Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Loss of chromosome Y in regulatory T cells.

BACKGROUND: Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples. RESULTS: Regulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells. CONCLUSIONS: Here, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.

Mosaicism in health and disease - clones picking up speed.

Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.

Enhancing compliance with waste sorting regulations through inspections and motivational interviewing.

This field experiment investigates the effect of first-time inspections of restaurants' waste sorting and explores whether motivational interviewing (MI) training of inspectors in this specific setting enhances the propensity of restaurants to be compliant with regulations. Our results show strong positive effects of first inspections with an average improvement of 55%. Also, the MI training of inspectors seems to affect compliance. However, this may also be a combined effect of the first inspection, MI training and more days between inspections. Further research is needed.

Increased rate of hospitalisation for COVID-19 among rituximab-treated multiple sclerosis patients: A study of the Swedish multiple sclerosis registry.

BACKGROUND: The primary objective of this study was to analyse the association between multiple sclerosis (MS) disease-modifying therapy (DMT) exposure and hospitalisation in patients infected with COVID-19. METHODS: Associations between MS DMT exposure and COVID-19 hospitalisation were analysed using univariable and multi-variable-clustered propensity score weighted logistic regression, where the models were clustered on the individual patients to control for patients contributing multiple COVID-19 episodes. FINDINGS: As of 18 January 2021, a total of 476 reported COVID-19 cases had been recorded in MS patients in the Swedish MS registry. Of these, 292 (61.3%) had confirmed COVID-19. The mean value (standard deviation (SD)) age at infection was 44.0 years (11.6). Of the 292 confirmed infections, 68 (23.2%) required hospitalisation. A total of 49 of the 164 confirmed COVID-19 patients on rituximab at baseline (29.9%) required hospitalisation, compared to a rate of 12.7% for all other DMTs combined. Rituximab in confirmed COVID-19 patients was associated with 2.95 times the odds of hospitalisation relative to any other DMT combined (odds ratio = 2.95; 95% confidence interval (CI) = 1.48-5.87). INTERPRETATION: Rituximab treatment, known to increase the risk of severe infections in general, also confers such a risk for MS patients with COVID-19, in comparison with other MS DMTs.

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.

Improved brain perfusion after electrical cardioversion of atrial fibrillation.

AIMS: Atrial fibrillation (AF) has been associated with reduced brain volume, cognitive impairment, and reduced cerebral blood flow. The causes of reduced cerebral blood flow in AF are unknown, but no reduction was seen in individuals without the arrhythmia in a previous study. The aim of this study was to test the hypothesis that brain perfusion, measured with magnetic resonance imaging (MRI), improves after cardioversion of AF to sinus rhythm (SR). METHODS AND RESULTS: All patients undergoing elective cardioversion at our institution were invited to participate. A total of 44 individuals were included. Magnetic resonance imaging studies were done before and after cardioversion with both brain perfusion and cerebral blood flow measurements. However, 17 did not complete the second MRI as they had a recurrence of AF during the observation period (recurrent AF group), leaving 17 in the SR group and 10 in the AF group to complete both measurements. Brain perfusion increased after cardioversion to SR by 4.9 mL/100 g/min in the whole brain (P < 0.001) and by 5.6 mL/100 g/min in grey matter (P < 0.001). Cerebral blood flow increased by 58.6 mL/min (P < 0.05). Both brain perfusion and cerebral blood flow remained unchanged when cardioversion was unsuccessful. CONCLUSION: In this study of individuals undergoing elective cardioversion for AF, restoration, and maintenance of SR for at least 10 weeks after was associated with an improvement of brain perfusion and cerebral blood flow measured by both arterial spin labelling and phase contrast MRI. In those individuals where cardioversion was unsuccessful, there was no change in perfusion or blood flow.

Providing objective feedback in supervision in motivational interviewing: results from a randomized controlled trial.

