Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses.

ABSTRACT: T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK/STAT signaling. To further develop related preclinical therapeutic concepts, we studied inhibitors of histone deacetylases ([H]DACs), B-cell lymphoma 2 (BCL2), cyclin-dependent kinase (CDK), mouse double minute 2 (MDM2), and classical cytostatics, using (1) single-agent and combinatorial compound testing in 20 well-characterized and molecularly profiled primary T-PLL (validated by additional 42 cases) and (2) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single agents and combinations (in vitro and in mice) included cladribine, romidepsin ([H]DAC), venetoclax (BCL2), and/or idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance toward MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activation and downstream signals (including enhanced accessibility of target-gene chromatin regions), in particular synergy with insults by cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.

Acceptability of artificial intelligence for cervical cancer screening in Dschang, Cameroon: a qualitative study on patient perspectives.

BACKGROUND: Cervical cancer is the fourth most frequent cancer among women, with 90% of cervical cancer-related deaths occurring in low- and middle-income countries like Cameroon. Visual inspection with acetic acid is often used in low-resource settings to screen for cervical cancer; however, its accuracy can be limited. To address this issue, the Swiss Federal Institute of Technology Lausanne and the University Hospitals of Geneva are collaborating to develop an automated smartphone-based image classifier that serves as a computer aided diagnosis tool for cancerous lesions. The primary objective of this study is to explore the acceptability and perspectives of women in Dschang regarding the usage of a screening tool for cervical cancer relying on artificial intelligence. A secondary objective is to understand the preferred form and type of information women would like to receive regarding this artificial intelligence-based screening tool. METHODS: A qualitative methodology was employed to gain better insight into the women's perspectives. Participants, aged between 30 and 49 were invited from both rural and urban regions and semi-structured interviews using a pre-tested interview guide were conducted. The focus groups were divided on the basis of level of education, as well as HPV status. The interviews were audio-recorded, transcribed, and coded using the ATLAS.ti software. RESULTS: A total of 32 participants took part in the six focus groups, and 38% of participants had a primary level of education. The perspectives identified were classified using an adapted version of the Technology Acceptance Model. Key factors influencing the acceptability of artificial intelligence include privacy concerns, perceived usefulness, and trust in the competence of providers, accuracy of the tool as well as the potential negative impact of smartphones. CONCLUSION: The results suggest that an artificial intelligence-based screening tool for cervical cancer is mostly acceptable to the women in Dschang. By ensuring patient confidentiality and by providing clear explanations, acceptance can be fostered in the community and uptake of cervical cancer screening can be improved. TRIAL REGISTRATION: Ethical Cantonal Board of Geneva, Switzerland (CCER, N°2017-0110 and CER-amendment n°4) and Cameroonian National Ethics Committee for Human Health Research (N°2022/12/1518/CE/CNERSH/SP). NCT: 03757299.

Globally, cervical cancer is the fourth most frequent cancer among women. However, 90% of all deaths caused by cervical cancer occur in low-and middle-income countries. Methods traditionally used in settings like Cameroon to detect cervical cancer unfortunately lack accuracy. Therefore, researchers at the Swiss Federal Institute of Technology Lausanne and the University Hospitals of Geneva are developing an artificial intelligence-based computer aided diagnosis tool to detect pre-cancerous lesions using a smartphone application. The aim of this study was to explore the acceptability and perspectives regarding an AI-based tool for cervical cancer screening for women in Dschang, a city in the west of Cameroon. A qualitative methodology was conducted with six focus groups and a total of 32 participants. The main concerns highlighted by the study are related to privacy, trust in the ability of the healthcare providers, accuracy of the tool as well as the potential negative impact of smartphones. In conclusion, our results show that a computer aided diagnosis tool using artificial intelligence is mostly acceptable to women in Dschang, as long as their confidentiality is preserved, and they are provided with clear explanations beforehand.

Does poor health influence residential selection? Understanding mobility among low-income housing voucher recipients in the Moving to Opportunity Study.

