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BACKGROUND: Pharyngeal Chlamydia trachomatis in women might contribute to autoinoculation and transmission to sexual partners. Data for effectiveness of different testing practices for pharyngeal C trachomatis are scarce. We therefore aimed to assess the prevalence of pharyngeal C trachomatis, determinants, and effectiveness of different testing practices in women.METHODS: We did a retrospective cohort study, in which surveillance data for all women visiting sexually transmitted infection clinics in all regions in the Netherlands between Jan 1, 2008, and Dec 31, 2017, were used. We collected consultation-level data and individual-level data from 2016 onwards for sociodemographic characteristics, sexual behaviour in the past 6 months, self-reported symptoms, and STI diagnoses. The primary outcome was the positivity rate of pharyngeal C trachomatis infection compared between routine universal testing (>85% tested pharyngeally per clinic year), selective testing (5-85% tested pharyngeally per clinic year), and incidental testing (FINDINGS: Between Jan 1, 2008, and Dec 31, 2017, a total of 550 615 consultations with at least one C trachomatis test was recorded, of which 541 945 (98·4%) consultations (including repeat visits) were included in this analysis. Pharyngeal C trachomatis positivity was lower in the routine universal testing group than in the selective testing group (1081 [2·4%; 95% CI 2·2-2·5] of 45 774 vs 3473 [2·9%; 2·8-3·0] of 121 262; pINTERPRETATION: No optimal testing scenario was available for pharyngeal C trachomatis, in which only a selection of high-risk women needs to be tested to find most pharyngeal C trachomatis infections. The relative low prevalence of pharyngeal-only C trachomatis (0·5%) and probably limited clinical and public health effect do not provide support for routine universal testing.FUNDING: Public Health Service South Limburg.

Objective To compare clinical, sports, work, and radiological outcomes between primary and secondary osteochondral lesions of the talus (OLTs; Design Secondary OLTs were matched to primary OLTs in a 1:2 ratio to assess the primary outcome measure—the Numeric Rating Scale (NRS) during activities. Secondary outcomes included the pre- and 1-year postoperative NRS at rest, American Orthopaedic Foot and Ankle Society score, Foot and Ankle Outcome Score subscales, and the EQ-5D general health questionnaire. The rates and time to return to work and sports were collected. Radiological examinations were performed preoperatively and at final follow-up using computed tomography (CT). Results After matching, 22 and 12 patients with small (Conclusion No differences in outcomes were observed between arthroscopic bone marrow stimulation in primary and secondary OLTs at 1-year follow-up. Repeat BMS may therefore be a viable treatment option for failed OLTs in the short term.

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.

Purpose Photo-optical TCpO2 (pTCpO2) has been proposed as a new method to determine the partial oxygen pressure of the lower extremity in patients with peripheral arterial disease. It is aimed to determine the level of agreement between pTCpO2 and the traditional electro-chemical transcutaneous oxygen tension measurement (eTCpO2). Methods Eighteen patients with intermittent claudication underwent simultaneous ankle-brachial index measurement, toe-pressure, pTCpO2 and eTCpO2 tests. Oxygen tension levels were measured on anterior chest and calf prior in rest (T0), during induced ischemia (T1) and after blood flow restoration (T2). TCpO2 agreement was assessed according to the principles of Bland and Altman. Results Absolute average TCpO2 values differed between eTCpO2 and pTCpO2 for calf in T2 (38,1 mmHg (σ 14,4) vs. 49,8 (σ 22.3) with P = 0.35). The Bland-Altman plots demonstrated eTCpO2 and pTCpO2 bias of 3,7 mmHg (σ 18,8), 11,6 mmHg (σ 17,6) and 6,7 mmHg (σ 23,5) for T0, T1 and T2 for the calf. Conclusion pTCpO2 is in agreement with eTCpO2 in measuring pO2 levels of the lower extremity in rest and during induced ischemia in patients with vascular claudication. The large variability between eTCpO2 and pTCpO2 should be accounted for, while pTCpO2 values have a tendency to demonstrate higher values in comparison to eTCpO2.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

The classical twin model can be reparametrized as an equivalent multilevel model. The multilevel parameterization has underexplored advantages, such as the possibility to include higher-level clustering variables in which lower levels are nested. When this higher-level clustering is not modeled, its variance is captured by the common environmental variance component. In this paper we illustrate the application of a 3-level multilevel model to twin data by analyzing the regional clustering of 7-year-old children’s height in the Netherlands. Our findings show that 1.8%, of the phenotypic variance in children’s height is attributable to regional clustering, which is 7% of the variance explained by between-family or common environmental components. Since regional clustering may represent ancestry, we also investigate the effect of region after correcting for genetic principal components, in a subsample of participants with genome-wide SNP data. After correction, region did no longer explain variation in height. Our results suggest that the phenotypic variance explained by region actually represent ancestry effects on height.

ObjectivesGeneral practitioners (GPs) and sexual health centres (SHCs) are the main providers of HIV testing and diagnose two-thirds of HIV infections in the Netherlands. We compared regional HIV testing and positivity by GPs versus SHCs to gain insight into strategies to improve HIV testing, to enable timely detection of HIV infections.MethodsLaboratory data (2011–2018) on HIV testing by GPs and SHCs in five Dutch regions with varying levels of urbanisation were evaluated. Regional HIV testing rates per 10 000 residents ≥15 years (mean over period and annual) were compared between providers using negative binomial generalised additive models and additionally stratified by sex and age (15–29 years, 30–44 years, 45–59 years, ≥60 years). χ2 tests were used to compare positivity percentage between the two groups of providers.ResultsIn the study period, 505 167 HIV tests (GP 36%, SHC 64%) were performed. The highest HIV testing rates were observed in highly urbanised regions, with large regional variations. The HIV testing rates ranged from 28 to 178 per 10 000 residents by GPs and from 30 to 378 per 10 000 by SHCs. Testing rates by GPs were lower than by SHCs in three regions and comparable in two. In all regions, men were tested less by GPs than by SHCs; for women, this varied by region. Among those aged 15–29 years old, GPs’ testing rates were lower than SHCs’, while this was reversed in older age categories in four out of five regions. The overall mean HIV positivity was 0.4%. In contrast to other regions, positivity in Amsterdam was significantly higher among individuals tested by GPs than by SHCs.ConclusionsThis retrospective observational study shows that besides SHCs, who perform opt-out testing for key groups, GPs play a prominent role in HIV testing, especially in non-key populations, such as women and older individuals. Large regional variation exists, requiring region-specific interventions to improve GPs’ HIV testing practices.

