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Abstract Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21+ cells, augmented expression of angiogenic markers, and a concomitant increase in the number of brain ECs and pericytes. Moreover, EC-KO mice displayed BBB leakage and enhanced cell adhesion molecule expression accompanied by peripheral immune cell infiltration into the brain. These findings were confined to the white matter, suggesting a regional susceptibility. Collectively, our results underline the role of endothelial aging as a driver of impaired BBB function, endothelial sprouting, and increased immune cell migration into the brain, thereby contributing to impaired brain homeostasis as observed during the aging process.

AimThe primary aim was to assess the efficacy of self-paced sprint interval training (SIT) with low-volume high-intensity interval training (LV-HIIT) when performed without encouragement on improving cardiorespiratory fitness (CRF). A secondary aim was to explore whether the effort exerted during protocols [power output (PO) and heart rate (HR)] influenced the change in CRF.MethodsIn a randomised cross-over design, 82 previously inactive adults (m/f: 26/56, 28 ± 10 years, BMI 25 ± 3 kg m−2) undertook 6-weeks of self-paced SIT (4–8 × 30 s with 120 s recovery) or LV-HIIT (6–10 × 1 min with 1 min recovery) separated by a 4-week washout period. Sessions were completed 3×/week using WattBikes, and a target of >80% HRmax was suggested during the intervals. Markers of cardio-metabolic health were assessed before and after each intervention.ResultsTraining increased VO2peak (SIT +3.1 ± 0.4 mL kg−1 min−1, LV-HIIT +2.7 ± 1.2 mL kg−1 min−1, P < 0.001) and decreased body fat % (P = 0.002), aortic pulse wave velocity (P = 0.002) and glucose tolerance 120 min following an oral glucose tolerance test (P = 0.024), with no difference between protocols (P > 0.05). When grouping participants into tertiles based on HR and PO responses (n = 27), those achieving a low HR had similar changes in VO2peak compared to the high HR group in both interventions (P > 0.05). For LV-HIIT, participants in the highest tertile for peak PO had a greater change in VO2peak compared to all other participants (Low 1.8 ± 4.1 mL kg−1 min−1, Medium 1.9 ± 3.3 mL kg−1 min−1, High 4.3 ± 3.6 ml kg−1 min−1, P = 0.020).DiscussionSix-weeks of self-paced SIT and LV-HIIT induce comparable improvements in CRF, body composition, arterial stiffness and glucose tolerance. Importantly, higher HR did not elicit superior changes in CRF, but PO achieved during LV-HIIT may influence improvements.

Abstract Analysis of clonal dynamics in human tissues is enabled by somatic genetic variation. Here, we show that analysis of mitochondrial mutations in single cells is dramatically improved in females when using X chromosome inactivation to select informative clonal mutations. Applying this strategy to human peripheral mononuclear blood cells reveals clonal structures within T cells that otherwise are blurred by non-informative mutations, including the separation of gamma-delta T cells, suggesting this approach can be used to decipher clonal dynamics of cells in human tissues.

Abstract Background Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM. Methods Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM‐derived cell lines. Validation was performed using multiplex immunofluorescence. Results In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF‐α levels. In vitro, MLiM cell lines released TNF‐α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour‐infiltrating lymphocytes. Conclusions MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses. Highlights Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen‐type I levels. Melanoma liver metastases tumour cells secrete enhanced levels of TNF‐α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes. Activation of CXCR4 promotes AKT and NF‐κB signalling pathways to promote collagen‐type I secretion in adjacent normal hepatocytes. Elevated collagen levels were associated with reduced tumour‐infiltrating lymphocytes

Abstract The incidence of sporadic early-onset colon cancer (EOCC) has increased worldwide. The molecular mechanisms in the tumor and the tumor microenvironment (TME) in EOCC are not fully understood. The aim of this study is to unravel unique spatial transcriptomic and proteomic profiles in tumor epithelial cells and cancer-associated fibroblasts (CAFs). Here, we divide the sporadic colon cancer tissue samples with transcriptomic data into patients diagnosed with EOCC (

We present an all-fiber-based laser gas analyzer (LGA) employing quartz-enhanced photoacoustic spectroscopy (QEPAS) and a side-polished fiber (SPF). The LGA comprises a custom quartz tuning fork (QTF) with 0.8 mm prong spacing, two acoustic micro-resonators (mR) located on either side of the prong spacing, and a single-mode fiber containing a 17 mm polished section passing through both mRs and QTF. The SPF polished face is positioned to enable the evanescent wave (EW) to create a photoacoustic wave and excite the fundamental flexural mode of the QTF. Sensor performance was demonstrated using methane in nitrogen gas mixtures, with CH4 mixing ratios ranging from 75 ppmv to 1% (by volume), measured with an accumulation time of 300 ms, and a minimum detection limit of 34 ppmv subsequently determined. The EW-QEPAS sensor is ideal for miniaturization, as it does not contain any free-space optics and is suitable for gas sensing in harsh environments and where mobility is required.

