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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Introduction: Patients with chronic diseases are known to benefit from exercise. Such patients often visit the emergency department (ED). There are few studies examining prescribing exercise in the ED. We wished to study if exercise prescription in the ED is feasible and effective. Methods: In this pilot prospective block randomized trial, patients in the control group received routine care, whereas the intervention group received a combined written and verbal prescription for moderate exercise (150 minutes/week). Both groups were followed up by phone at 2 months. The primary outcome was achieving 150 min of exercise per week. Secondary outcomes included change in exercise, and differences in reported median weekly exercise. Comparisons were made by Mann-Whitney and Fishers tests (GraphPad). Results: Follow-up was completed for 22 patients (11 Control; 11 Intervention). Baseline reported median (with IQR) weekly exercise was similar between groups; Control 0(0-0)min; Intervention 0(0-45)min. There was no difference between groups for the primary outcome of 150 min/week at 2 months (Control 3/11; Intervention 4/11, RR 1.33 (95%CI 0.38-4.6;p=1.0). There was a significant increase in median exercise from baseline in both groups, but no difference between the groups (Control 75(10-225)min; Intervention 120(52.5-150)min;NS). 3 control patients actually received exercise prescription as part of routine care. A post-hoc comparison of patients receiving intervention vs. no intervention, revealed an increase in patients meeting the primary target of 150min/week (No intervention 0/8; Intervention 7/14, RR 2.0 (95%CI 1.2-3.4);p=0.023). Conclusion: Recruitment was feasible, however our study was underpowered to quantify an estimated effect size. As a significant proportion of the control group received the intervention (as part of standard care), any potential measurable effect was diluted. The improvement seen in patients receiving intervention and the increase in reported exercise in both groups (possible Hawthorne effect) suggests that exercise prescription for ED patients may be beneficial.
Chagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline.
Introduction: The positive health outcomes of exercise have been well-studied, and exercise prescription has been shown to reduce morbidity in several chronic health conditions. However, patient attitudes around the prescription of exercise in the emergency department (ED) have not been explored. The aim of our pilot study is to explore patients’ willingness and perceptions of exercise being discussed and prescribed in the ED. Methods: This study is a survey of patients who had been previously selected for exercise prescription in a pilot study conducted at a tertiary care ED. This intervention group were given a standardized provincial written prescription to perform moderate exercise for 150 minutes per week. Participants answered a discharge questionnaire and were followed up by a telephone interview 2 months later. A structured interview of opinions around exercise prescription was conducted. Questions included a combination of non-closed style interview questions and Likert scale. Patients rated prescription detail, helpfulness and likelihood on a Likert scale from 1-5 (1 being strongly disagree and 5 being strongly agree). Median values (+/-IQRs) are presented, along with dominant themes. Results: 17 people consented to exercise prescription and follow up surveys. 2 were excluded due to hospital admission. 15 participants were enrolled and completed the discharge survey. Two-month follow up survey response rate was 80%. Patients rated the detail given in their prescription as 5 (+/-1). Helpfulness of prescription was rated as 4 (+/-2). Likelihood to continue exercising based on the prescription was rated as 4 (+/-2). 11/12 participants felt that exercise should be discussed in the Emergency Department either routinely or on a case-by-case basis.1 participant felt it should not be discussed at all. Conclusion: Our study demonstrates that most patients are open to exercise being discussed during their Emergency Department visit, and that the prescription format was well-received by study participants.
There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood.
Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361).
After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10–2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose–response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03–2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood.
Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
Central skull base osteomyelitis is clinically difficult to distinguish from malignancy.
The computed tomography and magnetic resonance imaging scans of six patients with central skull base osteomyelitis were compared with scans from patients with a range of skull base conditions.
Results and conclusion:
Computed tomography scans of central skull base osteomyelitis show much less bony destruction relative to the magnetic resonance imaging changes, whereas malignancy cases were associated with similar bony destruction on computed tomography and magnetic resonance imaging. In magnetic resonance imaging scans, it was possible to confirm previous findings of clival hypointensity on T1-weighted images relative to normal fatty marrow. In addition, there were signs of pre- and para-clival soft tissue infiltration, with the obliteration of normal fat planes and frank soft tissue masses in all six central skull base osteomyelitis patients. Signal intensity on T2-weighted images of the clivus was high in five central skull base osteomyelitis patients. With intravenous contrast, fascial plane anatomy appeared restored in central skull base osteomyelitis cases, almost in keeping with that of non-involved areas. This was not a feature in any of the malignant conditions.