Pathogenic variants in methyl-CpG protein 2 (MECP2; OMIM 300005) result in an X-linked, severe, and progressive epigenetic disorder, Rett syndrome (RTT, OMIM: 312750), that predominantly affects females (Rett, 1966). Using Neul's revised diagnostic criteria, affected individuals can be clinically classified as classic or atypical RTT (Neul et al., 2010). After 6–18 months of apparently normal development, girls with the classic form of RTT gradually start losing their previously acquired skills including spoken language and other communication, coordination, and social interaction. Along with acquired microcephaly, affected girls lose purposeful use of their hands and develop midline stereotypic hand movements, breathing irregularities, seizures, scoliosis, and disturbed sleeping patterns. The partial/complete loss of spoken language is one of the core diagnostic criteria which is essential to be present for an affected individual to be classified as an individual with classic RTT. However, it is not necessarily a required criterion when classifying individuals with atypical RTT (Neul et al., 2010; Schonewolf-Greulich et al., 2019). As per the definitions adopted in the article by Neul et al. (2010) “… an individual who had learned to babble but then loses this ability is considered to have a loss of acquired language …” Owing to the broad variability of the phenotype in individuals with RTT, a proportion of them satisfy some, but not all, of the necessary revised diagnostic criteria and are classified as atypical RTT. Furthermore, individuals may be classified as RTT-like, exhibiting some clinical features associated with RTT, but not enough to be classified as either classic or atypical RTT (Ip et al., 2018). Approximately 97% of individuals with classic RTT and 86% of individuals with atypical RTT have pathogenic variants in MECP2 (Neul et al., 2014). A small proportion of individuals with clinical features overlapping with RTT have been reported with pathogenic variants in cyclin-dependent kinase-like 5 (CDKL5, OMIM: 300203) and forkhead box G1 (FOXG1, OMIM: 164874); however, a significant proportion of individuals clinically classified as RTT remain without a definite genetic diagnosis (Armani et al., 2012).

It remains a challenge to determine whether children resemble their parents due to nature, nurture, or a mixture of both. Here we used a design that exploits the distinction between transmitted and non-transmitted alleles in genetic transmission from parent to offspring. Two separate polygenic scores (PGS) were calculated on the basis of the transmitted and non-transmitted alleles. The effect of the non-transmitted PGS is necessarily mediated by parental phenotypes, insofar as they contribute to the rearing environment of the offspring (genetic nurturing). We calculated transmitted and non-transmitted PGSs associated with adult educational attainment (EA) and PGSs associated with childhood ADHD in a general population sample of trios, i.e. child or adult offspring and their parents (N = 1120-2518). We tested if the EA and ADHD (non-)transmitted PGSs were associated with childhood academic achievement and ADHD in offspring. Based on the earlier findings for shared environment, we hypothesized to find genetic nurturing for academic achievement, but not for ADHD. In adults, both transmitted (R2 = 7.6%) and non-transmitted (R2 = 1.7%) EA PGSs were associated with offspring EA, evidencing genetic nurturing. In children around age 12, academic achievement was associated with the transmitted EA PGSs (R2 = 5.7%), but we found no support for genetic nurturing (R2 ~ 0.1%). The ADHD PGSs were not significantly associated with academic achievement (R2 ~ 0.6%). ADHD symptoms in children were only associated with transmitted EA PGSs and ADHD PGSs (R2 = 1-2%). Based on these results, we conclude that the associations between parent characteristics and offspring outcomes in childhood are mainly to be attributable to the effects of genes that are shared by parents and children.

Background & Aims: HCV has emerged as a sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). We evaluated HCV incidence and its risk factors among HIV-negative MSM using HIV pre-exposure prophylaxis (PrEP). Methods: Participants of the Amsterdam PrEP project were tested for HCV antibodies or HCV-RNA every 6 months. Participants used daily or event-driven PrEP and could switch regimens during follow-up. We calculated incidence rates (IRs) for overall HCV infection and separately for primary and re-infection. A univariable Bayesian exponential survival model was used to identify risk factors associated with incident HCV infection. The HCV NS5B gene fragment (709 bp) was sequenced and compared to HCV isolates from HIV-positive MSM and other risk groups (n = 419) using phylogenetic analysis. Results: Among 350 participants contributing 653.6 person-years (PYs), we detected 15 HCV infections in 14 participants (IR = 2.30/100PY). There were 8 primary infections (IR = 1.27/100PY) and 7 re-infections (IR = 27.8/100PY). IR was 2.71/100PY in daily and 1.15/100PY in event-driven PrEP users. Factors associated with incident HCV infection were higher number of receptive condomless anal sex acts with casual partners (posterior hazard ratio [HR] 1.57 per ln increase; 95% credibility interval [CrI] 1.09–2.20), anal STI (posterior HR 2.93; 95% CrI 1.24–7.13), injecting drug use (posterior HR 4.69; 95% CrI 1.61–12.09) and sharing straws when snorting drugs (posterior HR 2.62; 95% CrI 1.09–6.02). We identified robust MSM-specific HCV clusters of subtypes 1a, 4d, 2b and 3a, which included MSM with and without HIV. Conclusions: HIV-negative MSM using PrEP are at risk of incident HCV infection, while identified risk factors are similar to those in HIV-positive MSM. Regular HCV testing is needed, especially for those with a previous HCV infection and those reporting risk factors. Lay summary: We report that hepatitis C virus infections are frequently acquired among HIV-negative men who have sex with men (MSM) using pre-exposure prophylaxis to prevent HIV infection. New infections occurred more frequently in those reporting receptive anal sex without using condoms, having an anal sexually transmitted infection, injecting drugs, and sharing straws when snorting drugs. The viruses found in HIV-negative men using pre-exposure prophylaxis are genetically similar to those in HIV-positive men, but not in other hepatitis C risk groups, suggesting that (sexual) transmission is occurring between HIV-positive MSM and HIV-negative MSM using pre-exposure prophylaxis. Clinical Trial number: Dutch trial registration number NTR5411.