ObjectiveIn 2016, the SUicide PRevention Action NETwork (SUPRANET) was launched. The SUPRANET intervention aims at better implementing the suicide prevention guideline. An implementation study was developed to evaluate the impact of SUPRANET over time on three outcomes: 1) suicides, 2) registration of suicide attempts, and 3) professionals’ knowledge and adherence to the guideline.MethodsThis study included 13 institutions, and used an uncontrolled longitudinal prospective design, collecting biannual data on a 2-level structure (institutional and team level). Suicides and suicide attempts were extracted from data systems. Professionals’ knowledge and adherence were measured using a self-report questionnaire. A three-step interrupted time series analysis (ITSA) was performed for the first two outcomes. Step 1 assessed whether institutions executed the SUPRANET intervention as intended. Step 2 examined if institutions complied with the four guideline recommendations. Based on steps 1 and 2, institutions were classified as below or above average and after that, included as moderators in step 3 to examine the effect of SUPRANET over time compared to the baseline. The third outcome was analyzed with a longitudinal multilevel regression analysis, and tested for moderation.ResultsAfter institutions were labeled based on their efforts and investments made (below average vs above average), we found no statistically significant difference in suicides (standardized mortality ratio) between the two groups relative to the baseline. Institutions labeled as above average did register significantly more suicide attempts directly after the start of the intervention (78.8 per 100,000 patients, p

At the beginning of the COVID-19 pandemic, diagnostic testing was not accessible for mildly ill or asymptomatic individuals. Military operational circumstances exclude the usage of reference laboratory tests. For that reason, at the beginning of the pandemic alternative test methods were needed in order to gain insight into the SARS-CoV-2 status of military personnel. The objectives of this study are to assess whether SARS-CoV-2 antibody rapid lateral flow assay (LFA) in combination with semi-autonomous SARS-CoV-2 antisense and sense genomic RNA fluorescence in situ hybridization (FISH) could establish disease status in military personnel in a fieldable setting, and to assess how this combination performed and to determine which type of sample performed best. A proof of concept sub-study regarding the SARS-CoV-2 application of the fieldable Biotrack-MED® FISH analyzer, a semi-autonomous multi-sample filter cytometer, preceded this observational prospective cohort pilot study. Dutch military personnel were included in the 26 June 2020-11 May 2021 period. Blood, nasopharyngeal and oropharyngeal swabs and saliva were tested at days 0 and 14. SPSS version 25 descriptive statistics and Cohen's kappa assessed agreement between test methods. Both the sensitivity and specificity of the field tests were calculated with ELISA and PCR as reference. Saliva appeared to be the preferred sample type for FISH, where blood was not useful. FISH analysis and LFA results had a concordance of 42% for testing negative, 30% for recovered from infection, 22% for ongoing-and 58% for acute infection in a reference laboratory lab result outcome (RT-PCR or ELISA respectively). The LFA results on serum and full blood corresponded with the ELISA-obtained results (kappa of 0.61 and 0.63 respectively at day 0 and 0.81 and 0.77 respectively at day 14). LFA (full blood-serum), FISH and RT-PCR on saliva did not reach the 90% sensitivity level advised by WHO, with 64-54, 38 and 71% at day 0 and 80-79, 53 and 24% at day 14 respectively.

Optimising the timing of food intake relative to exercise may maximise the effectiveness of free-living exercise programmes on improvements in glycaemic control and cardio-metabolic health. This study aimed to assess the feasibility of a free-living, walking-based exercise programme and determine whether undertaking each exercise session before or after breakfast would most benefit longer-term metabolic health. Thirty-four people living with obesity (43±12 y, BMI 35.1±5.1 kg.m-2) undertook a 12-week walking-based programme, consisting of two continuous (30-60 min at 50% HRmax) and two interval exercise sessions per week (30-60 min, alternating 3 min at 85% HRmax and 3 min at 50% HRmax). Participants were allocated to exercise before (FASTED) or after (FED) breakfast (n = 17 per group). Feasibility (acceptability, adherence and compliance) to the exercise intervention were assessed, as well as changes in anthropometric variables, 24-hour continuous glucose monitoring, serum biochemistry including HbA1c, lipid profile and liver transaminases. Exercise adherence (FASTED: 93±4%, FED: 95±5%) and compliance (FASTED: 85±10%, FED: 88±10%) was high in both groups, and participants described exercise monitoring, programme structure and support as facilitators to this. Body mass, BMI, waist-to-hip ratio and HbA1c decreased similarly between groups (all P

Background We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high‐sensitivity cardiac troponin T, N‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long‐term mortality risk. Methods and Results BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high‐frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker‐based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all‐cause death were evaluated using accelerated failure time models (median follow‐up, 9.1 years; 141 deaths). Three biomarker‐based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long‐term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44–0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39–1.32; P=0.281) compared with patients with a repeat ACS. Conclusions Patients with subphenotypes of post‐ACS with different all‐cause mortality risks during long‐term follow‐up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Abstract Background Aims were to examine gender differences in patients with gout with regard to a) self-reported gout severity, b) illness perceptions (IP), c) impact on daily activities and Quality of Life (QoL), d) advice from healthcare professionals, e) having changed dietary- or alcohol habits. Methods Adult patients with gout identified in primary and secondary care in Sweden between 2015 and 2017 (n = 1589) were sent a questionnaire about demographics, gout disease severity, IP (using the Brief Illness Perception Questionnaire, (B-IPQ)) and disease management. T-tests, Chi square tests, ANalysis Of VAriance (ANOVA) and linear regression models were used for gender comparisons. Results Eight hundred sixty-eight patients responded to the questionnaire. Women, n = 177 (20%), experienced more severe gout symptoms (p = 0.011), albeit similar frequencies of flares compared to men. Women experienced modest but significantly worse IP with regard to consequences, identity, concerns and emotional response (p

Astrocytes and microglia play important roles in organizing the structure and function of neuronal networks in the central nervous system (CNS). The dorsal diencephalic connection system (DDCS) is a phylogenetically ancient regulatory system by which the forebrain influences the activity of cholinergic and ascending monoaminergic pathways in the midbrain. The DDCS is probably important in inducing aspects of mental disorders, such as depression and addiction. The habenula is the small but highly complex connecting center of the DDCS in the epithalamus that consists of a medial (MHb) and lateral (LHb) division. MHb and LHb are built differently and connect different brain structures. Studies in animal models and human biomarker research provide good evidence that astroglia and microglia also affect the symptoms of mental disorders (such as depression). The significance of these neuroglia in habenular neurotransmission has not been extensively studied. This review article provides arguments for doing so more thoroughly.