BACKGROUND: The effects of the use of objective feedback in supervision on the supervisory relationship and skill acquisition is unknown. AIMS: The objective of this study was to evaluate the effects of two different types of objective feedback provided during supervision in motivational interviewing (MI) on: (a) the supervisory relationship, including potential feelings of discomfort/distress, provoked by the supervision sessions, and (b) the supervisees' skill acquisition. METHOD: Data were obtained from a MI dissemination study conducted in five county councils across five county councils across Sweden. All 98 practitioners recorded sessions with standardized clients and were randomized to either systematic feedback based on only the behavioral component of a feedback protocol, or systematic feedback based on the entire protocol. RESULTS: The two different ways to provide objective feedback did not negatively affect the supervisory relationship, or provoke discomfort/distress among the supervisees, and the group that received the behavioural component of the feedback protocol performed better on only two of the seven skill measures. CONCLUSIONS: Objective feedback does not seem to negatively affect either the supervisor-supervisee working alliance or the supervisees' supervision experience. The observed differences in MI skill acquisition were small, and constructive replications are needed to ascertain the mode and complexity of feedback that optimizes practitioners' learning, while minimizing the sense of discomfort and distress.

Structural covariability hubs in old age.

Studies have shown that inter-individual differences in grey matter, as measured by voxel-based morphometry, are coordinated between voxels. This has been done by studying covariance maps based on a limited number of seed regions. Here, we used GPU-based (Graphics Processing Unit) accelerated computing to calculate, for the first time, the aggregated map of the total structural topographical organisation in the brain on voxel level in a large sample of 960 healthy individuals in the age range 68-83 years. This map describes for each voxel the number of significant correlations with all other grey matter voxels in the brain. Voxels that correlate significantly with many other voxels are called hubs. A majority of these hubs were found in the basal ganglia, the thalamus, the brainstem, and the cerebellum; subcortical regions that have been preserved through vertebrate evolution, interact with large portions of the neocortex and play fundamental roles for the control of a wide range of behaviours. No significant difference in the level of covariability could be found with increasing age or between men and women in these hubs.

Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

Self-reported sleep disturbances and prostate cancer morbidity and mortality in Swedish men: A longitudinal study over 40 years.

The present study, with an observational period of about 40 years, examined the association between self-reported sleep disturbances (i.e. problems with falling and staying asleep; use of hypnotics) and prostate cancer morbidity and mortality in initially 2322 men (all 50 years old at baseline). Self-reported sleep disturbances and established risk factors (e.g. age, lower urinary tract symptoms, smoking and family history of cancer) were measured at ages 50 and 70 years. Information about prostate cancer diagnosis and deaths as a result of prostate cancer was available from the National Cancer Registry and the Swedish Civil Registry of Morbidity. During the observational period, 263 participants developed prostate cancer (11% of the total cohort); 146 of them died as a result of prostate cancer. There was no association between sleep disturbances and prostate cancer morbidity or mortality (hazard ratio 1.09, 95% confidence interval (CI) 0.79, 1.52, and hazard ratio 1.21, 95% CI 0.77, 1.91, respectively). Similar findings were observed when examining associations between single sleep disturbance parameters and prostate cancer morbidity and mortality. Our study does not provide evidence that reports of sleep disturbances increase the risk of prostate cancer morbidity or mortality in middle to older-aged men. Therefore, assessing subjective sleep problems may not meaningfully help to identify men at risk of developing prostate cancer or dying of this devastating condition.

Loss of chromosome Y (LOY) in blood cells is associated with increased risk for disease and mortality in aging men.

Recent discoveries have shown that harboring cells without the Y chromosome in the peripheral blood is associated with increased risk for all-cause mortality and disease such as different forms of cancer, Alzheimer's disease, as well as other conditions in aging men. In the entire world, the life expectancy of men is shorter compared to women, a sex difference that has been known for centuries, but the underlying mechanism(s) are not well understood. As a male-specific genetic risk factor, an increased risk for pathology and mortality associated with mosaic loss of chromosome Y (LOY) in blood cells could help to explain that men on average live shorter lives compared to women. This review primarily focuses on observed associations between LOY in blood and various diseases in aging men. Other topics covered are known risk factors for LOY, methods to detect LOY, and a discussion regarding mechanisms such as immunosurveillance, that could possibly explain how an acquired mutation in blood cells can be associated with disease processes in other organs.

