Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Physiology of the widespread pulsating soft coral Xenia umbellata is affected by food sources, but not by water flow.

Coral energy and nutrient acquisition strategies are complex and sensitive to environmental conditions such as water flow. While high water flow can enhance feeding in hard corals, knowledge about the effects of water flow on the feeding of soft corals, particularly those pulsating, is still limited. In this study, we thus investigated the effects of feeding and water flow on the physiology of the pulsating soft coral Xenia umbellata. We crossed three feeding treatments: (i) no feeding, (ii) particulate organic matter (POM) in the form of phytoplankton and (iii) dissolved organic carbon (DOC) in the form of glucose, with four water volume exchange rates (200, 350, 500 and 650 L h-1) over 15 days. Various ecophysiological parameters were assessed including pulsation rate, growth rate, isotopic and elemental ratios of carbon (C) and nitrogen (N) as well as photo-physiological parameters of the Symbiodiniaceae (cell density, chlorophyll-a and mitotic index). Water flow had no significant effect but feeding had a substantial impact on the physiology of the X. umbellata holobiont. In the absence of food, corals exhibited significantly lower pulsation rates, lower Symbiodiniaceae cell density and lower mitotic indices compared to the fed treatments, yet significantly higher chlorophyll-a per cell and total N content. Differences were also observed between the two feeding treatments, with significantly higher pulsation rates and lower chlorophyll-a per cell in the DOC treatment, but higher C and N content in the POM treatment. Our findings suggest that the X. umbellata holobiont can be viable under different trophic strategies, though favouring mixotrophy. Additionally, the physiology of the X. umbellata may be regulated through its own pulsating behaviour without any positive or negative effects from different water flow. Therefore, this study contributes to our understanding of soft coral ecology, particularly regarding the competitive success and widespread distribution of X. umbellata.

[Useful knowledge regarding tattoos]. / Nützliches Wissen zu Tätowierungen.

The number of people with tattoos has continued to increase in recent years. In the USA about 23% and in Europe 9-12% of the population have tattoos. In the German media (2019) and by the infoportal Statista (2017), it is assumed that 21-25% of citizens have tattoos and that the trend is increasing (Statista 2018: 36%). Men and women wear tattoos equally. The age group 20-29 years dominates with almost 50% having tattoos. The following article describes the new regulations especially the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) regulation, legal basis, and governmental controls on the subject of "tattoos". The composition of tattooing agents and testing options relevant for the user before and for the performance of tattooing are presented. Dermatologically associated diseases and testing procedures are listed. Since 70% of the population denies knowledge of this information even when they have tattoos themselves, this update is written as an overview for treating physicians and users.

Twelve Weeks of Additional Fish Intake Improves the Cognition of Cognitively Intact, Resource-Limited Elderly People: A Randomized Control Trial.

INTRODUCTION: Dietary omega 3 polyunsaturated fatty acids (PUFA) may reduce the risk of dementia. Many studies have investigated PUFA supplementation in high-income countries, yet food-based randomized control trials using omega 3 PUFA rich fish in lower to middle income countries, are lacking. OBJECTIVE: To determine the effect on cognition of adding either fish or non-fish foods for twelve weeks to an enhanced diet of cognitively intact, independently living, resource-limited elderly people. DESIGN: Randomized control trial (National Health Trial register: DOH-27-061-6026). SETTING: Retirement center in urban South Africa. PARTICIPANTS: Fifty-seven (74% female, mean age: 72±7 years) elderly participants with cognitive function exceeding 22 on the Mini Mental State Examination were randomized into an intervention (n=31) and control (n=26) group. INTERVENTION: The usual diets of both groups were enhanced with context-appropriate foods to mimic elements of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. The intervention group additionally received canned pilchards and fish spread every week amounting to an additional (theoretical) intake of 2.2g omega 3 PUFA daily. The control group received canned meatballs and texturized soya every week. MEASUREMENTS: Cognition was measured twice before and once after the intervention phase using the Cognitive Abilities Screening Instrument (CASI). Adherence was assessed by a study-specific food frequency questionnaire and red blood cell (RBC) PUFA biomarkers. Data were analyzed using a non-parametric analysis of covariance (ANCOVA) with, and without, bootstrap imputation. RESULTS: Participants in the intervention group had a significantly higher post intervention (P=0.036) CASI score than the control group, when the model was fitted with imputation and controlled for baseline scores. Participants in the intervention group also had a significantly higher intake of calculated dietary omega 3 PUFA and higher levels of RBC eicosapentaenoic acid and docosapentaenoic acid content than the control group (P < 0.05). CONCLUSION: Twelve weeks of fish intake in the context of a modified MIND diet may improve the cognition of cognitively intact, resource-limited elderly people.

