OPTIMA-BP: empOwering PaTients in MAnaging Blood Pressure - protocol for a randomised parallel group study comparing use of Kvatchii web-based patient education portal as an addition to home blood pressure monitoring.

INTRODUCTION: Hypertension is the leading modifiable risk factor for cardiovascular disease and is implicated in half of all strokes and myocardial infarctions. One-third of the adults in Scotland have hypertension yet only a quarter of them have their blood pressure (BP) controlled to target (<140/90 mm Hg). Empowering patients to have a better understanding of their condition and becoming actively involved in the monitoring and management of hypertension may lead to improved patient satisfaction, improved BP control and health outcomes and reduction in the use of primary/secondary care hypertension clinics. METHODS AND ANALYSIS: OPTIMA-BP is a randomised parallel group pilot study comparing the use of home BP monitoring accompanied by access to the web-based cardiovascular educational portal (Kvatchii) and home BP monitoring (HBPM) alone in 200 patients with hypertension attending the Glasgow Blood Pressure Clinic, Queen Elizabeth University Hospital, Glasgow. Consented participants will be asked to complete surveys on lifestyle factors, medication adherence, quality of life and hypertension knowledge, understanding and home monitoring. The intervention group will be asked to complete a survey to help evaluate the Kvatchii portal. At 6 and 12 months, the surveys will be repeated via the CASTOR EDC. Both groups will input their HBPM results at 2-month intervals into a CASTOR-EDC survey. OPTIMA-BP will follow-up with participants over 12 months with the study running over 24 months. The primary outcome is HBPM systolic BP area under the curve between baseline and 6 months ETHICS AND DISSEMINATION: OPTIMA-BP was approved by the North of Scotland Research Ethics Committee 2 (22/NS/0095). Current protocol version 1.2 date 6 June 2023. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed journals and will be presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05575453. Registered 12 October 2022. https://clinicaltrials.gov/ct2/show/NCT05575453.

Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia.

A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50 < 50 nM).

Engineering a Clinical Microsystem to Decrease Workplace Violence for Medically and Psychiatrically Concurrently Decompensated Patients.

BACKGROUND: Hospitalized medical patients with concurrently decompensated psychiatric and medical conditions experience worse clinical outcomes. Health care providers caring for this patient population are at increased risk of workplace violence. The authors sought to understand the effects of a clinical microsystem specifically designed to care for patients too psychiatrically ill for medical units and too medically ill for psychiatry units. METHODS: The research team performed a quality improvement study in which a medicine-psychiatry co-managed clinical microsystem incorporating high performance teamwork principles was engineered in an urban academic medical center to improve patient and staff safety, as well as operational outcomes. Poisson regression was performed to determine differences between workplace violence events, falls, 30-day emergency department (ED) revisits, and hospital readmissions, comparing the baseline period to the intervention period. RESULTS: There were 321 patients discharged in the baseline period and 310 during the intervention period. Workplace violence events decreased by 65.6% (incidence rate ratio [IRR] 0.34, 95% confidence interval [CI] 0.20-0.57, p < 0.001) after implementation of the clinical microsystem when compared to the baseline period. The rate of ED utilization at 30 days postdischarge also decreased from 30.6% at baseline to 21.0% postintervention (adjusted odds ratio [aOR] 0.60, 95% CI 0.42-0.87, p = 0.006). No differences were detected in falls and 30-day readmissions. CONCLUSION: For patients with concurrently decompensated medical and psychiatric conditions, the incidence of workplace violence and postdischarge ED utilization can be improved by creating a clinical microsystem that integrates changes to both the physical environment and teamwork processes.

SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain.

In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.

Optimised detection of mitochondrial DNA strand breaks.

Intrinsic and extrinsic factors that induce cellular oxidative stress damage tissue integrity and promote ageing, resulting in accumulative strand breaks to the mitochondrial DNA (mtDNA) genome. Limited repair mechanisms and close proximity to superoxide generation make mtDNA a prominent biomarker of oxidative damage. Using human DNA we describe an optimised long-range qPCR methodology that sensitively detects mtDNA strand breaks relative to a suite of short mitochondrial and nuclear DNA housekeeping amplicons, which control for any variation in mtDNA copy number. An application is demonstrated by detecting 16-36-fold mtDNA damage in human skin cells induced by hydrogen peroxide and solar simulated radiation.

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

What is the role of mitochondrial dysfunction in skin photoaging?

Skin ageing is a complex process involving both internal and external factors, which leads to a progressive loss of cutaneous function and structure. Solar radiation is the primary environmental factor implicated in the development of skin ageing, and the term photoaging describes the distinct clinical, histological and structural features of chronically sun-exposed skin. The changes that accompany photoaging are undesirable for aesthetic reasons and can compromise the skin and make it more susceptible to a number of dermatological disorders. As a result, skin ageing is a topic that is of growing interest and concern to the general population, illustrated by the increased demand for effective interventions that can prevent or ameliorate the clinical changes associated with aged skin. In this viewpoint essay, we explore the role that mitochondria play in the process of skin photoaging. There is continuing evidence supporting the proposal that mitochondrial dysfunction and oxidative stress are important contributing factors in the development of skin photoaging. Further skin-directed mitochondrial research is warranted to fully understand the impact of mitochondrial status and function in skin health. A greater understanding of the ageing process and the regulatory mechanisms involved could lead to the development of novel preventative interventions for skin ageing.

Cannabis and development of dual diagnoses: A literature review.

