresses three levels of QIPS training: knowledge, practical skills at the microsystem level, and practical skills at the organization level. Aim Statement: To increase the UT FRCP emergency medicine residents absolute score on the QIKAT-R (Quality Improvement Knowledge Application Tool Revised) by 10% after the completion of the QIPS curriculum. Methods: Physicians and other healthcare professionals with QI expertise collaboratively designed and taught the curriculum. We used the QIKAT-R as the outcome measure to evaluate QI knowledge and its applicability. The QIKAT-R is a validated measure that assesses an individuals ability to decipher a QI issue within the healthcare context, and propose a change initiative to address it. The first cohort of residents completed the QIKAT-R prior to the first session in 2014 (pre) and at the completion of the curriculum in 2017 (post). Each response was anonymized and scored by physicians with QI expertise. The QIKAT-R scores and comments from course evaluations are used to make yearly iterative curriculum changes. Results: The QIPS curriculum was implemented in September 2014. All nine residents in the first cohort completed the curriculum; they demonstrated an absolute increase of 19.6% (5.3/27) in the mean QIKAT-R score (13.0 +/− 3.3 pre vs. 18.3 +/− 3.8 post, p=0.001). Of the pre-test responses, 26% were categorized as poor, 70% as good, and 4% as excellent, whereas of the post-test 11% of responses were categorized as poor, 37% as good, and 52% as excellent (p<0.001). Two iterative curriculum changes were made at the end of each academic year since 2014: (1) The time between sessions were decreased to promote knowledge retention, and (2) different PGY3 QI practical project options were provided to suit residents individual QI interests. QIKAT-R scores and resident feedback were used to evaluate the impact of the curriculum changes. Conclusion: A collaborative, modular, longitudinal QIPS curriculum for UT FRCP emergency medicine residents that met CanMEDS requirements was created using multiple educational methods. The first resident cohort that completed the curriculum demonstrated an absolute increase in QI knowledge and its applicability (as measured by the QIKAT-R) by 19.6%. Two PDSA cycles were completed to improve the curriculum with the change ideas generated from resident feedback. Ongoing challenges include limited staff availability to teach and supervise resident QI projects. Future directions include incentivising staff participation and providing mentorship for residents with a career interest in QI beyond what is offered by the curriculum.
Vaccination programmes are considered a main contributor to the decline of infectious diseases over the 20th century. In recent years, the national vaccination coverage in the Netherlands has been declining, highlighting the need for continuous monitoring and evaluation of vaccination programmes. Our aim was to quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919–2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. In the first 13 years of mass vaccinations, case notifications declined rapidly with 82.4% (95% credible interval (CI): 74.9–87.6) of notified cases of diphtheria averted, 92.9% (95% CI 85.0–97.2) cases of poliomyelitis, and 79.1% (95% CI 67.1–87.4) cases of mumps. Vaccination of 11-year-old girls against rubella averted 49.9% (95% CI 9.3–73.5) of cases, while universal vaccination averted 68.1% (95% CI 19.4–87.3) of cases. These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Cognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis.
Ninety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3–6 months post-treatment.
Patients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3–6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition.
CR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.
We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.
This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike’s information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.
Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).
These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype–phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.
A new genus and species of megalonychid sloth, Zacatzontli tecolotlanensis n. gen. n. sp., is described from the late Hemphillian of Jalisco, Mexico. Comparison and analysis of the type specimen, a mandible, with other megalonychid sloths shows a closer relationship to South American taxa than those from North America or the Caribbean. This suggests that during the early stages of the Great American Biotic Interchange there were two separate dispersal events of megalonychid sloths—an earlier one represented by Pliometanastes and the later one by Zacatzontli n. gen. While the morphology of the spout of Zacatzontli more closely resembles that of Megalonyx, based on the current record, Zacatzontli does does not enter North America until after the evolution of Megalonyx from Pliometanastes. The role of the northern neotropics in South America as a staging area for South American taxa that entered North America is discussed.