Housing mobility programs and housing choice vouchers provide low-income families with a potentially-transformative opportunity to move to low-poverty neighborhoods. However, families often face barriers to attaining upward residential mobility; poor health may be one important barrier, although few studies have examined this hypothesis. We used the experimental Moving to Opportunity (MTO) Study, constructed residential trajectories, and linked neighborhood opportunity measures to over 14,000 addresses of 3526 families across 7 years. We used latent growth curve longitudinal models to test how baseline health modified effects of MTO housing voucher treatment on neighborhood opportunity trajectories. Results show that poor baseline health adversely influenced how the voucher induced upward mobility. Voucher receipt strongly promoted residential mobility if families were healthy; moreover the low-poverty neighborhood voucher plus counseling treatment promoted higher opportunity neighborhood attainment compared to controls, regardless of the baseline health of the family. However families with health vulnerabilities did not retain the same initial neighborhood gains conferred by the housing choice voucher treatment, as families without health vulnerabilities. These results suggest that housing counseling may be one necessary element to expand neighborhood choice into higher opportunity neighborhoods for families with health challenges. Providing housing vouchers alone are insufficient to promote low-income family high opportunity moves, for families who have disabilities or special needs. The implications of these results point to scaling up housing mobility programs, to provide tailored support for low-income families to use housing choice vouchers to make high opportunity moves, which is particularly necessary for families with health challenges.

Sensory-Processing Sensitivity Is Associated with Increased Neural Entropy.

BACKGROUND: This study aimed at answering the following research questions: (1) Does the self-reported level of sensory-processing sensitivity (SPS) correlate with complexity, or criticality features of the electroencephalogram (EEG)? (2) Are there significant EEG differences comparing individuals with high and low levels of SPS? METHODS: One hundred fifteen participants were measured with 64-channel EEG during a task-free resting state. The data were analyzed using criticality theory tools (detrended fluctuation analysis, neuronal avalanche analysis) and complexity measures (sample entropy, Higuchi's fractal dimension). Correlations with the 'Highly Sensitive Person Scale' (HSPS-G) scores were determined. Then, the cohort's lowest and the highest 30% were contrasted as opposites. EEG features were compared between the two groups by applying a Wilcoxon signed-rank test. RESULTS: During resting with eyes open, HSPS-G scores correlated significantly positively with the sample entropy and Higuchi's fractal dimension (Spearman's ρ = 0.22, p < 0.05). The highly sensitive group revealed higher sample entropy values (1.83 ± 0.10 vs. 1.77 ± 0.13, p = 0.031). The increased sample entropy in the highly sensitive group was most pronounced in the central, temporal, and parietal regions. CONCLUSION: For the first time, neurophysiological complexity features associated with SPS during a task-free resting state were demonstrated. Evidence is provided that neural processes differ between low- and highly-sensitive persons, whereby the latter displayed increased neural entropy. The findings support the central theoretical assumption of enhanced information processing and could be important for developing biomarkers for clinical diagnostics.

Outcomes of second allogeneic stem cell transplantation and anti-relapse strategies in patients with relapsed/refractory acute myeloid leukemia: A unicentric retrospective analysis.

Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.

Housing mobility protects against alcohol use for children with socioemotional health vulnerabilities: An experimental design.

PURPOSE: Neighborhood context may influence alcohol use, but effects may be heterogeneous, and prior evidence is threatened by confounding. We leveraged a housing voucher experiment to test whether housing vouchers' effects on alcohol use differed for families of children with and without socioemotional health or socioeconomic vulnerabilities. TRIAL DESIGN: In the Moving to Opportunity (MTO) study, low-income families in public housing in five US cities were randomized in 1994 to 1998 to receive one of three treatments: (1) a housing voucher redeemable in a low-poverty neighborhood plus housing counseling, (2) a housing voucher without locational restriction, or (3) no voucher (control). Alcohol use was assessed 10 to 15 years later (2008 to 2010) in youth ages 13 to 20, N = 4600, and their mothers, N = 3200. METHODS: Using intention-to-treat covariate-adjusted regression models, we interacted MTO treatment with baseline socioemotional health vulnerabilities, testing modifiers of treatment on alcohol use. RESULTS: We found treatment effect modification by socioemotional factors. For youth, MTO voucher treatment, compared with controls, reduced the odds of ever drinking alcohol if youth had behavior problems (OR = 0.26, 95% CI [0.09, 0.72]) or problems at school (OR = 0.46, [0.26, 0.82]). MTO low-poverty treatment (vs. controls) also reduced the number of drinks if their health required special medicine/equipment (OR = 0.50 [0.32, 0.80]). Yet treatment effects were nonsignificant among youth without socioemotional vulnerabilities. Among mothers of children with learning problems, MTO voucher treatment (vs. controls) reduced past-month drinking (OR = 0.69 [0.47, 0.99]), but was harmful otherwise (OR = 1.22 [0.99, 1.45]). CONCLUSIONS: For low-income adolescents with special needs/socioemotional problems, housing vouchers protect against alcohol use.