The sourcing and use of high physical resemblance personal protective equipment to train healthcare workers, improve confidence and conserve medical-grade equipment.

Personal protective equipment (PPE) is essential for healthcare worker (HCW) safety. Conservation of PPE for clinical use during the COVID-19 pandemic reduced its availability for training, necessitating an innovative approach to sourcing high physical resemblance PPE (HPR-PPE). We present a case study of crowd-sourcing of HPR-PPE to train HCWs. Survey results indicated that HPR-PPE enabled high-fidelity practise of PPE application and removal, aided procedure recall, improved user confidence and was sufficiently similar to medical-grade PPE. HPR-PPE provided a novel and cost-effective alternative. We also demonstrated that medical-grade PPE can be sourced from non-medical institutions and businesses during a pandemic.

Teaching old precursors new tricks: Fast room temperature synthesis of surfactant-free colloidal platinum nanoparticles.

A fast, simple, instrument-free room temperature synthesis of stable electroactive surfactant-free colloidal Pt nanoparticles in alkaline methanol and methanol-water mixtures is presented. Pair distribution function (PDF) analysis suggests that methoxy substitution of chloride ligands from H2PtCl6 occurs in methanol. X-ray absorption spectroscopy (XAS) studies and UV-vis measurements show that solutions of H2PtCl6 in methanol age and are reduced to Pt(II) species over time. These species are ideal precursors to significantly reduce the induction period typically observed in colloidal Pt nanoparticle syntheses as well as the temperature needed to form nanoparticles. The room temperature synthesis presented here allows designing simple in situ studies of the nanoparticle formation. In situ infra-red spectroscopy gives insight into the formation and stabilization mechanism of surfactant-free nanoparticles by CO surface groups. Finally, the surfactant-free nanoparticles ca. 2-3 nm in diameter obtained are shown to be readily active electrocatalysts e.g. for methanol oxidation. The synthesis approach presented bears several advantages to design new studies and new syntheses of surfactant-free colloidal nanomaterials.

Identification of potential small-molecule protein-protein inhibitors of cancer metastasis by 3D epitope-based computational screening.

In cancer cells exposed to extracellular pressure or shear stress, AKT1-FAK interaction drives focal adhesion kinase (FAK) phosphorylation, leading to force-activated cancer cell adhesion and metastasis. Blocking the AKT1-FAK interaction is therefore an attractive target for cancer therapy, avoiding the side effects of global FAK inhibition. Starting with our previous identification of a short FAK peptide that binds AKT1, we identified a series of small-molecule inhibitor candidates using a novel approach for inhibiting protein-protein interactions. Using a 3D structural fragment of the FAK peptide as the query, millions of drug-like, commercially available molecules were screened to identify a subset mimicking the volume and chemistry of the FAK fragment to test for their ability to block pressure-sensitive FAK phosphorylation by AKT1. Two compounds reduced the stimulation of FAK phosphorylation in response to extracellular pressure in human SW620 colon cancer cells without affecting basal FAK phosphorylation. Thus, using a 3D protein interaction epitope as a novel query for ligand-based virtual screening can successfully identify small-molecules that show promise in modulating cancer cell adhesion and metastasis.