Fungal spores, especially those of coprophilous fungi, are present in dung middens of Rhinoceros unicornis (greater one-horned rhinoceros) in both forest and grassland areas of the Kaziranga National Park, India. The presence of coprophilous fungi on rhino dung, chiefly Sporormiella, Saccobolus, Ascodesmis, Cercophora, and Sordaria, is documented for the first time. The Sporormiella–Ascodesmis–Saccobolus assemblage is abundant and characterizes the rhino dung in forest and grassland areas. The presence of coprophilous fungi spores allows for an examination of the relationship between rhinoceros ecology and the flora and other fauna in the region. The overall dataset is useful in interpreting the present and past distribution of rhino and other associated animals based on the relative abundance of different types of coprophilous fungi spores and their relationship to paleoherbivory and paleoecology in India and adjoining areas.
To explore the mental health tribunal experiences of people admitted involuntarily under the Mental Health Act 2001.
Employing a qualitative descriptive study design, data were collected from 23 service users who had experienced mental health tribunals during a recent involuntary admission. Face-to-face semi-structured interviews were conducted ~3 months post-revocation of their involuntary admission order. Data were analysed using an inductive thematic process.
The majority of participants reported mixed experiences comprising positive and negative aspects in relation to information provision, emotional support and an inclusive atmosphere. Some participants reported receiving accessible information about the tribunal process, felt emotionally supported throughout, and encountered respectful and dignifying practices during the tribunal proceedings. However, many participants described experiencing non-inclusive practices, reported feeling ill-informed regarding the tribunal process, emotionally unsupported during and after the tribunal, and distressed by what they perceived as adversarial tribunal proceedings.
Systemic changes could ensure that the positive experiences encountered by the minority of participants in this study are more consistently experienced. Ongoing education and training of stakeholders in the provision of inclusive tribunal practices, and the provision of accessible information and emotional support to service users through the stages of the involuntary admission process appear likely to be beneficial. Service users should automatically be offered the option of having a support person of their choosing present during tribunals.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
Black men are known to have a higher risk for prostate cancer (PC). Carotenoids and retinol, linked to PC, have not been compared in different black populations at risk. We examined serum carotenoid and retinol levels between PC-free African-Caribbean (AC) Tobagonian men with a high PC risk (high-grade prostatic intraepithelial neoplasia, atypical foci or repeated abnormal PC screenings) and African-American (AA) men with elevated serum prostate-specific antigen (PSA) levels (≥4 ng/ml). AC men who participated in the 2003 lycopene clinical trial and AA men who participated in the 2001–2006 National Health and Nutrition Examination Survey were compared. Serum specimens were analysed for carotenoid (β-carotene, α-carotene, β-cryptoxanthin, lutein/zeaxanthin and lycopene) and retinol levels by isocratic HPLC. Quantile regression was used to examine the association between serum carotenoid and retinol levels and black ethnicity, overall and among men with elevated serum PSA. There were sixty-nine AC men and sixty-five AA men, aged 41–79 years, included. AC men were associated with lower serum lycopene and retinol levels, and higher serum α- and β-carotenes and lutein/zeaxanthin levels compared with AA men, after adjusting for age, BMI, ever smoked cigarettes, education and hypertension (P≤0·03). Among men with elevated PSA, serum retinol was no longer statistically significant with ethnicity (P=0·06). Possible differences may be attributed to dietary intake, genetics and/or factors that influence bioavailability of these micronutrients. Prospective studies are warranted that investigate whether these differences in micronutrients between AC Tobagonian and AA men influence PC risk.