"My motivation was to save": a qualitative study exploring factors influencing motivation of community healthcare workers in a cervical cancer screening program in Dschang, Cameroon.

BACKGROUND: Cervical cancer is a major public health issue among women in Cameroon and uptake of screening programs remains a challenge in many low- and middle-income countries. Community healthcare workers can play an important role in promoting cervical cancer services. This study aimed to explore factors affecting the motivation of community healthcare workers in a cervical cancer screening program in Dschang, Cameroon. METHODS: A qualitative approach including 11 in-depth individual interviews with community healthcare workers was used. The interviews were audio-recorded, transcribed and coded using thematic analysis assisted by ATLAS.ti software. RESULTS: Four women and seven men aged between 21 and 77 years old were interviewed. Community healthcare workers had high motivation. Factors affecting motivation were divided into individual and environmental level, based on a theoretical framework. Factors with a positive influence on motivation were mainly on the individual side while impeding factors were mainly associated with the environmental level. CONCLUSIONS: Key interventions to improve motivation among community healthcare workers include: (i) more training and supportive supervision; (ii) evaluation of remuneration systems by workload; and (iii) provision of job-enabling resources such as uniforms, cellphone cards and transport. TRIAL REGISTRATION: Geneva Cantonal Ethics Committee on Human Research (No. 2017-01110) and the Cameroonian National Ethics Committee for Human Health Research (No. 2018/07/1083/CE/CNERSH/SP).

Cervical cancer is the second leading cause of cancer-related death among women in Cameroon. This is mainly due to the absence of routine cervical cancer screening programs and the lack of treatment. However, even in case of availability of cervical cancer screening programs, barriers exist. Therefore, community healthcare workers have been involved successfully to increase the screening coverage. As retention of these actors remains a challenge, the main objective of this study was to identify key factors affecting their motivation aiming to suggest interventions to address motivational factors. 11 qualitative interviews with individual community healthcare workers were conducted at a cervical cancer screening program in Dschang, Cameroon. Motivation was generally high and affecting factors were divided into the individual and the environmental level. Factors with a positive influence on motivation were mainly on the individual side while impeding factors were mainly associated with the environmental level. Ongoing collaboration with community healthcare workers is beneficial for cervical cancer screening programs, and key interventions should therefore include: (i) more training and supportive supervision; (ii) evaluation of remuneration systems by workload; and (iii) provision of job-enabling resources such as uniforms, cellphone cards and transport.

Do Alcohol Outlets Mediate the Effects of the Moving to Opportunity Experiment on Adolescent Excessive Drinking? A Secondary Analysis of a Randomized Controlled Trial.

Background: Housing mobility impacts adolescent alcohol use, and the neighborhood built environment may impact this relationship. Methods: Moving to Opportunity (MTO) was a multi-site, three-arm, household-level experiment. MTO randomly assigned one of three treatment arms (1994-1997) allowing families living in public housing to (1) receive a voucher to be redeemed any neighborhood (2) receive a voucher to be redeemed in a neighborhood with less than 10% poverty (3) remain in public housing (control). MTO decreased girls' alcohol use, but increased boys' alcohol use. Treatment groups were pooled because they are similar conceptually and statistically on our primary outcome. Among youth aged 12-19 in 2001-2002 (N = 2829), we estimated controlled direct effects mediation of MTO treatment effects on youth with housing vouchers (N = 1950) vs. controls (N = 879) on past 30-day number of drinks per day on days drank, using gender-stratified Poisson regression. Mediators were density of on- and off-premises alcohol outlets per square mile at the families' census tract of residence in 1997. Results: Treatment group youth were randomized to live in 1997 census tracts with lower off-premises, but higher on-premises, outlet density. MTO treatment (vs. controls) decreased drinking for girls via alcohol outlet density, but only at higher levels of outlet density. Treatment was 18% more beneficial when girls moved to high density neighborhoods, compared to controls who stayed living in public housing in high density neighborhoods. Conclusion: Additional social processes unmeasured in the current study may play an important role in the alcohol use and other health risks for girls.