Habitat fragmentation may lead to spatial genetic structuring of plant populations, but the magnitude of this effect differs among species. In this study, the effects of fragmentation on spatial genetic structure of Manilkara maxima, an ecologically important tree species endemic to the Atlantic forest of southern Bahia, Brazil, were examined. To address this issue, 222 individuals were sampled across two large-forest sites (200 and 400 ha) and one site comprising eight small fragments (5, 10 and 25 ha) roughly 35 y old. Five microsatellite loci were used. In general, M. maxima exhibited limited genetic structuring within and across the sites examined. At the landscape scale, genetic structure was not shaped by isolation by distance. Within individual sites, weak to moderate genetic structure was observed for both adults and saplings, which represented pre- and post-fragmentation, respectively. Sapling genetic structure did not clearly vary among the study sites, suggesting fragmentation has not affected spatial genetic structure. High levels of migration were observed, which would help maintain genetic connectivity. Taken together, these results suggest M. maxima, a long-lived tree that naturally occurs in low densities, may have limited spatial genetic structuring both within and across forest patches.
The synthetic auxin herbicides, aminocyclopyrachlor and clopyralid, control dicotyledonous weeds in turf. Clippings of turfgrass treated with synthetic auxin herbicides have injured off-target plants exposed to herbicide-laden clippings. Labels of aminocyclopyrachlor and clopyralid recommend that clippings of treated turfgrass remain on the turf following a mowing event. Alternative uses for synthetic auxin-treated turfgrass clippings are needed because large quantities of clippings on the turf surface interfere with the functionality and aesthetics of golf courses, athletic fields, and residential turf. A white clover bioassay was conducted to determine the persistence and bioavailability of aminocyclopyrachlor and clopyralid in turfgrass clippings. Aminocyclopyrachlor and clopyralid were each applied at 79 g ae ha−1 to mature tall fescue at 56, 28, 14, 7, 3.5, and 1.75 d before clipping collection (DBCC). Clippings were collected, and the treated clippings were recycled onto adjacent white clover plots to determine herbicidal persistence and potential for additional weed control. Clippings of tall fescue treated with aminocyclopyrachlor produced a nonlinear regression pattern of response on white clover. Calculated values for 50% response (GR50) for visual control, for normalized difference vegetative index (NDVI), and for reduction in harvested biomass were 20.5, 17.3, and 18.7 DBCC, respectively, 8 wk after clippings were applied. Clippings of tall fescue treated with clopyralid did not demonstrate a significant pattern for white clover control, presumably because clopyralid was applied at a less-than-label rate. The persistence and bioavailability of synthetic auxin herbicides in clippings harvested from previously treated turfgrass creates the opportunity to recycle clippings for additional weed control.
(See the commentary by Pfeiffer and Beldavs, on pages 984–986.)
Describe the epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) and examine the effect of lower carbapenem breakpoints on CRE detection.
Inpatient care at community hospitals.
All patients with CRE-positive cultures were included.
CRE isolated from 25 community hospitals were prospectively entered into a centralized database from January 2008 through December 2012. Microbiology laboratory practices were assessed using questionnaires.
A total of 305 CRE isolates were detected at 16 hospitals (64%). Patients with CRE had symptomatic infection in 180 cases (59%) and asymptomatic colonization in the remainder (125 cases; 41%). Klebsiella pneumoniae (277 isolates; 91%) was the most prevalent species. The majority of cases were healthcare associated (288 cases; 94%). The rate of CRE detection increased more than fivefold from 2008 (0.26 cases per 100,000 patient-days) to 2012 (1.4 cases per 100,000 patient-days; incidence rate ratio (IRR), 5.3 [95% confidence interval (CI), 1.22–22.7]; P = .01). Only 5 hospitals (20%) had adopted the 2010 Clinical and Laboratory Standards Institute (CLSI) carbapenem breakpoints. The 5 hospitals that adopted the lower carbapenem breakpoints were more likely to detect CRE after implementation of breakpoints than before (4.1 vs 0.5 cases per 100,000 patient-days; P < .001; IRR, 8.1 [95% CI, 2.7–24.6]). Hospitals that implemented the lower carbapenem breakpoints were more likely to detect CRE than were hospitals that did not (3.3 vs 1.1 cases per 100,000 patient-days; P = .01).
The rate of CRE detection increased fivefold in community hospitals in the southeastern United States from 2008 to 2012. Despite this, our estimates are likely underestimates of the true rate of CRE detection, given the low adoption of the carbapenem breakpoints recommended in the 2010 CLSI guidelines.
We describe the efficacy of enhanced infection control measures, including those recommended in the Centers for Disease Control and Prevention’s 2012 carbapenem-resistant Enterobacteriaceae (CRE) toolkit, to control concurrent outbreaks of carbapenemase-producing Enterobacteriaceae (CPE) and extensively drug-resistant Acinetobacter baumannii (XDR-AB).
Before-after intervention study.
Fifteen-bed surgical trauma intensive care unit (ICU).