South African women's perspectives on self-sampling for cervical cancer screening: A mixed-methods study.

BACKGROUND: Self-sampling as a method of screening for cervical cancer and its precursors is an attractive option for low-resource settings. However, to allow successful integration of self-sampling into national screening programmes, it is necessary to understand women's perceptions and beliefs surrounding this method of sampling the cervix. OBJECTIVES: To explore women's attitudes to self-collection of samples for cervical screening in a low-resource setting in South Africa (SA). METHODS: Mixed methods were used to meet the study objectives. We recruited women aged 30 - 65 years into a study in Cape Town, SA, to participate in a cross-sectional survey. All women collected a vaginal self-sample, and underwent visual inspection with acetic acid, colposcopy, and collection of cervical samples and appropriate histology specimens by a doctor. Women had a quantitative questionnaire-based exit interview. A subset of these women participated in focus group discussions (FGDs). RESULTS: A total of 822 women answered the exit survey questionnaire and 41 women participated in the FGDs. Most women from the survey had a positive perception of self-sampling, with 93.6% of the women reporting not feeling embarrassed and 89.4% reporting experiencing no discomfort at all when taking a self-sample. This was corroborated by the FGD participants, who found self-sampling easier, more comfortable and less embarrassing than clinician sampling. However, many women (64.7%) felt more confident when the sample was taken by a clinician, despite having a positive attitude towards self-sampling. In most cases this was because they thought that the clinician would take a better sample, as explained by the FGD participants. Although 93.9% of the women were willing to collect a self-sample, the women in the FGDs expressed a preference for doing so at the health facility rather than at home. There were many reasons for this, including the cost of returning to the clinic with the sample. CONCLUSIONS: Attitudes regarding self-sample collection were positive in this study population. Participants were willing to perform self-sampling, but expressed concerns regarding the quality of the specimen and the financial implications of returning to the clinic with it. Pilot implementation studies will be useful before this method of sampling is adopted and integrated into screening programmes.

Lamivudine monotherapy in children and adolescents: The devil is in the detail.

Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.

Biomimetic calcium phosphate/polyelectrolyte multilayer coatings for sequential delivery of multiple biological factors.

Combinations of growth factors synergistically enhance tissue regeneration, but typically require sequential, rather than co-delivery from biomaterials for maximum efficacy. Polyelectrolyte multilayer (PEM) coatings can deliver multiple factors without loss of activity; however, sequential delivery from PEM has been limited due to interlayer diffusion that results in co-delivery of the factors. This study shows that addition of a biomimetic calcium phosphate (bCaP) barrier layer to a PEM coating effectively prevents interlayer diffusion and enables sequential delivery of two different biomolecules via direct cell access. A simulated body fluid method was used to deposit a layer of bCaP followed by 30 bilayers of PEM made with poly-l-Lysine (+) and poly l-Glutamic acid (-) (bCaP-PEM). Measurements of MC3T3-E1 proliferation and viability over time on bCaP-PEM were used to demonstrate the sequential delivery kinetics of a proliferative factor [fibroblast growth factor-2 (FGF-2)] followed by a cytotoxic factor (antimycin A, AntiA). FGF-2 and AntiA both retained their bioactivity within bCaP-PEM, yet no release of FGF-2 or AntiA from bCaP-PEM was observed when cells were absent indicating a cell-mediated, local delivery process. This coating technique is useful for a variety of applications that would benefit from highly localized, sequential delivery of multiple biomolecules governed by cell initiated degradation that avoids off-target effects associated with diffusion-based release. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1500-1509, 2017.

HIV-associated neurodevelopmental delay: prevalence, predictors and persistence in relation to antiretroviral therapy initiation and viral suppression.