To evaluate whether infants with complex congenital heart disease (CCHD) have an increased risk of impaired quality of motor behavior and delayed motor milestones.A cohort of 69 infants with CCHD (43 males, 26 females) were assessed with the Infant Motor Profile (IMP) at three time periods between 6 to 18 months, mean ages in months (SD): 6.4 (0.7); 12.7 (1.0); 18.5 (0.7) IMP data were available from a reference sample of 300 Dutch infants. Analyses included multivariable logistic regression analysis to estimate differences in IMP scores below the 15th centile between children with CCHD and the reference group, and linear mixed-effects models to assess the effect of ventricular physiology and systemic oxygen saturation (SpO2) of less than 90% on IMP outcomes.Infants with CCHD had increased risks of total IMP scores below the 15th centile (lowest odds ratio [OR] at 18mo: 6.82 [95% confidence interval {CI} 2.87-16.19]), especially because of lower scores in the domains of variation, adaptability, and performance. Children with single ventricle CCHD scored consistently 3.03% (95% CI 1.00-5.07) lower than those with two ventricle physiology, mainly from contributions of the variation and performance domains. SpO2 of less than 90% was associated with 2.52% (95% CI 0.49-4.54) lower IMP scores.CCHD, especially single ventricle physiology, increases risk of impaired motor development.Complex congenital heart disease (CCHD) substantially increases risk of impaired motor development. CCHD is associated with motor delay and reduced motor variation and adaptability. Single ventricle physiology increases the risk of impaired motor behavior.

Pharyngeal Chlamydia trachomatis (CT) was diagnosed in 1.2% and pharyngeal-only CT in 0.5% of routinely universally tested men who have sex with men (MSM). In these 3-anatomic-site tested MSM, pharyngeal-only CT comprised 4.8% of all CT. The low positivity of pharyngeal-only CT indicates low public health impact of pharyngeal CT.

Background Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection (STI) worldwide. CT is mainly asymptomatic. Test-and-treat strategies are widely implemented to prevent transmission and complications. Strategies are not without controversy in asymptomatic women and men who have sex with men (MSM). Concerns are emerging to test and treat asymptomatic persons for urogenital CT (‘Controversy 1’) and pharyngeal or rectal CT (‘Controversy 2’), whereby testing symptomatic persons is not under debate. Opposed views in CT treatment involve using azithromycin versus doxycycline (‘Controversy 3’). The objective of this review is to provide coverage of these public health and clinical controversies by reviewing the current scientific evidence. Methods A literature search was performed using PubMed for relevant publications between 2018 and September 2021, and iterative retrieval of additional relevant publications. Results Controversy 1. In women, the majority of asymptomatic CT are at the urogenital site, and detections mostly include viable CT. CT easily transmits to a partner and potentially also between the vaginal and rectal areas; the clinical impact of urogenital CT is established, although risks for adverse outcomes are uncertain. Wide-scale testing in asymptomatic women has not resulted in reduced prevalence. In MSM, evidence for the clinical impact of asymptomatic urogenital CT is lacking. Controversy 2. Rectal CT is common in women diagnosed with urogenital CT, but the clinical impact of asymptomatic rectal CT is uncertain. In MSM, rectal CT is common, and most CT infections are at the rectal site, yet the risk of longer term complications is unknown. In both sexes, pharyngeal CT is uncommon and has no documented clinical impact. Controversy 3. In the treatment of rectal CT, doxycycline has superior effectiveness to azithromycin. Evidence has also accumulated on the harms of test-and-treat strategies. Conclusions Current practices vary widely, from widescale test-and-treat approaches to more individual patient- and partner-level case management. Choosing which asymptomatic people to test at what anatomic site, and whether to test or not, requires an urgent (re-)definition of the goals of testing and treating asymptomatic persons. Treatment guidelines are shifting toward universal doxycycline use, and clinical practice now faces the challenge of implementation.

BackgroundThe Glanville fritillary (Melitaea cinxia) butterfly is a model system for metapopulation dynamics research in fragmented landscapes. Here, we provide a chromosome-level assembly of the butterfly's genome produced from Pacific Biosciences sequencing of a pool of males, combined with a linkage map from population crosses.ResultsThe final assembly size of 484 Mb is an increase of 94 Mb on the previously published genome. Estimation of the completeness of the genome with BUSCO indicates that the genome contains 92–94% of the BUSCO genes in complete and single copies. We predicted 14,810 genes using the MAKER pipeline and manually curated 1,232 of these gene models.ConclusionsThe genome and its annotated gene models are a valuable resource for future comparative genomics, molecular biology, transcriptome, and genetics studies on this species.

The accumulation of β-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and β-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ± 7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating β-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and β-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p0.05) between local β-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex β-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of β-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of β-amyloid, iron and other causes of altered magnetic susceptibility.

PURPOSE: To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model. METHODS: Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness. RESULTS: Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels. CONCLUSIONS: These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME. ispartof: Investigative Ophthalmology & Visual Science vol:62 issue:13 pages:1-13 ispartof: location:United States status: published

Kaposi sarcoma is an vascular neoplasm caused by infection with human herpesvirus-8. Known risk groups are Mediterranean, eastern European Jewish and African ancestry men or men with AIDS. Nowadays we distinguish more subgroups.We present a healthy 39 year old man with a lesion on the right foot, having homosexual contacts, without HIV infection. Previous histology revealed signs of hemangioma. Recent clinical signs and histology confirmed multifocal Kaposi sarcoma. He was treated with radiotherapy. We also present a 65 year old MSM with and a lesion on the sole of the foot. Histology revealed for a solitary nodular Kaposi sarcoma. A short term relapse after surgical excision occurred.Kaposi sarcoma is subdivided into different categories. Kaposi Sarcoma in HIV-negative MSM is seen more frequently today, yet usually shows an indolent course. An adjusted less aggressive treatment and follow-up is therefore justified.