The Antarctic Roadmap Challenges (ARC) project identified critical requirements to deliver high priority Antarctic research in the 21st century. The ARC project addressed the challenges of enabling technologies, facilitating access, providing logistics and infrastructure, and capitalizing on international co-operation. Technological requirements include: i) innovative automated in situ observing systems, sensors and interoperable platforms (including power demands), ii) realistic and holistic numerical models, iii) enhanced remote sensing and sensors, iv) expanded sample collection and retrieval technologies, and v) greater cyber-infrastructure to process ‘big data’ collection, transmission and analyses while promoting data accessibility. These technologies must be widely available, performance and reliability must be improved and technologies used elsewhere must be applied to the Antarctic. Considerable Antarctic research is field-based, making access to vital geographical targets essential. Future research will require continent- and ocean-wide environmentally responsible access to coastal and interior Antarctica and the Southern Ocean. Year-round access is indispensable. The cost of future Antarctic science is great but there are opportunities for all to participate commensurate with national resources, expertise and interests. The scope of future Antarctic research will necessitate enhanced and inventive interdisciplinary and international collaborations. The full promise of Antarctic science will only be realized if nations act together.
Background: Despite the critical role played by neurosurgeons in performing radiosurgery, neurosurgery residents in Canada have limited exposure to radiosurgery during their training. A survey of neurosurgery residents and faculty along with radiation oncology faculty was conducted to analyze perspectives regarding incorporating formal radiosurgery training into the neurosurgery residency curriculum Methods: An online survey platform was employed. Descriptive statistics were used to summarize center and respondent characteristics. Categorical variables were compared using odds ratios and corresponding 95% confidence intervals. The chi-squared test was utilized to assess statistical significance. A value of p<0.05 was considered significant Results: The response rate was 31% (119/381); 87% (102/119) of respondents were from the neurosurgical specialty and 13% (17/119) from radiation oncology. Some 46% of residents (18/40) were “very uncomfortable” with radiosurgery techniques, and 57% of faculty (42/73) believed that dedicated radiosurgery training would be beneficial though impractical. No respondents felt that “no training” would be beneficial. A total of 46% of residents (19/41) felt that this training would be beneficial and that time should be taken away from other rotations, if needed, while 58% of faculty (42/73) and 75% (28/41) of residents believed that either 1 or 1-3 months of time dedicated to training in radiosurgery would suffice Conclusions: Canadian neurosurgeons are actively involved in radiosurgery. Despite residents anticipating a greater role for radiosurgery in their future, they are uncomfortable with the practice. With the indications for radiosurgery expanding, this training gap can have serious adverse consequences for patients. Considerations regarding the incorporation and optimal duration of dedicated radiosurgery training into the Canadian neurosurgery residency curriculum are necessary.
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: ACT DMD is a Phase 3, randomized, double-blind study. Males 7-16 years with nmDMD and a screening six-minute walk distance (6MWD) ≥150 m and <80%-predicted were randomized to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients with baseline 6MWD 300-400 m. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (those patients meeting ACT DMD entry criteria) was pre-specified in the statistical plan. Results: In the overall ACT DMD population (N=228), changes in TFTs favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant (p<0.01) for 4-stair climb and descend. Results are supported by the meta-analysis (N=291), which demonstrated significant differences (p<0.05) in 10-meter walk/run, 4-stair climb, 4-stair descend. Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400 m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.
To evaluate and compare the opinions of key stakeholders involved in the involuntary admission and treatment of patients under the Mental Health Act (MHA) 2001 regarding their views towards the operation of the legislation.
We employed a descriptive survey design. A questionnaire was distributed to stakeholders involved in the operation of the MHA 2001 (except service users, whose views were explored in a separate qualitative study) via paper or online versions evaluating their opinions regarding the operation of the MHA 2001 in relation to assessment, care, rights, transfer and information available.
Stakeholders agreed that in their opinion that patients generally benefit from the care they receive (79%) and that the MHA 2001 ensures an independent and fair review of the person’s detention (65%). However, only 23% of stakeholders were satisfied with the process of transferring patients to hospital and with the clinical assessment procedures therein (37%), with the greatest levels of dissatisfaction amongst Gardai (Police), general practitioners (GPs) and family members.
While the introduction of the MHA 2001 has assisted delivery of care to patients with improved adherence to international human rights frameworks applicable at the time of its enactment, substantial dissatisfaction with the implementation of the MHA 2001 in practice is experienced by stakeholders particularly at the distressing phase of clinical assessment and transfer to hospital.