CONTEXT: HIV infection in infancy may influence the developing brain, leading to adverse neurodevelopmental consequences. OBJECTIVE: We aim to describe neurodevelopmental characteristics of a cohort of HIV-infected infants and young children prior to antiretroviral therapy (ART) initiation and after achieving viral suppression. METHODS: As part of the Neverest 2 trial, 195 HIV-infected children under 2 years of age were assessed using the Ages and Stages Questionnaire (ASQ) prior to ART initiation and at subsequent age-appropriate time points after ART had been started. The ASQ is a simple screening questionnaire used to identify children at risk of neurodevelopmental delays. Questionnaires completed by the parent/caregiver assess neurodevelopmental functioning in five domains: communication, gross motor, fine motor, problem solving and personal-social. RESULTS: Median age pre-ART was 8.8 months (range 2.2-24.9) and 53.9% were male. Mean time to viral suppression was 9.4 months (range 5.9-14.5). Compared with pre-ART better outcomes were reported at time of viral suppression with a lower proportion of children failing the gross motor (31.5% vs. 13%, p = 0.0002), fine motor (21.3% vs. 10.2%, p = 0.017), problem solving (26.9% vs. 9.3%, p = 0.0003) and personal-social (19.6% vs. 7.4%, p = 0.019) domains. However, there was no change in the communication domain (14.8% vs. 12.0%, p = 0.6072). CONCLUSION: Although achieving viral suppression on ART resulted in significant improvements in markers of neurodevelopmental function of young HIV-infected children, potential neurodevelopmental delays still persisted in a large proportion. Further interventions are needed to limit potential disabilities and maximize developmental outcomes.

In situ diagnostics of the crystal-growth process through neutron imaging: application to scintillators.

Neutrons are known to be unique probes in situations where other types of radiation fail to penetrate samples and their surrounding structures. In this paper it is demonstrated how thermal and cold neutron radiography can provide time-resolved imaging of materials while they are being processed (e.g. while growing single crystals). The processing equipment, in this case furnaces, and the scintillator materials are opaque to conventional X-ray interrogation techniques. The distribution of the europium activator within a BaBrCl:Eu scintillator (0.1 and 0.5% nominal doping concentrations per mole) is studied in situ during the melting and solidification processes with a temporal resolution of 5-7 s. The strong tendency of the Eu dopant to segregate during the solidification process is observed in repeated cycles, with Eu forming clusters on multiple length scales (only for clusters larger than ∼50 µm, as limited by the resolution of the present experiments). It is also demonstrated that the dopant concentration can be quantified even for very low concentration levels (∼0.1%) in 10 mm thick samples. The interface between the solid and liquid phases can also be imaged, provided there is a sufficient change in concentration of one of the elements with a sufficient neutron attenuation cross section. Tomographic imaging of the BaBrCl:0.1%Eu sample reveals a strong correlation between crystal fractures and Eu-deficient clusters. The results of these experiments demonstrate the unique capabilities of neutron imaging for in situ diagnostics and the optimization of crystal-growth procedures.

Peripherally inserted central catheter-related deep vein thrombosis: contemporary patterns and predictors.

BACKGROUND: Despite growing use, peripherally inserted central catheters (PICCs) are associated with risk of deep vein thrombosis (DVT). We designed a study to determine patient, provider and device factors associated with this outcome. METHODS: This was a retrospective cohort study of adults who underwent PICC placement between 1 June 2009 to 30 June 2012. Symptomatic PICC-associated DVT was confirmed by ultrasound. Because PICCs are also recognized risk factors for lower-extremity DVT, lower-extremity DVT occurring while the PICC was in situ was included. Multivariable logistic and Cox-proportional hazards regression models were fit to examine the association between covariates specified a priori and PICC-DVT. Odds ratios (ORs) and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were generated. RESULTS: Of 966 unique PICC placements, 33 patients developed symptomatic PICC-associated DVT and 9 developed lower-extremity DVT, accounting for 42 thrombotic events. On bivariate analysis, recent diagnosis of cancer, interventional radiology placement, chemotherapy administration, number of lumens and PICC-gauge were associated with PICC-DVT. Following multivariable adjustment, recent cancer diagnosis (OR 1.95 [95% CI 1.01-3.76]) and PICC gauge (HR 2.21 [95%CI 1.04-4.70] and HR 3.56 [95%CI 1.31-9.66] for 5-Fr and 6-Fr PICCs, respectively) remained associated with thrombosis. CONCLUSIONS: Recent diagnosis of cancer and PICC gauge are associated with PICC-DVT. These findings have important clinical ramifications and suggest that placement of large gauge PICCs or PICCs in patients with cancer may provoke thrombosis. Improved policies and procedural oversights in these areas appear necessary to prevent PICC-DVT.