Author(s): van der Markt, Afra; Klumpers, Ursula MH; Dols, Annemiek; Draisma, Stasja; Boks, Marco P; van Bergen, Annet; Ophoff, Roel A; Beekman, Aartjan TF; Kupka, Ralph W | Abstract: ObjectiveTo assess the clinical utility of two staging models for bipolar disorder by examining distribution, correlation, and the relationship to external criteria. These are primarily defined by the recurrence of mood episodes (model A), or by intra-episodic functioning (model B).MethodsIn the Dutch Bipolar Cohort, stages according to models A and B were assigned to all patients with bipolar-I-disorder (BD-I; N = 1396). The dispersion of subjects over the stages was assessed and the association between the two models calculated. For both models, change in several clinical markers were concordant with the stage was investigated.ResultsStaging was possible in 87% of subjects for model A and 75% for model B. For model A, 1079 participants (93%) were assigned to stage 3c (recurrent episodes). Subdividing stage 3c with cut-offs at 5 and 10 episodes resulted in subgroups containing 242, 510, and 327 subjects. For model B, most participants were assigned to stage II (intra-episodic symptoms, N = 431 (41%)) or stage III (inability to work, N = 451 (43%)). A low association between models was found. For both models, the clinical markers "age at onset," "treatment resistance," and "episode acceleration" changed concordant with the stages.ConclusionThe majority of patients with BD-I clustered in recurrent stage 3 of Model A. Model B showed a larger dispersion. The stepwise change in several clinical markers supports the construct validity of both models. Combining the two staging models and sub-differentiating the recurrent stage into categories with cut-offs at 5 and 10 lifetime episodes improves the clinical utility of staging for individual patients.

The use of juvenile conventional pigs as a preclinical animal model to perform pharmacokinetic (PK), pharmacodynamic (PD) and safety studies for the paediatric population is increasing. Repetitive oral administration of drugs to juvenile pigs is however challenging. A representative method which can be used from birth till adulthood is necessary. The current study presents the placement and use of a gastrostomy button in pigs with a weight ranging from 2.4 to 161 kg. The surgical placement was performed via a laparotomic procedure on, each time, 12 pigs (six male, six female) of 1 week, 4 weeks, 8 weeks and 6–7 months old. For every age category, eight pigs were part of a PK study with a non-steroidal anti-inflammatory drug (NSAID) and four pigs served as a control group. No severe complications were observed during surgery. The button remained functional for 10 days in 40 out of 48 pigs. No significant differences in body temperature or white blood cell count were observed during the trial. Three control pigs showed signs of inflammation indicating a NSAID might be warranted. Autopsy revealed minimal signs of major inflammation in the abdominal cavity or the stomach. A limited number of pigs showed mucosal inflammation, ulcers or abscesses in the stomach or around the fistula. These results indicate that the laparotomic placement of a gastrostomy button might be considered safe and easy in growing pigs to perform repetitive oral dosing preclinical studies. However, the method is not advised in pigs weighing more than 100 kg.

Objectives In the Netherlands, general practitioners (GPs) perform two-thirds of sexually transmitted infection (STI) consultations and diagnose one-third of HIV infections. GPs are, therefore, a key group to target to improve provider-initiated HIV testing. We describe the design and implementation of an educational intervention to improve HIV testing by Amsterdam GPs and explore trends in GPs’ testing behaviour. Methods Interactive sessions on HIV and STI using graphical audit and feedback started in 2015. Participating GPs developed improvement plans that were evaluated in follow-up sessions. Laboratory data on STI testing by Amsterdam GPs from 2011 to 2017 were collected for graphical audit and feedback and effect evaluation. The primary outcome was the HIV testing rate: number of HIV tests per 10 000 person-years (PY). Secondary endpoints were chlamydia and gonorrhoea testing rates and HIV positivity ratios. Results Since 2015, 41% of GPs participated. HIV testing rate declined from 2011 to 2014 (from 175 to 116 per 10 000 PY), more in women than men (176 to 101 versus 173 to 132), and stabilized from 2015 to 2017. The HIV positivity ratio declined from 0.8% in 2011 to 0.5% in 2017. From 2011 to 2017, chlamydia and gonorrhoea testing rates declined in women (from 618 to 477 per 10 000 PY) but remained stable in men (from 270 to 278). Conclusions The stabilization of the downward trend in HIV testing coincided with this educational intervention. Follow-up data are needed to formally assess the intervention’s impact on GP testing behaviour whilst considering contextual factors and secular trends.

Background Population segmentation and risk stratification are important strategies for allocating resources in public health, health care and social care. Social exclusion, which is defined as the cumulation of disadvantages in social, economic, cultural and political domains, is associated with an increased risk of health problems, low agency, and as a consequence, a higher need for health and social care. The aim of this study is to test social exclusion against traditional social stratifiers to identify high-risk/high-need population segments. Methods We used data from 33,285 adults from the 2016 Public Health Monitor of four major cities in the Netherlands. To identify at-risk populations for cardiovascular risk, cancer, low self-rated health, anxiety and depression symptoms, and low personal control, we compared relative risks (RR) and population attributable fractions (PAF) for social exclusion, which was measured with the Social Exclusion Index for Health Surveys (SEI-HS), and four traditional social stratifiers, namely, education, income, labour market position and migration background. Results The analyses showed significant associations of social exclusion with all the health indicators and personal control. Particular strong RRs were found for anxiety and depression symptoms (7.95) and low personal control (6.36), with corresponding PAFs of 42 and 35%, respectively. Social exclusion was significantly better at identifying population segments with high anxiety and depression symptoms and low personal control than were the four traditional stratifiers, while the two approaches were similar at identifying other health problems. The combination of social exclusion with a low labour market position (19.5% of the adult population) captured 67% of the prevalence of anxiety and depression symptoms and 60% of the prevalence of low personal control, as well as substantial proportions of the other health indicators. Conclusions This study shows that the SEI-HS is a powerful tool for identifying high-risk/high-need population segments in which not only ill health is concentrated, as is the case with traditional social stratifiers, but also a high prevalence of anxiety and depression symptoms and low personal control are present, in addition to an accumulation of social problems. These findings have implications for health care practice, public health and social interventions in large cities.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