[Healthcare-associated infections and antimicrobial use in long-term care facilities. German results of the third European point prevalence survey HALT-3]. / Nosokomiale Infektionen und Antibiotikaanwendung in Langzeitpflegeeinrichtungen. Deutsche Ergebnisse der dritten europäischen Punkt-Prävalenz-Erhebung HALT-3.

BACKGROUND AND OBJECTIVE: The essential role of infection prevention in long-term care facilities has become evident during the current SARS-CoV­2 pandemic. In order to obtain a reliable database on nosocomial infections and antibiotic use, the European Centre for Disease Prevention and Control (ECDC) initiated the third point prevalence survey in European long-term care facilities from 2016 to 2017 (HALT-3). MATERIAL AND METHODS: In Germany, 131 facilities with 10,565 residents participated voluntarily. On a single day in 2016, the number of nosocomial infections and/or uses of antibiotics as well as care characteristics and risk factors of the residents were recorded. Infections were documented based on symptoms using an algorithm in accordance with the McGeer surveillance criteria for long-term care facilities. RESULTS: A nosocomial infection was documented in 177 residents, which corresponds to a prevalence of 1.7% (95% CI: 1.3-2.1), still low in comparison with the European prevalence (mean value 3.9%). Urinary tract infections were the most common infections at almost 50%, followed by respiratory, skin, and soft-tissue infections. The type of infection was consistent with the most common indications for antibiotic use. Antibiotic use was documented in 143 residents (prevalence of 1.4%, 95% CI: 1.1-1.7). The frequent use of fluoroquinolones with over 20% of all prescriptions was noticeable. CONCLUSIONS: The establishment of facility-based surveillance of the most common infections and antibiotic consumption, together with the creation of guidelines specifically tailored to the geriatric population, could contribute to improving infection prevention and control as well as a more rational use of antibiotics, thus increasing the quality and safety of care.

Temporal trends of mercury levels in fish (dab, Limanda limanda) and sediment from the German Bight (North Sea) in the period 1995-2020.

As a toxic and harmful global pollutant, mercury (Hg) enters the marine environment through natural sources, and human activities. It bioaccumulates through the food chain and therefore, Hg is of great importance for environmental monitoring. This study aims to answer the question if Hg contamination in fish and sediment from the German Bight follows temporal trends. Therefore, 496 individual female dab (Limanda limanda) were analyzed. The Hg concentrations in the muscle of dab from the German Bight showed significant increase in function of time with an annual percental change of 1.4%, leading to a 41% increase in Hg contamination level within 25 years of monitoring. At the same time, Hg concentrations in sediment-analyzed in 86 samples-significantly decreased in the nearby North Sea environment. This surprising contradiction is shown in the present study and possible causes are discussed. It could be clearly shown that contamination in sediment and biota can follow completely different time courses and therefore, different environmental matrices should be considered in future monitoring studies. Age of the fish turned out to be a biological factor of particular importance for temporal trend analysis.

Does the Temporal Pattern of Moving to a Higher-Quality Neighborhood Across a 5-Year Period Predict Psychological Distress Among Adolescents? Results From a Federal Housing Experiment.