Dropout from psychological or pharmacological treatment for anxiety and depressive disorders is common. It is especially problematic in adolescents and young adults because of the adverse consequences for their development. Reasons for treatment dropout can be divided into therapy-process related factors, attitudinal aspects, and practical issues. Adjusting treatment to patient preferences and shared decision making, improving the therapeutic alliance, and interventions such as (family) psychoeducation, motivational interviewing, and help with practical issues are promising strategies to optimize engagement and adherence.

ObjectivePatients with obsessive-compulsive disorder (OCD) and poor insight show higher symptom severity, lower quality of life (QoL), and a reduced treatment response compared to patients with good insight. Little is known about changes in insight. This study explored the course of insight and its association with OCD severity and QoL among 253 patients with OCD participating in the prospective naturalistic Netherlands Obsessive Compulsive Disorder Association (NOCDA) Study.ResultsIn 70% of the participants with available insight data, the level of insight changed during the four-year course. Insight was most variable in participants with poor insight. Improvement of insight scores was statistically significantly associated with improvement of Y-BOCS scores (r = 0.19), but not with changes in QoL scores. Change in insight in the first 2 years was not statistically significantly predictive of OCD severity or QoL at four-year follow-up.ConclusionThese findings suggest that patients’ levels of insight may change during the natural four-year course of OCD and that improvement in the level of insight have a positive association with improvement in OCD severity.

Recessive X-linked ichthyosis (RXLI), a genetic disorder caused by deletion or point mutations of the steroid sulfatase (STS) gene, is the second most common form of ichthyosis. It is a disorder of keratinocyte cholesterol sulfate retention and the mechanism of extracutaneous phenotypes such as corneal opacities and attention deficit hyperactivity disorder are poorly understood. To understand the pathomechanisms of RXLI, the transcriptome of differentiated primary keratinocytes with STS knockdown was sequenced. The results were validated in a stable knockdown model of STS, to confirm STS specificity, and in RXLI skin. The results show that there was significantly reduced expression of genes related to epidermal differentiation and lipid metabolism, including ceramide and sphingolipid synthesis. In addition, there was significant downregulation of aldehyde dehydrogenase family members and the oxytocin receptor which have been linked to corneal transparency and behavioural disorders respectively, both of which are extracutaneous phenotypes of RXLI. These data provide a greater understanding of the causative mechanisms of RXLI’s cutaneous phenotype, and show that the keratinocyte transcriptome and lipidomics can give novel insights into the phenotype of patients with RXLI.

In the hydropower sector, the weight of electro-mechanical equipment is an important input data. During the design stage, it allows to estimate material cost, to perform Life Cycle Assessments and to consider adequate load factors on the supporting structures. At the end of the lifetime, in case of dismantling or retrofitting, the estimation of the equipment weight allows to appraise the material value and to plan the operational activities. However, the engineering knowledge is quite fragmented and limited on this topic, and only a few weight equations are available in the literature. In this contribution, the available equations are firstly reviewed and discussed. Secondly, data were collected both from the literature and from hydropower companies, and generalized to provide expeditious equations. The equations presented in this paper allow for a preliminary estimate of the weight of: 1) the runner of Pelton, Kaplan, Bulb, Cross-Flow (Banki type) and Francis turbines, and water wheels; 2) the casing of Pelton and reaction turbines; 3) draft tubes; 4) electric generators. Data on Vortex, Turgo and Hydrokinetic turbines, Archimedes screws and guide vanes are presented. The opportunities associated to innovative and lighter construction materials are discussed.

Abstract Background Previous research on barriers and facilitators regarding treatment-seeking of adults with depressive and anxiety disorders has been primarily conducted in the Anglosphere. This study aims to gain insight into treatment-seeking behaviour of adults with depressive and anxiety disorders in a European healthcare system. Methods In-depth semi-structured interviews were conducted with 24 participants, aged ≥18 years and diagnosed with an anxiety disorder and/or depressive disorder according to DSM-IV. Participants were purposively sampled from an outpatient department for mental health care in the Netherlands. The seven steps of framework analysis were used to identify relevant themes emerging from the interviews. Results Data analysis suggested an interplay between individual aspects, personal social system, healthcare system and sociocultural context influences. Amongst the most relevant themes were mental health illiteracy, stigma, a negative attitude toward professional help, the influence of significant others and general practitioner, and waiting time. Financial barriers were not of relevance. Conclusions Even in a country with a well-developed mental health care system and in absence of financial barriers, there are many barriers to treatment-seeking in adult patients with depressive and anxiety disorders. National campaigns to increase awareness and decrease stigma in the general population, and to empower the social environment might reduce the treatment gap.