The trend toward large-scale collaborative studies gives rise to the challenge of combining data from different sources efficiently. Here, we demonstrate how Bayesian evidence synthesis can be used to quantify and compare support for competing hypotheses and to aggregate this support over studies. We applied this method to study the ordering of multi-informant scores on the ASEBA Self Control Scale (ASCS), employing a multi-cohort design with data from four Dutch cohorts. Self-control reports were collected from mothers, fathers, teachers and children themselves. The available set of reporters differed between cohorts, so in each cohort varying components of the overarching hypotheses were evaluated. We found consistent support for the partial hypothesis that parents reported more self-control problems than teachers. Furthermore, the aggregated results indicate most support for the combined hypothesis that children report most problem behaviors, followed by their mothers and fathers, and that teachers report the fewest problems. However, there was considerable inconsistency across cohorts regarding the rank order of children’s reports. This article illustrates Bayesian evidence synthesis as a method when some of the cohorts only have data to evaluate a partial hypothesis. With Bayesian evidence synthesis, these cohorts can still contribute to the aggregated results.

The progressive and sight-threatening disease, age-related macular degeneration (AMD), is a growing public health concern due to ageing demographics, with the highest unmet medical need for the advanced stage of dry AMD, geographic atrophy. The pathogenesis underlying AMD is driven by a complex interplay of genetic and environmental factors. There is ample evidence that inflammation is strongly involved in AMD development. Interleukin-33 (IL-33) has been proposed to be critically involved in retinal degeneration, but a protective role in eye pathophysiology was also demonstrated. The current study investigated the therapeutic potential of IL-33trap, a novel IL-33-neutralizing biologic, in dry AMD/geographic atrophy and, based on controversial data regarding the protective versus detrimental functions of IL-33 in neovascularization, evaluated the risk of progression to wet AMD by IL-33 neutralization. Repeated intravitreal (IVT) injections of IL-33trap in the mouse laser-induced choroidal neovascularization model did not exacerbate neovascularization or leakage, while it significantly inhibited inflammatory cell infiltration in the retinal pigment epithelium and choroid. On the contrary, IVT treatment with IL-33trap significantly induced retinal inflammation and could not prevent retinopathy induction in the mouse sodium iodate (NaIO3) model. Overall, these data suggest a complex and dichotomous role of IL-33 in eye pathology and indicate that IL-33 neutralization is not able to prevent onset and progression of dry AMD pathogenesis.

A genomic locus 8 kb downstream of the transcription factor GFI1B (Growth Factor Independence 1B) predisposes to clonal hematopoiesis and myeloproliferative neoplasms. One of the most significantly associated polymorphisms in this region is rs621940-G. GFI1B auto-represses GFI1B, and altered GFI1B expression contributes to myeloid neoplasms. We studied whether rs621940-G affects GFI1B expression and growth of immature cells. GFI1B ChIP-seq showed clear binding to the rs621940 locus. Preferential binding of various hematopoietic transcription factors to either the rs621940-C or -G allele was observed, but GFI1B showed no preference. In gene reporter assays the rs621940 region inhibited GFI1B promoter activity with the G-allele having less suppressive effects compared to the C-allele. However, CRISPR-Cas9 mediated deletion of the locus in K562 cells did not alter GFI1B expression nor auto-repression. In healthy peripheral blood mononuclear cells GFI1B expression did not differ consistently between the rs621940 alleles. Long range and targeted deep sequencing did not detect consistent effects of rs621940-G on allelic GFI1B expression either. Finally, we observed that myeloid colony formation was not significantly affected by either rs621940 allele in 193 healthy donors. Together, these findings show no evidence that rs621940 or its locus affect GFI1B expression, auto-repression or growth of immature myeloid cells.

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons, and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.

The capability to adapt to changing conditions is crucial for safe and successful performance in physical activities and sports. According to the affordance-based control perspective, individuals act in such a way as to take into account the limits of their capability to act. However, it is not clear how strength interacts with skill in shaping performer-environment interactions. We, therefore, determined whether fingertip strength influences patterns of gaze and climbing behavior on new routes of ever-increasing difficulty. We expected that comparatively weaker climbers would show less complex behavior because of an inability to perceive and act. Stronger climbers would show more complex visuo-motor behavior because more opportunities for action remain, even as route difficulty increases. For very strong climbers the route would not be challenging enough, and less complex patterns suffice. Twenty climbers, ranging from lower grade to elite level participated. Maximum fingertip strength was obtained. Participants previewed and then climbed two separate 3 m long traverses, gradually decreasing in edge depth. Gaze and hip positions were collected for subsequent computation of gaze transition entropy (during preview) and hip displacement entropy (during climbing). Data revealed statistically significant curvilinear relationships between both fingertip strength and gaze transition entropy, and fingertip strength, and hip displacement entropy. Visuo-motor complexity is scaled by how close the individual must act relative to boundaries of what the environment affords and does not afford for action given the individual constraints. Future research should examine in greater detail relationships between action capabilities and functional movement variability.

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival., Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA Sarrah, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.