HLA-G 14 bp deletion/insertion polymorphism and mother-to-child transmission of HIV.

The human leukocyte antigen HLA-G, highly expressed at the maternal-fetal interface, has a pivotal role in mediating immune tolerance. In this study we investigated the influence of HLA-G 14 bp insertion polymorphism in human immunodeficiency virus (HIV)-1 mother-to-child HIV-1 transmission. The 14 bp insertion polymorphism was analyzed among 99 HIV-1 positive mothers and 329 infants born to HIV-positive mothers in Zambia, among whom vertical transmission status and timing had been determined. HLA-G 14 bp insertion polymorphism was detected using a custom TaqMan single nucleotide polymorphisms (SNPs) genotyping assay. Logistic regression was conducted to examine the associations between HLA-G alleles and the risk of HIV transmission. The 14 bp insertion allele was more frequent in HIV exposed-uninfected (EU) infants than in infected infants, and was associated with reduced risk of both in utero (IU) and intrapartum (IP) HIV transmission, after adjusting for maternal cluster of differentiation 4 (CD4) cell count and plasma viral load. Maternal HLA-G 14 bp insertion genotype and HLA-G concordance between mother and child were not associated with the risk of perinatal HIV transmission. The presence of the 14 bp insertion associates with protection toward IU and IP HIV infection in children from Zambia, suggesting that HLA-G could be involved in the vertical transmission of HIV.

Improved controlled atmosphere high temperature scanning probe microscope.

To locally access electrochemical active surfaces and interfaces in operando at the sub-micron scale at high temperatures in a reactive gas atmosphere is of great importance to understand the basic mechanisms in new functional materials, for instance, for energy technologies, such as solid oxide fuel cells and electrolyzer cells. Here, we report on advanced improvements of our original controlled atmosphere high temperature scanning probe microscope, CAHT-SPM. The new microscope can employ a broad range of the scanning probe techniques including tapping mode, scanning tunneling microscopy, scanning tunneling spectroscopy, conductive atomic force microscopy, and Kelvin probe force microscopy. The temperature of the sample can be as high as 850 °C. Both reducing and oxidizing gases such as oxygen, hydrogen, and nitrogen can be added in the sample chamber and the oxygen partial pressure (pO2) is monitored by an oxygen sensor. We present here some examples of its capabilities demonstrated by high temperature topography with simultaneously ac electrical conductance measurements during atmosphere changes, electrochemical impedance spectroscopy at various temperatures, and measurements of the surface potential. The improved CAHT-SPM, therefore, holds a great potential for local sub-micron analysis of high-temperature and gas induced changes of a wide range of materials.

Transmission electron microscopy specimen preparation method for multiphase porous functional ceramics.

An optimum method is proposed to prepare thin foil transmission electron microscopy (TEM) lamellae of multiphase porous functional ceramics: prefilling the pore space of these materials with an epoxy resin prior to focused ion beam milling. Several advantages of epoxy impregnation are demonstrated by successful preparation of TEM specimens that maintain the structural integrity of the entire lamella. Feasibility of the TEM alignment procedure is demonstrated, and ideal TEM analyses are illustrated on solid oxide fuel cell and solid oxide electrolysis cell materials. Some potential drawbacks of the TEM specimen preparation method are listed for other samples.