Using data from the Moving to Opportunity (MTO) experiment (1994-2002), this study examined how a multidimensional measure of neighborhood quality over time influenced adolescent psychological distress, using instrumental variable (IV) analysis. Neighborhood quality was operationalized with the independently validated 19-indicator Child Opportunity Index (COI), linked to MTO family addresses over 4-7 years. We examined whether being randomized to receive a housing subsidy (versus remaining in public housing) predicted neighborhood quality across time. Using IV analysis, we tested whether experimentally induced differences in COI across time predicted psychological distress on the Kessler Screening Scale for Psychological Distress (n = 2,829; mean ß = -0.04 points (standard deviation, 1.12)). The MTO voucher treatment improved neighborhood quality for children as compared with in-place controls. A 1-standard-deviation change in COI since baseline predicted a 0.32-point lower psychological distress score for girls (ß = -0.32, 95% confidence interval: -0.61, -0.03). Results were comparable but less precisely estimated when neighborhood quality was operationalized as simply average post-random-assignment COI (ß = -0.36, 95% confidence interval: -0.74, 0.02). Effect estimates based on a COI excluding poverty and on the most recent COI measure were slightly larger than other operationalizations of neighborhood quality. Improving a multidimensional measure of neighborhood quality led to reductions in low-income girls' psychological distress, and this was estimated with high internal validity using IV methods.

An in vitro pharmacodynamic spiking study of befovacimab, a tissue factor pathway inhibitor monoclonal antibody, in blood samples from patients with severe FVIII deficiency.

INTRODUCTION: Tissue factor pathway inhibitor (TFPI) is an endogenous protein that inhibits the extrinsic (tissue factor) pathway and negatively regulates thrombin production during coagulation. Inhibiting TFPI may become a useful target for haemophilia drug development to allow greater thrombin generation without use of the intrinsic (contact) pathway. AIMS: The in vitro effects of befovacimab, a humanized TFPI neutralizing antibody, were studied in whole blood and plasma samples from patients with severe FVIII deficiency. METHODS: Blood and plasma obtained from participants was supplemented in vitro with befovacimab (0.5, 1, 5, 10 and 100 nM) or recombinant factor VIII (rFVIII) 5-, 10- and 40% and analysed using rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay. The in vitro coagulation effects of befovacimab were compared to samples supplemented with rFVIII. RESULTS: Befovacimab induced consistent pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in α-angle; induced reductions in dPT clotting time; and improvements in TGA parameters (reduced lag time and increased thrombin generation parameters). There was a modest concentration-dependent response generally from 0.5- to 10 nM, after which, the pharmacodynamic effect plateaued through the 100 nM concentration. Befovacimab concentrations of 5 to 10 nM showed pro-coagulant activity comparable to blood samples supplemented with rFVIII 10-40%. CONCLUSIONS: Befovacimab has modest dose-response effects from 0.5 to 10 nM with minimal improvement with higher concentrations. In vitro befovacimab blood concentrations of 5 to 10 nM had pro-coagulant effects similar to blood supplemented with rFVIII 10- to 40%.

"Cervical cancer screening: awareness is not enough". Understanding barriers to screening among women in West Cameroon-a qualitative study using focus groups.

BACKGROUND: Cervical cancer is the second leading cause of cancer-related death among women in sub-Saharan countries, constituting a major public health concern. In Cameroon, cervical cancer ranks as the second most common type of cancer among women and the leading cause of cancer-related deaths, mainly due to the lack of prevention. OBJECTIVES: Our first and main objective was to understand the barriers affecting women's decision-making process regarding participation in a cervical cancer screening program in the Dschang district (West Cameroon). Second, we aimed to explore the acceptability and perception of a single-visit approach (screen and treat). METHODS: A qualitative study using focus groups (FGs) was conducted from February to March 2020. Female participants aged between 30 and 49 years and their male partners were invited to participate. Thematic analysis was used, and barriers were classified according to the three-delay model of Thaddeus and Maine. RESULTS: In total, six FGs with 43 participants (31 women and 12 men) were conducted. The most important barriers were lack of health literacy, low accessibility of the program (in respect to cost and distance), and disrespectful treatment by healthcare workers. CONCLUSIONS: Our study identified three needs: (1) enhancing health literacy; (2) improving the delivery of cervical cancer screening in rural areas; and (3) providing training for healthcare providers and community healthcare workers to improve patient-provider-communication. Trial registration Ethical Cantonal Board of Geneva, Switzerland (CCER, N°2017-0110 and CER-amendment n°3) and Cameroonian National Ethics Committee for Human Health Research (N°2018/07/1083/CE/CNERSH/SP). NCT: 03757299.