ObjectivesThere is limited insight into gender differences in suicide-related communication (SRC) in youths. SRC is defined as“the act of conveying one’s own suicide ideation,intent or behaviours to another person”. Increasing our understanding of SRC in youths will enable us to recognize and specify needs of female versus male youths. The current study explores SRC in a sample of Dutch suicide victims aged under 20 and examines gender differences.MethodsInterview data from a psychological autopsy study of 35 youths who died by suicide in the Netherlands in 2017 were analysed. Qualitative analyses were performed to examineexplicitSRC throughout the youths’ lives andimplicitSRC during the last months prior to suicide. We employed the Constant Comparative Method to explore patterns in the debut, form, frequency, medium, content, type of recipient, and SRC in the last months prior to suicide death.ResultsWe identified commonalities in the SRC of youths, including the content of suicide notes and an emphasis on suicide method and preparation in the last months. Girls, however, had an earlier debut of SRC, a higher frequency ofexplicitSRC, and more often directed SRC towards varied types of recipients compared to boys. Moreover, SRC of girls seemed focused on coping and achieving support from others more than SRC of boys. The SRC of boys in comparison to girls was often ambiguous or diluted by “humorous” connotations.ConclusionUnique patterns in SRC of boys and girls posed corresponding challenges for next of kin to interpret communications and respond adequately to SRC. The early debut of girls’ SRC highlights the importance of early screening and prevention efforts in girls, while the late debut and ambiguity in boys’ SRC implores professionals and next of kin to encourage young males to be unequivocal about suicide ideation or intent.

Contains fulltext : 222224.pdf (Publisher’s version ) (Open Access) Objectives: In the Netherlands, there was a sharp increase in the number of suicides among 10- to 19-year-olds in 2017. A multi-method psychological autopsy study (PA) was conducted to assess feasibility, identify related factors, and study the interplay of these factors to inform suicide prevention strategies. Methods: Coroners identified youth suicides in 2017 in their records and then general practitioners (GPs) contacted the parents of these youths. Over a period of 7 months, 66 qualitative interviews were held with the parents, peers, and teachers, providing information on precipitating factors and five topics involving 35 cases (17 boys and 18 girls, mean age 17 years). Furthermore, 43 parents and care professionals filled in questionnaires to examine risk and care-related factors. Qualitative and quantitative analyses were performed. Results: Although registration problems faced by coroners and resistance to contacting bereaved families by GPs hampered the recruitment, most parents highly appreciated being interviewed. Several adverse childhood experiences played a role at an individual level, such as (cyber) bullying, parental divorce, sexual abuse, as well as complex mental disorders, and previous suicide attempts. Two specific patterns stood out: (1) girls characterized by insecurity and a perfectionist attitude, who developed psychopathology and dropped out of school, and (2) boys with a developmental disorder, such as autism, who were transferred to special needs education and therefore felt rejected. In addition, adolescents with complex problems had difficulty finding appropriate formal care. Regarding potential new trends, contagion effects of social media use in a clinical setting and internet use for searching lethal methods were found. Conclusion: This first national PA study showed that, as expected, a variety of mostly complex clusters of problems played a role in youth suicides. An infrastructure is needed to continuously monitor, evaluate, and support families after each youth suicide and thereby improve prevention strategies. 19 p.

Background Research has shown a higher prevalence of individuals lying dead unnoticed in their homes (domestic-setting corpses) in Amsterdam, compared to adjacent less urbanized cities and villages. Objective To determine if there is a difference in incidence of domestic-setting corpses in the four major cities in the Netherlands and identifying demographic patterns accounting for possible differences. Methods Data of domestic-setting corpses with a post mortem interval of at least 14 days were extracted from forensic registrations of the four largest cities in the Netherlands. These data were analysed using Poisson-regression and compared to numbers of Statistics Netherlands to calculate the incidence rate of domestic-setting corpses. Only single households were included. Results The incidence of DSC14 is not significantly different between Amsterdam, The Hague and Rotterdam. The incidence rate of DSC in these cities is almost twice as high compared to Utrecht (corrected for age and sex 1,9; 95% CI:1,1–3,0). Conclusion: The incidence rate of DSC14 is comparable in the three largest cities of the Netherlands, and significantly higher compared to the smallest of the four (Utrecht). Possibly the lower number in Utrecht is related to less loneliness, a higher social participation and a difference in architecture.

Patients with severe developmental delay, dysmorphism, and brain abnormalities were identified as having pathogenic mutations in EXOC2, a critical component of the exocyst complex involved in vesicle trafficking, which caused secretory vesicle transport defects in patient-derived cell lines., The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected individuals have severe developmental delay, dysmorphism, and brain abnormalities; variability associated with epilepsy; and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.

Background: The Disabilities of the Arm, Shoulder and Hand (DASH) instrument was developed to assess the disability experienced by patients with any musculoskeletal condition of the upper extremity and to monitor change in symptoms and upper-limb function over time. The 30 items are scored on a 5-point rating scale. The Dutch-language version of the DASH instrument (DASH-DLV) has been examined with the classical test theory in patients with a humeral shaft fracture. This study aimed to examine the DASH-DLV with a more rigorous and extensive analysis by applying the Rasch model. Methods: Data of 400 patients included in a multicenter, prospective study comparing operative and nonoperative treatment of adult patients with a humeral shaft fracture were used. The person-item map, item fit statistics, reliability, response category ordering, and dimensionality were examined. Raw data were converted to linear measures using the Rasch model. Results: The DASH-DLV showed a good fit to the Rasch model, except for item 26 (“Tingling [pins and needles] in your arm, shoulder or hand”). The person reliability was 0.92. In general, the category functioning of the 5-point rating scale was working well. Dimensionality analysis revealed that the DASH-DLV is a unidimensional scale. Differential item functioning for sex was not detected, and only item 26 exhibited differential item functioning as a function for age. Conclusion: The DASH-DLV fits the stringent Rasch model in a clinical situation with a group of adult patients with a humeral shaft fracture. Adequate measurement for scientific research can be obtained to evaluate longitudinal intervention research.

