Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

Background: We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data. Method and results: A panel of congenic sub-strains were generated containing Wistar-Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function. Conclusion: This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge

Differential expression of microRNA-206 and its target genes in pre-eclampsia

Objectives: Pre-eclampsia is a multi-system disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify novel circulating miRNAs in maternal plasma that may be associated with pre-eclampsia. Methods: Plasma samples were obtained at 16 and 28 weeks of gestation from 18 women who later developed pre-eclampsia (cases) and 18 matched women with normotensive pregnancies (controls). We studied miRNA expression profiles in plasma and subsequently confirmed miRNA and target gene expression in placenta samples. Placental samples were obtained from an independent cohort of 19 women with pre-eclampsia matched with 19 women with normotensive pregnancies. Results: From the microarray, we identified 1 miRNA that was significantly differentially expressed between cases and controls at 16 weeks of gestation and 6 miRNAs that were significantly differentially expressed at 28 weeks. Following qPCR validation only one, miR-206, was found to be significantly increased in 28 week samples in women who later developed pre-eclampsia (1.4 fold change ± 0.2). The trend for increase in miR-206 expression was mirrored within placental tissue from women with pre-eclampsia. In parallel, IGF-1, a target gene of miR-206, was also found to be down-regulated (0.41 ± 0.04) in placental tissue from women with pre-eclampsia. miR-206 expression was also detectable in myometrium tissue and trophoblast cell lines. Conclusions: Our pilot study has identified miRNA-206 as a novel factor up-regulated in pre-eclampsia within the maternal circulation and in placental tissue

Levels of physical activity and sleep patterns among older people with dementia living in long-term care facilities: A 24-hour snapshot

Objectives To objectively measure over a 24-hour period the daytime and nighttime levels of physical activity and sleep patterns of older people with dementia living in long-term care facilities. Study design Nested within a larger research program, this cross-sectional study involved 415 residents, aged ≥60 years, with a documented diagnosis of dementia, from 28 long-term care facilities in south-east Queensland, Australia. Main outcome measures Residents wore SenseWear® activity armbands continuously for 24 hours, with data recorded for: step count; total energy expenditure; metabolic equivalent of task (MET); and the amount of time spent physically active, lying down, awake and asleep. Residents’ levels of cognitive impairment (assessed using the Rowland Universal Dementia Assessment Scale) and agitation (assessed using the Cohen-Mansfield Agitation Inventory-Short Form), and demographic data were also collected. Results From a total of 415 residents monitored with the SenseWear® activity armbands, 192 met the valid wear-time of 21 hours or more, and had activity and sleep data recorded. These residents were largely inactive during the daytime (engaged in an average of 1.8 hours of light physical activity), but achieved recommended amounts of sleep at night (average of 6.8 hours). There was considerable variation within the sample, and activity and sleep differed by sex (p<.001), age (p=.010), mobility (p<.001), and antipsychotic usage (p=.030). Conclusions These data can be used by long-term care clinicians to assist in planning interventions and care approaches which promote physical activity and good sleep practices, and are individualized to physical and cognitive capabilities. Australian New Zealand Clinical Trials Registry (ACTRN12614000508673).NHMR

The compendium of self-enactable techniques to change and self-manage motivation and behaviour v.1.0

Behaviour change techniques describe the content of behaviour change interventions, but do not adequately account for the actions that people must themselves undertake to successfully change or self-manage motivation or behaviour. This paper describes the development of a compendium of self-enactable techniques, combining behaviour- and motivation-regulation techniques across six existing classifications of behaviour change techniques and three scoping reviews. The compendium includes 123 techniques, each of which is labelled, defined and presented with instructive examples to facilitate self-enactment. Qualitative feedback was gathered from intervention developers and the general public to improve the utility, congruence and ease of self-enactability of the techniques. This integrative index of self-enactable techniques can assist intervention developers in selecting appropriate self-directed techniques to help people self-manage their motivation and behaviour. Future research with this compendium can expand on the number of behaviours covered by the instructive examples and link techniques with their potential impacts on factors that influence behaviours.Peer reviewe

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

Abstract Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P &lt; 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact

Gesture and naming therapy for people with severe aphasia: a group study

In this study, the authors (a) investigated whether a group of people with severe aphasia could learn a vocabulary of pantomime gestures through therapy and (b) compared their learning of gestures with their learning of words. The authors also examined whether gesture therapy cued word production and whether naming therapy cued gestures

Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease

Background: The effect of salt on cerebral small vessel disease (SVD) is poorly understood. We assessed the effect of dietary salt on the cerebral tissue of the strokeprone spontaneously hypertensive rat (SHRSP) - a relevant model of sporadic SVD - at both the gene and protein level. Methods: Brains from 21 week old SHRSP and Wistar-Kyoto rats, half additionally salt-loaded (via a 3 week regime of 1% NaCl in drinking water) were split into 2 hemispheres and sectioned coronally – one hemisphere for mRNA microarray and qRT-PCR, the other for immunohistochemistry using a panel of antibodies targeting components of the neurovascular unit. Results: We observed differences in gene and protein expression affecting the acute phase pathway and oxidative stress (ALB, AMBP, APOH, AHSG and LOC100129193, up-regulated in salt-loaded WKY versus WKY, &gt;2-fold), active microglia (increased Iba-1 protein expression in salt-loaded SHRSP versus saltloaded WKY, p&lt;0.05), vascular structure (ACTB &amp; CTNNB, up-regulated in saltloaded SHRSP versus SHRSP, &gt;3-fold; CLDN-11,VEGF and VGF downregulated &gt;- 2-fold in salt-loaded SHRSP versus SHRSP) and myelin integrity (MBP downregulated in salt loaded WKY rats versus WKY, &gt;2.5-fold). Changes of salt-loading were more pronounced in SHRSP and occurred without an increase in blood pressure in WKY rats. Conclusion: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short and long-term effect of dietary salt in SVD

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication

COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important. Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process. Human endothelial cells were exposed to SARS-CoV-2 spike protein, S1 subunit (rS1p) and pro-inflammatory signaling and inflammatory mediators assessed. ACE2 was modulated pharmacologically and by siRNA. Endothelial cells were also exposed to SARS-CoV-2. rSP1 increased production of IL-6, MCP-1, ICAM-1 and PAI-1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury. ACE2 interacting proteins involved in inflammation and RNA biology were identified in rS1p-treated cells. Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS-CoV-2 virus did not exhibit viral replication. We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID-19- associated endotheliitis

Prevalence and correlates of common mental health problems and recent suicidal thoughts and behaviours among female sex workers in Nairobi, Kenya.

BACKGROUND: Adverse childhood experiences (ACEs), poverty, violence and harmful alcohol/substance use are associated with poor mental health outcomes, but few studies have examined these risks among Female Sex Workers (FSWs). We examine the prevalence and correlates of common mental health problems including suicidal thoughts and behaviours among FSWs in Kenya. METHODS: Maisha Fiti is a longitudinal study among FSWs randomly selected from Sex Worker Outreach Programme (SWOP) clinics across Nairobi. Baseline behavioural-biological survey (n = 1003) data were collected June-December 2019. Mental health problems were assessed using the Patient Health Questionnaire (PHQ-9) for depression, the Generalised Anxiety Disorder tool (GAD-7) for anxiety, the Harvard Trauma Questionnaire (HTQ-17) for Post-Traumatic Stress Disorder (PTSD) and a two-item tool to measure recent suicidal thoughts/behaviours. Other measurement tools included the WHO Adverse Childhood Experiences (ACE) score, WHO Violence Against Women questionnaire, and the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Descriptive statistics and multivariable logistic regression were conducted using a hierarchical modelling approach. RESULTS: Of 1039 eligible FSWs, 1003 FSWs participated in the study (response rate: 96%) with mean age 33.7 years. The prevalence of moderate/severe depression was 23.2%, moderate/severe anxiety 11.0%, PTSD 14.0% and recent suicidal thoughts/behaviours 10.2% (2.6% suicide attempt, 10.0% suicidal thoughts). Depression, anxiety, PTSD and recent suicidal thoughts/behaviours were all independently associated with higher ACE scores, recent hunger (missed a meal in last week due to financial difficulties), recent sexual/physical violence and increased harmful alcohol/substance. PTSD was additionally associated with increased chlamydia prevalence and recent suicidal thoughts/behaviours with low education and low socio-economic status. Mental health problems were less prevalent among women reporting social support. CONCLUSIONS: The high burden of mental health problems indicates a need for accessible services tailored for FSWs alongside structural interventions addressing poverty, harmful alcohol/substance use and violence. Given the high rates of ACEs, early childhood and family interventions should be considered to prevent poor mental health outcomes

Conducting Violence and Mental Health Research with Female Sex Workers during the COVID-19 Pandemic: Ethical Considerations, Challenges, and Lessons Learned from the Maisha Fiti Study in Nairobi, Kenya.

Conducting violence and mental health research during the COVID-19 pandemic with vulnerable groups such as female sex workers (FSWs) required care to ensure that participants and the research team were not harmed. Potential risks and harm avoidance needed to be considered as well as ensuring data reliability. In March 2020, COVID-19 restrictions were imposed in Kenya during follow-up data collection for the Maisha Fiti study (n = 1003); hence data collection was paused. In June 2020, the study clinic was re-opened after consultations with violence and mental health experts and the FSW community. Between June 2020 and January 2021, data were collected in person and remotely following ethical procedures. A total of 885/1003 (88.2%) FSWs participated in the follow-up behavioural-biological survey and 47/47 (100%) participated in the qualitative in-depth interviews. A total of 26/885 (2.9%) quantitative surveys and 3/47 (6.4%) qualitative interviews were conducted remotely. Researching sensitive topics like sex work, violence, and mental health must guarantee study participants' safety and privacy. Collecting data at the height of COVID-19 was crucial in understanding the relationships between the COVID-19 pandemic, violence against women, and mental health. Relationships established with study participants during the baseline survey-before the pandemic-enabled us to complete data collection. In this paper, we discuss key issues involved in undertaking violence and mental health research with a vulnerable population such as FSWs during a pandemic. Lessons learned could be useful to others researching sensitive topics such as violence and mental health with vulnerable populations