Abstract Objectives We describe the harmonized MRI acquisition and quality assessment of an ongoing global OCD study, with the aim to translate representative, well‐powered neuroimaging findings in neuropsychiatric research to worldwide populations. Methods We report on T1‐weighted structural MRI, resting‐state functional MRI, and multi‐shell diffusion‐weighted imaging of 140 healthy participants (28 per site), two traveling controls, and regular phantom scans. Results Human image quality measures (IQMs) and outcome measures showed smaller within‐site variation than between‐site variation. Outcome measures were less variable than IQMs, especially for the traveling controls. Phantom IQMs were stable regarding geometry, SNR, and mean diffusivity, while fMRI fluctuation was more variable between sites. Conclusions Variation in IQMs persists, even for an a priori harmonized data acquisition protocol, but after pre‐processing they have less of an impact on the outcome measures. Continuous monitoring IQMs per site is valuable to detect potential artifacts and outliers. The inclusion of both cases and healthy participants at each site remains mandatory.

The problem of tracking a two-dimensional Cartesian state of a target using polar observations is well known. At a close range, a traditional extended Kalman filter (EKF) can fail owing to nonlinearity introduced by the Cartesian-to-polar transformation in the observation prediction step of the filter. This is a byproduct of the nonlinear transformation acting on the state variables, which make up a bivariate Gaussian distribution. The nonlinear transformation in question is the arctangent of Cartesian state variables $X$ and $Y$ , which corresponds to the target bearing. At long range, the bearing behaves as a wrapped Gaussian random variable, and behaves well for the EKF. At close range, the bearing is shown to be non-Gaussian, converging to the wrapped uniform distribution when $X$ and $Y$ are uncorrelated. This study provides a concise derivation of the probability density function (PDF) for bearing for the EKF observation prediction step and explores the limiting behavior for this distribution while parameterizing the target range.

Nanopore direct RNA Sequencing data contain information about the presence of RNA modifications, but their detection poses substantial challenges. Here the authors introduce Nanocompore, a new methodology for modification detection from Nanopore data.

Background: Weight loss can induce changes in appetite-regulating hormone levels, possibly linked to increases in appetite and weight regain. However, hormonal changes vary across interventions. Here, we studied levels of appetite-regulating hormones during a combined lifestyle intervention (CLI: healthy diet, exercise and cognitive behavioral therapy).Methods: We measured levels of long-term adiposity-related hormones (leptin, insulin, high-molecular-weight (HMW) adiponectin) and short-term appetite hormones (PYY, cholecystokinin, gastric-inhibitory polypeptide, pancreatic polypeptide, FGF21, AgRP) in overnight-fasted serum of 39 patients with obesity. Hormone levels were compared between T0 (baseline), T1 (after 10 weeks) and T2 (end of treatment, 1.5 years). T0-T1 hormone changes were correlated with T1-T2 anthropometric changes.Results: Initial weight loss at T1 was maintained at T2 (−5.0%, p < 0.001), and accompanied by decreased leptin and insulin levels at T1 and T2 (all p < 0.05) compared to T0. Most short-term signals were not affected. Only PP levels were decreased at T2 compared to T0 (p < 0.05). Most changes in hormone levels during initial weight loss did not predict subsequent changes in anthropometrics, except for T0-T1 decreases in FGF21 levels and T0-T1 increases in HMW adiponectin levels tended to be associated with larger T1-T2 increases in BMI (p < 0.05 and p = 0.05, respectively).Conclusion: CLI-induced weight loss was associated with changes in levels of long-term adiposity-related hormones towards healthy levels, but not with orexigenic changes in most short-term appetite signals. Our data indicates that the clinical impact of alterations in appetite-regulating hormones during modest weight loss remains questionable. Future studies should investigate potential associations of weight-loss-induced changes in FGF21 and adiponectin levels with weight regain.

Classical non-homologous end-joining (cNHEJ) is the dominant pathway used by human cells to repair DNA double-strand breaks (DSBs) and maintain genome stability. Here the authors show that PARP1-driven chromatin expansion allows the recruitment of ZNF384, which in turn recruits Ku70/Ku80 to facilitate cNHEJ.

Computer models capable of representing the intrinsic personal electrophysiology (EP) of the heart in silico are termed virtual heart technologies. When anatomy and EP are tailored to individual patients within the model, such technologies are promising clinical and industrial tools. Regardless of their vast potential, few virtual technologies simulating the entire organ-scale EP of all four-chambers of the heart have been reported and widespread clinical use is limited due to high computational costs and difficulty in validation. We thus report on the development of a novel virtual technology representing the electrophysiology of all four-chambers of the heart aiming to overcome these limitations. In our previous work, a model of ventricular EP embedded in a torso was constructed from clinical magnetic resonance image (MRI) data and personalized according to the measured 12 lead electrocardiogram (ECG) of a single subject under normal sinus rhythm. This model is then expanded upon to include whole heart EP and a detailed representation of the His-Purkinje system (HPS). To test the capacities of the personalized virtual heart technology to replicate standard clinical morphological ECG features under such conditions, bundle branch blocks within both the right and the left ventricles under two different conduction velocity settings are modeled alongside sinus rhythm. To ensure clinical viability, model generation was completely automated and simulations were performed using an efficient real-time cardiac EP simulator. Close correspondence between the measured and simulated 12 lead ECG was observed under normal sinus conditions and all simulated bundle branch blocks manifested relevant clinical morphological features.