Development can bias the independent evolution of traits sharing ontogenetic pathways, making certain evolutionary changes less likely. The eyespots commonly found on butterfly wings each have concentric rings of differing colors and these serially repeated pattern elements have been a focus for evo-devo research. In the butterfly family Nymphalidae, eyespots have been shown to function in startling or deflecting predators, and to be involved in sexual selection. Previous work on a model species of Mycalesina butterfly,Bicyclus anynana, has provided insights into the developmental control of the size and color composition of individual eyespots. Experimental evolution has also shown that the relative size of a pair of eyespots on the same wing surface is highly flexible, whereas they are resistant to diverging in color-composition, presumably due to the underlying shared developmental process. This fixed color-composition has been considered as a prime example of developmental bias with significant consequences for wing pattern evolution. Here we test this proposal by surveying eyespots across the whole subtribe of Mycalesina butterflies and demonstrate that developmental bias shapes evolutionary diversification, except in the genusHeteropsiswhich has gained independent control of eyespot color-composition. Experimental manipulations of pupal wings reveal that the bias has been released through a novel regional response of the wing tissue to a conserved patterning signal. Our study demonstrates that development can bias the evolutionary independence of traits, but it also shows how bias can be released through developmental innovations, thus allowing rapid morphological change, facilitating evolutionary diversification.

ObjectiveIn the Netherlands, the Gonococcal Resistance to Antimicrobials Surveillance (GRAS) programme is carried out at Centres for Sexual Health (CSH), which provide care for sexual high-risk populations. However, half of gonorrhoea infections are diagnosed in general practice (GP). We performed a pilot study to explore expanding GRAS to GPs using laboratory-based surveillance. Additionally, antimicrobial resistance patterns of GP and CSH patients were compared.MethodsThree laboratories from different regions were included, which all perform gonorrhoea diagnostics for GPs and used ESwab for patient sampling. Additional culturing for all GP patients with gonorrhoea took place from February to July 2018. After positive PCR-nucleic acid amplification test, residual ESwab material was used for culture. In positive cultures, susceptibility testing was performed for azithromycin, ciprofloxacin, cefotaxime and ceftriaxone using Etest.ResultsDuring the study period, 484 samples were put in culture. 16.5% of cultures were positive (n=80). Antimicrobial resistance levels were low, with 2.6% resistance to azithromycin, 21.5% to ciprofloxacin and 0.0% to cefotaxime and ceftriaxone. Resistance levels in CSH GRAS data (first half of 2018) were 19.2% for azithromycin, 31.5% for ciprofloxacin, 1.9% for cefotaxime and 0.0% for ceftriaxone.ConclusionsCulture positivity rates for GP patients were low, probably due to long transportation times and awaiting PCR test results before attempting culture. Positivity rates might be improved by making changes in sampling and/or transportation methods, but that would require involvement of GPs and patients instead of keeping the surveillance lab based. Resistance levels appeared to be lower at GPs than at the CSH, indicating that resistance might emerge first in more high-risk populations. It is important to consider all potentially relevant patient populations when establishing a gonococcal antimicrobial resistance surveillance programme. However, based on the findings from this study the current GRAS programme will not be extended to GPs.

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

This study compared the effects of mother-child reminiscing coaching on mothers of typically developing children (community sample) and mothers of children with conduct problems (clinical sample). It also tested whether intervention effects generalize to mothers' preferences for elaborative and mental-state oriented talk with their children in other contexts. Mother-child dyads (n = 88) in each sample were randomly allocated to condition: reminiscing intervention or active control. Pre-intervention, sample differences emerged. Mothers in the community sample were more elaborative during reminiscing than mothers in the clinical sample, and also expressed stronger preferences for elaborative talk in everyday contexts. Post-intervention, an intervention effect emerged. In both the community and clinical samples, mothers who had participated in the elaborative reminiscing intervention were more elaborative and emotion-focused during reminiscing than mothers in the active control condition. They also increased their preferences for elaborative and mental-state-oriented language in everyday contexts. While the mothers in the community sample remained more elaborative than mothers in the clinical sample, both experienced equivalent intervention gains. These findings highlight the value of reminiscing coaching for changing mothers’ interactional preferences and behaviours.

Spatial communication tasks, such as following route directions through unfamiliar environments, place considerable demands on multiple cognitive processes, including language comprehension and memory. Gestures accompanying spoken route directions may aide task performance by enhancing cognitive processes such as language and memory processing. It is not yet clear whether different kinds of gesture might influence the processing of route information in different ways. In 2 experiments, we examined how different gestures would enhance or reduce listeners' recall of spatial information when given route directions through an unfamiliar building. Adults were randomly allocated to one of three gesture conditions: no gesture (speech only), beat gesture (speech accompanied by simple rhythmic gestures), or iconic-deictic gesture (speech accompanied by iconic and deictic gestures). Recall was measured verbally, by recalling the route aloud, then physically, by walking the route. In Experiment 1, redundant gestures that mirrored verbal route directions did not enhance listeners' verbal recall or route navigation. In Experiment 2, when the verbal route directions were edited to be incomplete, nonredundant gestures enhanced recall to the level seen when hearing all information through speech. These findings suggest that gestures enhance recall when compensating for missing verbal information, but not when they replicate verbal information. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Item does not contain fulltext Brain decoding algorithms form an important part of the arsenal of analysis tools available to neuroscientists, allowing for a more detailed study of the kind of information represented in patterns of cortical activity. While most current decoding algorithms focus on estimating a single, most likely stimulus from the pattern of noisy fMRI responses, the presence of noise causes this estimate to be uncertain. This uncertainty in stimulus estimates is a potentially highly relevant aspect of cortical stimulus processing, and features prominently in Bayesian or probabilistic models of neural coding. Here, we focus on sensory uncertainty and how best to extract this information with fMRI. We first demonstrate in simulations that decoding algorithms that take into account correlated noise between fMRI voxels better recover the amount of uncertainty (quantified as the width of a probability distribution over possible stimuli) associated with the decoded estimate. Furthermore, we show that not all correlated variability should be treated equally, as modeling tuning-dependent correlations has the greatest impact on decoding performance. Next, we examine actual noise correlations in human visual cortex, and find that shared variability in areas V1-V3 depends on the tuning properties of fMRI voxels. In line with our simulations, accounting for this shared noise between similarly tuned voxels produces important benefits in decoding. Our findings underscore the importance of accurate noise models in fMRI decoding approaches, and suggest a statistically feasible method to incorporate the most relevant forms of shared noise. 10 p.