Cervical cancer is the second leading cause of cancer-related death among women in sub-Saharan countries, constituting a major public health concern. In Cameroon, cervical cancer ranks as the second most common type of cancer among women and is the leading cause of cancer-related deaths, mainly due to the lack of prevention measures, such as cervical cancer screening.The main aim of the current study was to understand barriers that affect women's decision-making processes regarding participation in a cervical cancer screening program in the Dschang district in West Cameroon.A qualitative study methodology using focus group discussions was conducted from February to March 2020. Female participants aged between 30 and 49 years and their male partners were invited to participate.In total, six discussion groups with 43 participants (31 women and 12 men) were conducted. The most important barriers were a lack of health literacy, limited access to the program because of cost and distance, and disrespectful treatment by healthcare workers.Our results identified three key areas for improvement: first, increasing health literacy; second, providing cervical cancer screening in rural areas; and third, training healthcare providers and community healthcare workers in better patient-provider-communication.

Longitudinal effects of family psychopathology and stress on pubertal maturation and hormone coupling in adolescent twins.

Adolescents experience profound neuroendocrine changes, including hormone "coupling" between cortisol, testosterone, and dehydroepiandrosterone. Emerging research has only begun to elucidate the role of hormone coupling, its genetic and environmental etiology, and the extent to which coupling is impacted by gender, puberty, and family context. We included measures on parent and child mental health, parenting stress, and family conflict of 444 twin pairs and their parents across two timepoints, when youth were on average 8 and 13 years old, respectively. Structural equation models examined the impact of family context effects on coupling during adolescence. Biometric twin models were then used to probe additive genetic, shared, and non-shared environmental effects on hormone coupling. Hormones were more tightly coupled for females than males, and coupling was sensitive to parental depression and co-twin psychopathology symptoms and stress exposure in females. The association between family context and coupling varied across specific neuroendocrine measures and was largely distinct from pubertal maturation. Biometric models revealed robust shared and non-shared environmental influences on coupling. We found that family antecedents modify the strength of coupling. Environmental influences account for much of the variation on coupling during puberty. Gender differences were found in genetic influences on coupling.

Deep impact? Is mercury in dab (Limanda limanda) a marker for dumped munition? Results from munition dump site Kolberger Heide (Baltic Sea).

Dumped munitions contain various harmful substances which can affect marine biota like fish. One of them is mercury (Hg), included in the common explosive primer Hg fulminate. There is still a lack of knowledge whether dumped munitions impact the Hg concentrations in the Baltic Sea environment. This study aims to answer the question if dab caught at the dump site Kolberger Heide show higher Hg concentrations released from munition sources and whether Hg in fish is a usable marker for munition exposure. Therefore, a total of 251 individual dab (Limanda limanda) were analysed including 99 fish from the dump site. In fish from the Kolberger Heide, no elevated Hg concentrations were found compared to reference sites when age-dependent bioaccumulation of mercury was considered. Therefore we conclude that Hg in fish is no suitable indicator for exposure to munition dumping, e.g. in the frame of possible future monitoring studies as Hg exposure originating from dumped munition is only a small contributor to overall Hg exposure of fish.

Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterisation study.

BACKGROUND: Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis. METHODS: We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients. RESULTS: Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69+ T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69+ cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69+ and CD69- populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis. CONCLUSIONS: This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.

Using Transportability to Understand Differences in Mediation Mechanisms Across Trial Sites of a Housing Voucher Experiment.

BACKGROUND: Randomized trials may have different effects in different settings. Moving to Opportunity (MTO), a housing experiment, is one such example. Previously, we examined the extent to which MTO's overall effects on adolescent substance use and mental health outcomes were transportable across the sites to disentangle the contributions of differences in population composition versus differences in contextual factors to site differences. However, to further understand reasons for different site effects, it may be beneficial to examine mediation mechanisms and the degree to which they too are transportable across sites. METHODS: We used longitudinal data from MTO youth. We examined mediators summarizing aspects of the school environment over the 10-15 year follow-up. Outcomes of past-year substance use, mental health, and risk behavior were assessed at the final timepoint when participants were 10-20 years old. We used doubly robust and efficient substitution estimators to estimate (1) indirect effects by MTO site and (2) transported indirect effects from one site to another. RESULTS: Differences in indirect effect estimates were most pronounced between Chicago and Los Angeles. Using transport estimators to account for differences in baseline covariates, likelihood of using the voucher to move, and mediator distributions partially to fully accounted for site differences in indirect effect estimates in 10 of the 12 pathways examined. CONCLUSIONS: Using transport estimators can provide an evidence-based approach for understanding the extent to which differences in compositional factors contribute to differences in indirect effect estimates across sites, and ultimately, to understanding why interventions may have different effects when applied to new populations.