We investigated the impact of enhanced infection control measures in response to clusters of CPE and XDR-AB infections in an ICU from April 2009 to March 2010. Polymerase chain reaction was used to detect the presence of blaKPC and resistance plasmids in CRE. Pulsed-field gel electrophoresis was performed to assess XDR-AB clonality. Enhanced infection-control measures were implemented in response to ongoing transmission of CPE and a new outbreak of XDR-AB. Efficacy was evaluated by comparing the incidence rate (IR) of CPE and XDR-AB before and after the implementation of these measures.
The IR of CPE for the 12 months before the implementation of enhanced measures was 7.77 cases per 1,000 patient-days, whereas the IR of XDR-AB for the 3 months before implementation was 6.79 cases per 1,000 patient-days. All examined CPE shared endemic blaKPC resistance plasmids, and 6 of the 7 XDR-AB isolates were clonal. Following institution of enhanced infection control measures, the CPE IR decreased to 1.22 cases per 1,000 patient-days (P = .001), and no more cases of XDR-AB were identified.
Use of infection control measures described in the Centers for Disease Control and Prevention’s 2012 CRE toolkit was associated with a reduction in the IR of CPE and an interruption in XDR-AB transmission.
Clinical and ethical implications of personality and mood changes in Parkinson's disease (PD) patients treated with subthalamic deep brain stimulation (STN-DBS) are under debate. Although subjectively perceived personality changes are often mentioned by patients and caregivers, few empirical studies concerning these changes exist. Therefore, we analysed subjectively perceived personality and mood changes in STN-DBS PD patients.
In this prospective study of the ELSA-DBS group, 27 PD patients were assessed preoperatively and 1 year after STN-DBS surgery. Two categories, personality and mood changes, were analysed with semi-structured interviews. Patients were grouped into personality change yes/no, as well as positive/negative mood change groups. Caregivers were additionally interviewed about patients’ personality changes. Characteristics of each group were assessed with standard neurological and psychiatric measurements. Predictors for changes were analysed.
Personality changes were perceived by six of 27 (22%) patients and by 10 of 23 caregivers (44%). The preoperative hypomania trait was a significant predictor for personality change perceived by patients. Of 21 patients, 12 (57%) perceived mood as positively changed. Higher apathy and anxiety ratings were found in the negative change group.
Our results show that a high proportion of PD patients and caregivers perceived personality changes under STN-DBS, emphasizing the relevance of this topic. Mood changed in positive and negative directions. Standard measurement scales failed to adequately reflect personality or mood changes subjectively perceived by patients. A more individualized preoperative screening and preparation for patients and caregivers, as well as postoperative support, could therefore be useful.
Aminocyclopyrachlor (AMCP) is a newly developed synthetic auxin herbicide for broadleaf weed control in turfgrass systems. AMCP has been observed to undergo rapid photodecomposition in shallow water when exposed to sunlight. Most herbicide applications on golf courses occur during the morning when dew is still present on the turfgrass canopy. These conditions could result in efficacy loss if photolysis occurred while AMCP is suspended in dew droplets. Research was conducted to determine the effect of ambient moisture on AMCP efficacy. AMCP (79 and 105 g ae ha−1), aminopyralid (280 g ae ha −1), and two AMCP granular formulations (84 g ha−1) were applied to dew-covered (WET) and dew-excluded (DRY) ‘Tifway' bermudagrass plots. Herbicide treatments applied to WET plots had greater visually rated bermudagrass injury than respective treatments applied to DRY plots at 7 and 21 d after treatment (DAT), with the exception of aminopyralid at 21 DAT. Normalized difference vegetative index on turfgrass quality complemented visual ratings, indicating greater turfgrass quality reductions when applied to WET vs. DRY plots. These results indicate that AMCP applications made to dew-covered turfgrass can increase herbicidal efficacy, and no significant losses due to photodegradation were observed.
Buffer leakage in aluminum gallium nitride/gallium nitride (AlGaN/GaN) heterostructure transistors is recognized as an issue that has deleterious consequences on device performance for high-power, high-frequency transistors and has been related to the presence of uncharged threading screw dislocations. In this study, we demonstrate that measurements of buffer leakage in AlGaN/GaN heterostructures grown on bulk gallium nitride (GaN) substrates are consistent with a mechanism based on the concept of dislocations acting as quantum wires in series with unintentional silicon (Si) impurity incorporation at the bulk GaN substrate/GaN buffer interface. The number of electronic channels N deduced from the leakage data using Landauer’s formula for the quantum resistance of N electronic channels is consistent with the number of dislocations along the ohmic contact pads determined from panchromatic cathodoluminescence and x-ray diffraction measurements of the dislocation density. This mechanism is consistent with Shockley’s suggestion that dislocations can act as one-dimensional conductors due to the presence of edge states along the dislocation core.
The first experimental investigation of an optical limiting device based on a suspension of spherical particles in a surrounding liquid is presented. The expected property is the non-linear light scattering based on a refractive index mismatch between the two components that appears at high intensity. Several experiments performed at 532 nm with nanosecond laser pulses provide good indication that such non-linear scattering is observed.