Allometric scaling of brain regions to intra-cranial volume: An epidemiological MRI study.

There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N = 3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. © 2016 Wiley Periodicals, Inc.

Relational Skills and Client Language Predict Outcome in Smoking Cessation Treatment.

BACKGROUND: We currently lack insight into the predictive processes of Motivational Interviewing (MI) in smoking cessation treatment. More knowledge is necessary to be able to further enhance the treatment effect in smoking cessation interventions. OBJECTIVES: To examine certain hypothesized active components of MI in smoking cessation treatment delivered in an ordinary clinical setting. METHODS: Audio-recordings of 106 smoking cessation treatment sessions were analyzed using the Motivational Interviewing Sequential Code for Observing Process Exchanges (MI-SCOPE) Coder's Manual and the Motivational Interviewing Treatment Integrity code (MITI) Manual, version 3.1. The outcome measure was self-reported 6-month continuous abstinence at 12-month follow-up. RESULTS: Client Activation utterances in favor of change were positively associated with smoking cessation at follow-up. The combined category of client language expressing a Desire or a Need to continue to smoke was negatively predictive of smoking cessation. In addition, we found preliminary support for a negative interaction effect between counselors' demonstration of the spirit of MI and clients Activation utterances in favor of change. Conclusions/Importance: Our data suggest that if smoking cessation counselors cultivate client Activation utterances in favor of abstinence and softening client utterances expressing desire or perceived need to smoke, this could contribute to higher rates of treatment success. In addition, counselors' demonstration of the spirit of MI was a statistically significant predictor of outcome when the negative interaction effect between Activation utterances in favor of change and MI spirit was taken into account. These findings should be evaluated in larger studies in the future.

Supervision in Motivational Interviewing: An Exploratory Study.

BACKGROUND: Although supervision is believed to be an important strategy for training practitioners in evidence-based practice, little is known about how it should be organized and conducted to promote implementation fidelity. AIMS: To explore supervisor behaviours that might facilitate supervisees' proficiency in motivational interviewing. METHOD: In this exploratory study, ten supervisors from a primary prevention intervention of childhood obesity responded to semi-structured interviews about their supervision behaviours. A mixed method approach was used; both qualitative and quantitative data were collected and analysed. RESULTS: The supervisors reported using several sources of information for evaluating and providing systematic feedback on supervisees' performance. However, the majority did not use the available objective measures of proficiency as the primary source. Moreover, half of the supervisors argued that objective feedback might have a punishing effect on the supervisees. CONCLUSIONS: Variation in the use of supervision components that previous research has proposed to be potentially influential to the process and outcome may lead to less efficient supervision. Findings suggest that appropriate supervision activities conducted in each supervision session require clear supervision principles that specify the content and procedure of the supervision, as well as regular adherence monitoring of the supervision sessions.

Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content.

AIMS: To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 µg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability. METHODS AND RESULTS: We examined 57 breast surgical specimens with multifocal (46/57) and unifocal (11/57) cancers. Punch biopsies were obtained from tissue slices under multimodal radiological guidance, and the colour-coded sampling sites were identified in large-format histology slides. The study comprised 415 DNA isolations from tumour (n = 105) and normal (n = 283) tissue, including skin (n = 27) samples. A single 2-mm core from invasive tumour contained sufficient DNA in 91.4% (96/105) of cases, depending on tumour type (3.8-108.2 µg/sample), number and size of additional foci in multifocal cases (P = 0.001), tumour consistency, and degree of necrosis. Three biopsies obtained with a 4-mm device were required from normal breast tissue, at least 10 mm from the tumour. Cold ischaemia for up to 82 min did not influence the yield of DNA. CONCLUSIONS: Radiological disease mapping is useful for guiding optimal specimen slicing and for targeting breast lesions. A single 2-mm core from tumour and multiple 4-mm cores from normal breast tissue yield adequate DNA in the majority of samples.