Genome-wide SNP typing of ancient DNA: Determination of hair and eye color of Bronze Age humans from their skeletal remains.

OBJECTIVE: A genome-wide high-throughput single nucleotide polymorphism (SNP) typing method was tested with respect of the applicability to ancient and degraded DNA. The results were compared to mini-sequencing data achieved through single base extension (SBE) typing. The SNPs chosen for the study allow to determine the hair colors and eye colors of humans. MATERIAL AND METHODS: The DNA samples were extracted from the skeletal remains of 59 human individuals dating back to the Late Bronze Age. The 3,000 years old bones had been discovered in the Lichtenstein Cave in Lower Saxony, Germany. The simultaneous typing of 24 SNPs for each of the ancient DNA samples was carried out using the 192.24 Dynamic Array™ by Fluidigm®. RESULTS: Thirty-eight of the ancient samples (=64%) revealed full and reproducible SNP genotypes allowing hair and eye color phenotyping. In 10 samples (=17%) at least half of the SNPs were unambiguously determined, in 11 samples (=19%) the SNP typing failed. For 23 of the 59 individuals, a comparison of the SNP typing results with genotypes from an earlier performed SBE typing approach was possible. The comparison confirmed the full concordance of the results for 90% of the SNP typings. In the remaining 10% allelic dropouts were identified. DISCUSSION: The high genotyping success rate could be achieved by introducing modifications to the preamplification protocol mainly by increasing the DNA input and the amplification cycle number. The occurrence of allelic dropouts indicates that a further increase of DNA input to the preamplification step is desirable.

High impact of COVID-19 in long-term care facilities, suggestion for monitoring in the EU/EEA, May 2020.

Residents in long-term care facilities (LTCF) are a vulnerable population group. Coronavirus disease (COVID-19)-related deaths in LTCF residents represent 30-60% of all COVID-19 deaths in many European countries. This situation demands that countries implement local and national testing, infection prevention and control, and monitoring programmes for COVID-19 in LTCF in order to identify clusters early, decrease the spread within and between facilities and reduce the size and severity of outbreaks.

[Prevalence of multiresistant gram-negative bacteria in inhabitants of long-term care facilities in 2019 in Thuringia]. / Prävalenz von multiresistenten gramnegativen Erregern bei Bewohnern von stationären Pflegeeinrichtungen 2019 in Thüringen.

BACKGROUND: Multidrug-resistant gram-negative bacteria (MDRGN) pose an emerging threat in German hospitals and in the outpatient sector. However, only few studies have investigated the prevalence of MDRGN in nonhospital settings and the associated risk factors for colonization. OBJECTIVE: In our study we determined the prevalence of MDRGN in inhabitants of long-term care facilities (LTCFs) and associated risk factors for colonization in the region Weimar, Weimarer Land, and Jena. METHODS: Between May and August 2019, deep rectal swabs were taken from 307 inhabitants of 13 facilities and examined microbiologically for the presence of MDRGN. Furthermore, using a standardized questionnaire, the characteristics of the inhabitants were collected and their association with the likelihood for colonization with MDRGN was analyzed. RESULTS: MDRGN were found in 59 swabs, predominantly Escherichia coli (95%). The weighted prevalence of extended spectrum beta-lactamase-producing bacteria was 19.1% and for MDRGN with additional resistances to fluoroquinolones was 12.3%. Resistances to carbapenems or carbapenemases were not found. Multivariable as well as univariable analysis recognized the presence of chronic wounds to be a potential risk factor (OR: 2,66 [95 %-CI: 1,54-4,60]). Additionally, the univariable analysis detected the necessity of a wheelchair and the accommodation in double rooms as risk factors. DISCUSSION: The prevalence of MDRGN found in our study is similar to findings of previous German studies. The result shows the importance of strict compliance with basic hygiene guidelines for all inhabitants of LTCFs for the prevention of transmission of MDRGN.