Despite evidence suggesting that parent involvement was beneficial for infant and parent outcomes, the Family Integrated Care (FICare) programme was one of the first pragmatic approaches to enable parents to become primary caregivers in the neonatal intensive care unit (NICU). We aimed to analyse the effect of FICare on infant and parent outcomes, safety, and resource use.In this multicentre, cluster-randomised controlled trial, we stratified 26 tertiary NICUs from Canada, Australia, and New Zealand by country and size, and assigned them, using a computer-generated random allocation sequence, to provide FICare or standard NICU care. Eligible infants were born at 33 weeks' gestation or earlier, and had no or low-level respiratory support; parents gave written informed consent for enrolment. To be eligible, parents in the FICare group had to commit to be present for at least 6 h a day, attend educational sessions, and actively care for their infant. The primary outcome, analysed at the individual level, was infant weight gain at day 21 after enrolment. Secondary outcomes were weight gain velocity, high frequency breastfeeding (≥6 times a day) at hospital discharge, parental stress and anxiety at enrolment and day 21, NICU mortality and major neonatal morbidities, safety, and resource use (including duration of oxygen therapy and hospital stay). This trial is registered with ClinicalTrials.gov, number NCT01852695.From Oct 1, 2012, 26 sites were randomly assigned to provide FICare (n=14) or standard care (n=12). One site assigned to FICare discontinued because of poor site enrolment. Parents and infants were enrolled between April 1, 2013, and Aug 31, 2015, with 895 infants being eligible in the FICare group and 891 in the standard care group. At day 21, weight gain was greater in the FICare group than in the standard care group (mean change in Z scores -0·071 [SD 0·42] vs -0·155 [0·42]; p0·0002). Average daily weight gain was significantly higher in infants receiving FICare than those receiving standard care (mean daily weight gain 26·7 g [SD 9·4] vs 24·8 g [9·5]; p0·0001). The high-frequency exclusive breastmilk feeding rate at discharge was higher for infants in the FICare group (279 [70%] of 396) than those in the standard care group (394 [63%] of 624; p=0·016). At day 21, parents in the FICare group had lower mean stress scores than did parents in the standard care group (2·3 [SD 0·8] vs 2·5 [0·8]; p0·00043), and lower mean anxiety scores (70·8 [20·1] vs 74·2 [19·9]; p=0·0045). There were no significant differences between groups in the rates of the secondary outcomes of mortality, major morbidity, duration of oxygen therapy, and duration of hospital stay. Although the safety assessment was not completed, there were no adverse events.FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care. Further research is required to examine if these results translate into better long-term outcomes for families.Canadian Institutes of Health Research Partnerships for Health System Improvement, and Ontario Ministry of Health and Long-Term Care.

To perform prospective memory (PM) tasks in day-to-day life, we often enlist the help of others. Yet the effects of collaboration on PM are largely unknown. Adopting the methodology of the "collaborative recall paradigm", we tested whether stranger dyads (Experiment 1) and intimate couples (Experiment 2) would perform better on a "Virtual Week" task when working together or each working separately. In Experiment 1, we found evidence of collaborative inhibition: collaborating strangers did not perform to their pooled individual potential, although the effect was modulated by PM task difficulty. We also found that the overall collaborative inhibition effect was attributable to both the retrospective and prospective components of PM. In Experiment 2 however, there was no collaborative inhibition: there was no significant difference in performance between couples working together or separately. Our findings suggest potential costs of collaboration to PM. Intimate relationships may reduce the usual costs of collaboration, with implications for intervention training programmes and for populations who most need PM support.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.FUNDING: Bayer AG.

In a digital orientating survey of gender differences among 156 male and 98 female dentists in the Netherlands, many similarities were found between the two groups. Men and women generally report that they are in good health, experience comparable levels of burnout (about 10%) and are equally satisfied with their choice of profession. To a large extent, they perceive the same aspects of their work as attractive, with 'patient care' as by far the most attractive feature. According to the dentists as well as 122 assistants and dental hygienists (who were also questioned in this survey), they have comparable leadership styles, while the dentists, on average, rate their leadership behaviour more highly than the assistants and dental hygienists do. In addition, a limited number of significant gender differences were found in the sample. Women feel less competent in conducting complex interventions than men, and they find surgical interventions and complex restorative treatments less attractive aspects of their work. Women consult colleagues more often and their preference for working in a team is greater.In een verkennend onderzoek, door middel van digitale enquête, naar sekseverschillen onder 156 mannelijke en 98 vrouwelijke tandartsen in Nederland werden veel overeenkomsten tussen beide groepen gevonden. Mannen en vrouwen rapporteerden over het algemeen een goede gezondheid, gelijke percentages voor burn-out (circa 10%) en tevredenheid met hun beroepskeuze. Voor een groot deel ervaarden ze dezelfde onderdelen van hun werk als aantrekkelijk, waarbij de omgang met patiënten verreweg het hoogste scoorde. Ook gaven zij, zowel volgens zichzelf als volgens 122 assistenten en mondhygiënisten (die hierop in dit onderzoek ook werden bevraagd), op een vergelijkbare manier leiding en schatten hun leiderschapsgedrag gemiddeld hoger in dan assistenten en mondhygiënisten deden. Daarnaast was er een beperkt aantal binnen de steekproef significante sekseverschillen gevonden. Vrouwen voelden zich minder competent bij complexe ingrepen dan mannen en vonden chirurgische ingrepen en complexe restauratieve behandelingen minder aantrekkelijk. Zij consulteerden vaker collega’s en hun voorkeur voor werken in teamverband was groter.