Introduction: Frozen section (FS) is often performed to confirm negative margins during pancreaticoduodenectomies (PD). This incurs significant cost, despite lack of evidence of survival benefit. We sought to determine the frequency of positive FS during PD, associated costs per positive margin identified, and association with locoregional recurrence (LRR) and overall survival (OS). Methods: A database of 526 PDs performed from 2014 to 2017 at a multi-institution integrated health-care system was queried. Charts and imaging were reviewed for systemic treatment, FS and PM results, pathologic stage, LRR and OS. Direct facility and professional costs for FS were determined from billing data. Cox proportional hazards for LRR and OS were performed. Results: 9.2% of all initial FS were positive. Average cost per FS was $148, with a cost of $1,538 per positive FS identified. Positive FS was not associated with LRR (HR 1.32, 95% CI: 0.50–3.52, p = 0.58) or median OS (25.9 vs 36.2 months, p = 0.38). Conclusion: Routine FS during PD is a low-yield test with significant associated costs. Positive FS was not associated with locoregional recurrence or overall survival. Routine FS does not provide substantial benefit for value-based care when performing PD.

Abstract Vulnerability markers for onset of anxiety disorders are scarce. In depression, patients at risk tend to respond with a negative mood to ‘acute tryptophan depletion’ (ATD), while healthy volunteers and current patients do not. The serotonergic system thus provides indications for vulnerability for depression. It is unknown whether ATD reveals vulnerability in anxiety too. This study systematically reviews the effects of ATD on anxiety and assesses whether challenging anxiety modifies the response. PubMed, Embase and PsychInfo were systematically searched up to April 2019 for studies in which (1) healthy volunteers or patients with a (remitted) anxiety disorder underwent ATD and (2) levels of anxiety were reported. In total, 21 studies were included. Studies conducted in healthy volunteers (n = 13), and patients with a remitted (n = 6) or current (panic, social or generalised) anxiety disorder (n = 4). Studies were mostly of poor quality and heterogeneous regarding population, challenge test used and outcome measures. ATD did not consistently affect anxiety in any of the groups. Moreover, a challenge test after ATD (n = 17 studies) did not consistently provoke anxiety in healthy volunteers or remitted patients. A 35% CO2 challenge did consistently increase anxiety in patients with a current panic disorder (PD). To conclude, this systematic review found no clear indications that ATD provokes anxiety in those at risk for anxiety disorders. Hence, unlike in depression, ATD does not indicate vulnerability to develop an anxiety disorder. Because included studies were heterogeneous and mostly of poor quality, there is an urgent need for high quality research in homogeneous samples.

Abstract Background Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia. Methods In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). Results PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04–2.54) and rs946961*CC (OR = 5.17, 95% CI: 1.20–22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR = 0.53, 95% CI: 0.29–0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one. Conclusions Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia.

Abstract Background Many patients with poorly controlled multiple chronic conditions (MCC) also have unhealthy behaviors, mental health challenges, and unmet social needs. Medical management of MCC may have limited benefit if patients are struggling to address their basic life needs. Health systems and communities increasingly recognize the need to address these issues and are experimenting with and investing in new models for connecting patients with needed services. Yet primary care clinicians, whose regular contact with patients makes them more familiar with patients’ needs, are often not included in these systems. Methods We are starting a clinician-level cluster-randomized controlled trial to evaluate how primary care clinicians can participate in these community and hospital solutions and whether doing so is effective in controlling MCC. Sixty clinicians in the Virginia Ambulatory Care Outcomes Research Network will be matched by age and sex and randomized to usual care (control condition) or enhanced care planning with clinical-community linkage support (intervention). From the electronic health record we will identify all patients with MCC, including cardiovascular disease or risks, diabetes, obesity, or depression. A baseline assessment will be mailed to up to 50 randomly selected patients for each clinician (3000 total). Ten respondents per clinician (600 patients total) with uncontrolled MCC will be randomly selected for study inclusion, with oversampling of minorities. The intervention includes two components. First, we will use an enhanced care planning tool, My Own Health Report (MOHR), to screen patients for health behavior, mental health, and social needs. Patients will be supported by a patient navigator, who will help patients prioritize needs, create care plans, and write a personal narrative to guide the care team. Patients will update care plans every 1 to 2 weeks. Second, we will create community-clinical linkage to help address patients’ needs. The linkage will include community resource registries, personnel to span settings (patient navigators and a community health worker), and care team coordination across team members through MOHR. Discussion This study will help inform efforts by primary care clinicians to help address unhealthy behaviors, mental health needs, and social risks as a strategy to better control MCC. Trial registration ClinicalTrials.gov: NCT03885401 . Registered on 19 September 2019.

Recombinant T-cells receptors can redirect naïve T cells but often have low or uneven expression. Here, the authors model mutations in TCR constant domains to increase T cell receptor expression, assembly, and stability and generate bispecific molecules.

Abstract Background Unhealthy alcohol use is the third leading cause of preventable death in the United States. Evidence demonstrates that screening for unhealthy alcohol use and providing persons engaged in risky drinking with brief behavioral and counseling interventions improves health outcomes, collectively termed screening and brief interventions. Medication assisted therapy (MAT) is another effective method for treatment of moderate or severe alcohol use disorder. Yet, primary care clinicians are not regularly screening for or treating unhealthy alcohol use. Methods and analysis We are initiating a clinic-level randomized controlled trial aimed to evaluate how primary care clinicians can impact unhealthy alcohol use through screening, counseling, and MAT. One hundred and 25 primary care practices in the Virginia Ambulatory Care Outcomes Research Network (ACORN) will be engaged; each will receive practice facilitation to promote screening, counseling, and MAT either at the beginning of the trial or at a 6-month control period start date. For each practice, the intervention includes provision of a practice facilitator, learning collaboratives with three practice champions, and clinic-wide information sessions. Clinics will be enrolled for 6–12 months. After completion of the intervention, we will conduct a mixed methods analysis to identify changes in screening rates, increase in provision of brief counseling and interventions as well as MAT, and the reduction of alcohol intake for patients after practices receive practice facilitation. Discussion This study offers a systematic process for dissemination and implementation of the evidence-based practice of screening, counseling, and treatment for unhealthy alcohol use. Practices will be asked to implement a process for screening, counseling, and treatment based on their practice characteristics, patient population, and workflow. We propose practice facilitation as a robust and feasible intervention to assist in making changes within the practice. We believe that the process can be replicated and used in a broad range of clinical settings; we anticipate this will be supported by our evaluation of this approach. Trial registration ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT04248023 , Registered 5 February 2020.

Interactions between pathogens, host microbiota and the immune system influence many physiological and pathological processes. In the 20th century, widespread dermal vaccination with vaccinia virus (VACV) led to the eradication of smallpox but how VACV interacts with the microbiota and whether this influences the efficacy of vaccination are largely unknown. Here we report that intradermal vaccination with VACV induces a large increase in the number of commensal bacteria in infected tissue, which enhance recruitment of inflammatory cells, promote tissue damage and influence the host response. Treatment of vaccinated specific-pathogen-free (SPF) mice with antibiotic, or infection of genetically-matched germ-free (GF) animals caused smaller lesions without alteration in virus titre. Tissue damage correlated with enhanced neutrophil and T cell infiltration and levels of pro-inflammatory tissue cytokines and chemokines. One month after vaccination, GF and both groups of SPF mice had equal numbers of VACV-specific CD8+ T cells and were protected from disease induced by VACV challenge, despite lower levels of VACV-neutralising antibodies observed in GF animals. Thus, skin microbiota may provide an adjuvant-like stimulus during vaccination with VACV and influence the host response to vaccination. Author summary Smallpox was caused by variola virus and was eradicated by widespread dermal vaccination with vaccinia virus (VACV), a related orthopoxvirus of unknown origin. Eradication was declared in 1980 without an understanding of the immunological correlates of protection, or knowledge of the effect of smallpox vaccination on the local microbiota. Here we demonstrate that intradermal infection of mice with VACV induces a ~1000-fold expansion of commensal skin bacteria that influence the recruitment of inflammatory cells into the infected tissue and enhance the size of the vaccination lesion. Antibiotic treatment reduced lesion size without changing virus titres. VACV vaccination induced robust protection from infection with microbiota-independent formation of antigen-specific CD8+ T cellular immunity. We also observed lower levels of VACV neutralising antibodies in genetically-matched germ-free (GF) mice in comparison with specific pathogen free (SPF) controls. Thus, dermal infection by VACV enhanced bacterial growth and these bacteria promote pathology and enhance the innate immune response. This finding has implication for dermal vaccination with live vaccines and may influence their immunogenicity.

ObjectiveTherapeutic alliance has consistently been found to predict treatment outcomes across various psychotherapies and patient diagnosis. However, the relationship between therapeutic alliance and outcome in Cognitive Behavioral Therapy (CBT) has shown mixed results. This study investigated the impact of different aspects of therapeutic alliance in CBT for Obsessive-Compulsive Disorder (OCD).MethodData from two previously completed randomized controlled trials of 208 patients with OCD and their therapists were analyzed. Therapeutic alliance was assessed at week 4 of treatment with the patient-rated and therapist-rated Working Alliance Inventory (WAI), which includes three subscales to measure alliance domains (Goal, Task and Bond). Higher WAI score reflects a better therapeutic relationship. OCD severity was rated by independent assessors at baseline and post-treatment using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Linear regression analyses were used to examine the effects of the different aspects of therapeutic alliance on treatment outcome, adjusted for baseline symptom severity.ResultsA higher total WAI score as rated by therapists significantly predicted a lower post-treatment Y-BOCS. Further, higher scores on the Goal and Task subscales of the WAI were associated with lower post-treatment severity. However, these significant outcomes reflected only small effect sizes.ConclusionsIn the treatment of OCD, the strength of the therapeutic alliance contributes to outcomes, though to a limited extent. Effective OCD treatment involves the delivery of specific therapy interventions, in the context of a strong therapeutic alliance.

Sudden cardiac arrest (SCA) is a leading cause of mortality and morbidity in affluent societies, which underscores the need to identify persons at risk. The etiology of SCA is however complex, with predisposing and precipitating factors interacting. Although anxiety and mental stress have been linked to SCA for decades, their precise role and impact remain unclear and the biological underpinnings are insufficiently understood. In this paper, we systematically reviewed various types of observational studies (total n = 20) examining the association between anxiety or mental stress and SCA. Multiple methodological considerations challenged the summarizing and interpretation of the findings. For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95% CI: 1.06–5.59; n = 3). However, in populations at risk for SCA (n = 4), associations were heterogeneous but not significant. Anxiety may partly predispose to SCA by contributing to other risk factors such as cardiovascular disease and diabetes mellitus via mechanisms such as unhealthy lifestyle and metabolic abnormalities. Mental stress appears to precipitate SCA, presumably by more directly impacting on the cardiac ion channels that control the heart's electrical properties. This may lead to ventricular fibrillation, the arrhythmia that underlies SCA. To advance this field of research, experimental studies that unravel the underlying biological mechanisms are deemed important, and most easily designed for mental stress as a precipitating factor because of the short timeframe. These proof-of-concept studies should examine the whole pathway from the brain to the autonomic nervous system, and eventually to cardiac ion channels. Ultimately, such studies may facilitate the identification of persons at risk and the development of novel preventive strategies.

Age-related cardiovascular diseases (CVDs) remain among the leading global causes of death, and vascular smooth muscle cell (VSMC) remodeling plays an essential role in its pathology. Reduced NO-cGMP pathway signaling is a major feature and pathogenic mechanism underlying vasodilator dysfunction. Recently, we identified phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides cAMP and cGMP, and thereby provides a potential treatment target for restoring age-related vascular dysfunction due to aging of VSMC. Based on this hypothesis, we here tested the effects of PDE1 inhibition in a model of SMC-specific accelerated aging mice. SMC-KO and their WT littermates received either vehicle or the PDE1 inhibitor lenrispodun for 8 weeks. Vascular function was measured both in vivo (Laser Doppler technique) and ex vivo (organ bath). Moreover, we deployed UV irradiation in cell culture experiments to model accelerated aging in an in vitro situation. SMC-KO mice display a pronounced loss of vasodilator function in the isolated aorta, the cutaneous microvasculature, and mesenteric arteries. Ex vivo, in isolated vascular tissue, we found that PDE1 inhibition with lenrispodun improves vasodilation, while no improvement was observed in isolated aorta taken from mice after chronic treatment in vivo. However, during lenrispodun treatment in vivo, an enhanced microvascular response in association with upregulated cGMP levels was seen. Further, chronic lenrispodun treatment decreased TNF-α and IL-10 plasma levels while the elevated level of IL-6 in SMC-KO mice remained unchanged after treatment. PDE1 and senescence markers, p16 and p21, were increased in both SMC-KO aorta and cultured human VSMC in which DNA was damaged by ultraviolet irradiation. This increase was lowered by chronic lenrispodun. In contrast, lenrispodun increased the level of PDE1A in both situations. In conclusion, we demonstrated that PDE1 inhibition may be therapeutically useful in reversing aspects of age-related VSMC dysfunction by potentiating NO-cGMP signaling, preserving microvascular function, and decreasing senescence. Yet, after chronic treatment, the effects of PDE1 inhibition might be counteracted by the interplay between differential PDE1A and C expression. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment.

Plasmodium falciparum, a protozoan parasite and causative agent of human malaria, has one of the most A/T-biased genomes sequenced to date. This may give the genome and the transcriptome unusual structural features. Recent progress in sequencing techniques has made it possible to study the secondary structures of RNA molecules at the transcriptomic level. Thus, in this study we produced the in vivo RNA structurome of a protozoan parasite with a highly A/U-biased transcriptome. We showed that it is possible to probe the secondary structures of P. falciparum RNA molecules in vivo using two different chemical probes, and obtained structures for more than half of all transcripts in the transcriptome. These showed greater stability (lower free energy) than the same structures modelled in silico, and structural features appeared to influence translation efficiency and RNA decay. Finally, we compared the P. falciparum RNA structurome with the predicted RNA structurome of an A/U-balanced species, P. knowlesi, finding a bias towards lower overall transcript stability and more hairpins and multi-stem loops in P. falciparum. This unusual protozoan RNA structurome will provide a basis for similar studies in other protozoans and also in other unusual genomes.

Exercise referral schemes (ERS) are used to promote physical activity within primary care. Traditionally, ERS are conducted in a gym or leisure-center setting, with exercise prescriptions based on moderate-intensity continuous training (MICT). Home-based high-intensity interval training (Home-HIIT) has the potential to reduce perceived barriers to exercise, including lack of time and access to facilities, compared to traditional MICT prescription used with ERS and improve health related outcomes. We hypothesized that Home-HIIT would mediate greater improvement in cardiorespiratory fitness (CRF) by virtue of greater adherence and compliance to the exercise prescription, compared to MICT.Methods: Patients enrolled on an ERS (Liverpool, United Kingdom) were recruited for a pragmatic trial. Participants self-selected either 12 weeks of MICT (45–135 min/week at 50–70% HRmax) or Home-HIIT (4–9 min × 1 min intervals at ≥80% of HRmax, interspersed with 1 min rest). The primary outcome was the change in CRF (VO2peak) at post-intervention (12 weeks) and follow-up (3-month post intervention), using intention-to-treat analysis.Results: 154 participants (age 48 ± 10y; BMI 30.5 ± 6.1 kg/m2) were recruited between October 2017 and March 2019, 87 (56%) participants chose Home-HIIT and 67 (44%) MICT. VO2peak increased post-intervention in both groups (MICT 3.9 ± 6.0 ml.kg–1.min–1, Home-HIIT 2.8 ± 4.5 ml.kg–1.min–1, P < 0.001), and was maintained at follow-up (P < 0.001). Fat mass was only reduced post MICT (MICT −1.5 ± 6.3 kg, P < 0.05, Home-HIIT −0.2 ± 2.0 kg, P = 1.00), but the reduction was not maintained at follow-up (MICT −0.6 ± 5.1 kg, Home-HIIT 0.0 ± 2.2 kg, P > 0.05). Adherence to the prescribed programs was similar (MICT 48 ± 35%, Home-HIIT 39 ± 36%, P = 0.77).Conclusion: This is the first study to evaluate the use of Home-HIIT for individuals in a primary care setting. Contrary to our hypothesis, adherence to both exercise prescriptions was poor, and CRF improved to a similar extent in both groups with improvements maintained at 3-month follow-up. We provide evidence that, although not superior, Home-HIIT could be an effective and popular additional exercise choice for patients within primary care based ERS.Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04553614].

Abstract Background The Delphi technique is a proven and reliable method to create common definitions and to achieve convergence of opinion. This study aimed to prioritize suicide prevention guideline recommendations and to develop a set of quality indicators (QIs) for suicide prevention in specialist mental healthcare. Methods This study selected 12 key recommendations from the guideline to modify them into QIs. After feedback from two face-to-face workgroup sessions, 11 recommendations were rephrased and selected to serve as QIs. Next, a Delphi study with the 11 QIs was performed to achieve convergence of opinion among a panel of 90 participants (23 suicide experts, 23 members of patients’ advisory boards or experts with experiences in suicidal behavior and 44 mental healthcare professionals). The participants scored the 11 QIs on two selection criteria: relevance (it affects the number of suicides in the institution) and action orientation (institutions or professionals themselves can influence it) using a 5-point Likert scale. Also, data analysts working in mental healthcare institutions (MHIs) rated each QI on feasibility (is it feasible to monitor and extract from existing systems). Consensus was defined as 70% agreement with priority scores of four or five. Results Out of the 11 recommendations, participants prioritized five recommendations as relevant and action-oriented in optimizing the quality of care for suicide prevention: 1) screening for suicidal thoughts and behavior, 2) safety plan, 3) early follow-up on discharge, 4) continuity of care and 5) involving family or significant others. Only one of the 11 recommendations early follow-up on discharge reached consensus on all three selection criteria (relevance, action orientation, and feasibility). Conclusions The prioritization of relevant and action-oriented suicide prevention guideline recommendations is an important step towards the improvement of quality of care in specialist mental healthcare.

Abstract Background Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Abstract Background Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes). Methods The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls. Discussion This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment. Trial registration Trialregister.nl Number of identification: NTR3460, May 2012.

The midbody is an organelle present at the bridge connecting two cells at the end of cell division. Here, the authors use mass spectrometry to define the midbody interactome and uncover a role for PP1 phosphatases in microtubule dynamics and regulation of cytokinesis.

Sequencing of newly synthesised RNA can reveal the transcriptional dynamics in a population of cells. Here the authors develop NASC-seq to bring this sensitivity and temporal resolution to single-cell analysis.

Abstract Background Selection of the optimal initial treatment in patients with major depressive disorder (MDD) in need of highly specialized care has the potential to benefit treatment outcomes and cost-effectiveness of treatment strategies. However, to date, there is a paucity of measures that could guide the selection of the initial treatment, in particular to indicate which patients with MDD are in need of highly specialized care. Recognizing this gap, this paper reports on the development and psychometric evaluation of the Decision Tool Unipolar Depression (DTUD), aimed to facilitate the early identification of patients with MDD in need of highly specialized care. Methods The DTUD was developed using a mixed-methods approach, consisting of a systematic review and a concept mapping study. To evaluate the psychometric features of the DTUD, a cross-sectional multicenter study was conducted. A total of 243 patients with MDD were evaluated with the DTUD. Feasibility was operationalized as the time required to complete the DTUD and the content clarity of the DTUD. Inter-rater reliability was evaluated using Krippendorf’s alpha. The Maudsley Staging Method (MSM) and the Dutch Measure for quantification of Treatment Resistance in Depression (DM-TRD) were administered to assess the convergent validity. A receiver operator characteristic curve was generated to evaluate the criterion validity and establish the optimal cut-off value. Results The mean administration time was 4.49 min (SD = 2.71), and the content of the total DTUD was judged as clear in 94.7% of the evaluations. Inter-rater reliability values ranged from 0.69 to 0.91. Higher scores on the DTUD were associated with higher scores on the MSM (rs = 0.47) and DM-TRD (rs = 0.53). Based on the maximum Youden index (0.494), maximum discrimination was reached at a cut-off score of ≥5 (sensitivity 67%, specificity 83%). Conclusion The DTUD demonstrated to be a tool with solid psychometric properties and, therefore, is a promising measure for the early identification of patients with MDD in need of highly specialized care. Use of the DTUD has the potential to facilitate the selection and initiation of the optimal initial treatment in patients with MDD, which in turn may improve the clinical effectiveness and cost-effectiveness of treatment strategies.

The present study aims to clarify the confused taxonomy of Z. schaufussi von Frauenfeld, 1862 and Zospeum suarezi Gittenberger, 1980. Revision of Iberian Zospeum micro snails is severely hindered by uncertainties regarding the identity of the oldest Iberian Zospeum species, Z. schaufussi von Frauenfeld, 1862. In this paper, we clarify its taxonomic status by designating a lectotype from the original syntype series and by describing its internal and external shell morphology. Using SEM-EDX, we attempt to identify the area of the type locality cave more precisely than “a cave in Spain”. The shell described and illustrated by Gittenberger (1980) as Z. schaufussi appears not to be conspecific with the lectotype shell, and is considered a separate species, Z. gittenbergeri Jochum, Prieto & De Winter, sp. n. Zospeum suarezi was described from various caves in NW Spain. Study of the type material reveals that these shells are not homogenous in shell morphology. The holotype shell of Z. suarezi is imaged here for the first time. The paratype shell, illustrated by Gittenberger (1980) from a distant, second cave, is described as Zospeum praetermissum Jochum, Prieto & De Winter, sp. n. The shell selected here as lectotype of Z. schaufussi, was also considered a paratype of Z. suarezi by Gittenberger (1980). Since this specimen is morphologically very similar to topotypic shells of Z. suarezi, the latter species is considered a junior synonym of Z. schaufussi (syn. n.). The internal shell morphology of all these taxa is described and illustrated using X-ray Micro Computer Tomography (Micro-CT).

Abstract Background Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia. Methods A set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone. Results One statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs. Conclusions Our results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.