BACKGROUND: The use of cannabis has garnered more attention recently with ongoing efforts at marijuana legalization. The consequences of cannabis use are not clearly understood and remain a concern. OBJECTIVES: To review the acute and persistent effects of cannabis use and associations with psychiatric disorders. METHODS: Using Pubmed and PsychInfo, we conducted a narrative review of the literature on cannabis and psychiatric comorbidity using the keywords cannab*, marijuana, schizo*, psychosis, mood, depression, mania, bipolar, and anxiety. RESULTS: There is substantial evidence of cannabis use leading to other illicit drug use and of an association between cannabis use and psychosis. A few reports suggest an association with bipolar disorder while the association with depression and anxiety disorders is mixed. CONCLUSIONS: Whenever an association is observed between cannabis use and psychiatric disorders, the relationship is generally an adverse one. Age at the time of cannabis use appears to be an important factor with stronger associations observed between adolescent onset cannabis use and later onset of psychiatric disorders. Additional studies taking into account potential confounds (such as withdrawal symptoms, periods of abstinence, and other substance use) and moderators (such as age of initiation of cannabis use, the amount and frequency of drug use, prior history of childhood maltreatment, and gender) are needed to better understand the psychiatric consequences of cannabis use.

Cognitive Function in Individuals With Psychosis: Moderation by Adolescent Cannabis Use.

Prior cannabis use, compared to nonuse, is reported to be associated with less cognitive impairment in schizophrenia. The age of cannabis use and the persistent influence of cannabis use on cognitive function has not been examined across the psychosis dimension. Ninety-seven volunteers with psychosis (schizophrenia, schizoaffective, or bipolar psychosis) and 64 controls were recruited at the Dallas site of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Cannabis use history obtained in a semi-structured manner was used to categorize subjects into nonusers, adolescent-onset users, and late-onset users. The a priori hypothesis tested was that individuals with psychosis and a history of adolescent cannabis use (ACU) would have better global neuropsychological performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) battery, compared to those with psychosis and no cannabis use history. BACS Composite scores were significantly higher in individuals with psychosis with ACU compared to individuals with psychosis and no prior cannabis use. In subgroup analyses, ACU influenced global cognition in the schizophrenia/schizoaffective (SCZ) subgroup but not the bipolar psychosis subgroup. Exploratory analyses within the SCZ group, suggest that ACU was associated with better performance in specific domains compared to non-ACU groups. There are distinct associations between age of cannabis use and neuropsychological function across psychotic illnesses. Specifically, ACU is associated with better cognitive function in SCZ but not bipolar psychosis. This age-dependent and diagnosis-specific influence of cannabis may need to be factored into the design of future cognitive studies in SCZ.

Teaching psychiatry residents about suicide loss: impact of an educational program.

OBJECTIVE: The aim of this report is to study the impact of a pilot educational event on psychiatry residents' attitudes towards suicidal patients, understanding of their family members' experience, and intended management of patients who died by suicide. METHODS: A panel of suicide loss survivors spoke to psychiatry residents during an educational event. Psychiatry residents who attended the event were asked to complete a survey after the event. RESULTS: About a third of residents (29.4 %) reported encountering a patient suicide during training. Overall, psychiatry residents subjectively felt the program had a positive impact on their understanding of suicide loss and on their attitudes towards suicide and towards engagement with family members of patients who died by suicide. CONCLUSIONS: The data collected in this study suggest that educational programs focused on patient suicide from the surviving families' perspective may have a positive impact on the attitudes and future practice of residents.

In vitro expanded CD4+CD25+Foxp3+ regulatory T cells maintain a normal phenotype and suppress immune-mediated ocular surface inflammation.

PURPOSE: To determine whether in vitro expanded CD4(+)CD25(+)Foxp3(+) regulatory T cells can suppress immune-mediated ocular surface inflammation in a mouse model of dry eye. METHODS: C57BL/6 or BALB/c mice were exposed to a dry, desiccating environment produced by maintaining low humidity (<40%), injections of scopolamine, and air flow produced by a fan. CD4(+)CD25(+) regulatory T cells were isolated and expanded in vitro in the presence of rmIL-2 and beads coated with anti-CD28 and anti-CD3. In vitro expanded regulatory T cells were phenotypically compared with freshly isolated regulatory T cells by flow cytometry and immunofluorescence. T-cell-deficient nude mice were reconstituted with CD4(+) T-effector cells from donor mice exposed to a desiccating environment for 5 days, in combination with or without freshly isolated or in vitro expanded regulatory T cells. Tear cytokine levels were determined by a multiplex bead-based immunoassay. RESULTS: In vitro regulatory T cells maintained normal levels of CD4(+), CD25(+), and intracellular Foxp3(+), as determined by flow cytometry and immunohistochemistry. Freshly isolated and in vitro regulatory T cells were titrated in the presence of CD4(+) pathogenic T cells (CD4(+Path) T cells) in reconstitution experiments and most efficiently ablated tear cytokine levels and conjunctival cellular infiltration at a ratio of 1:1 (T Regs:CD4(+Path)). CONCLUSIONS: Regulatory T cells expressed CD4(+), CD25(+), and intracellular Foxp3(+) at normal levels and retained their inhibitory function after in vitro expansion, providing a useful tool to determine the mechanism regulatory T cells use to sustain a homeostatic environment on the ocular surface.

Neural processing underlying tactile microspatial discrimination in the blind: a functional magnetic resonance imaging study.

Although blindness alters neocortical processing of non-visual tasks, previous studies do not allow clear conclusions about purely perceptual tasks. We used functional magnetic resonance imaging (fMRI) to examine the neural processing underlying tactile microspatial discrimination in the blind. Activity during the tactile microspatial task was contrasted against that during a tactile temporal discrimination task. The spatially selective network included frontoparietal and visual cortical regions. Activation magnitudes in left primary somatosensory cortex and in visual cortical foci predicted acuity thresholds. Effective connectivity was investigated using multivariate Granger causality analyses. Bilateral primary somatosensory cortical foci and a left inferior temporal focus were important sources of connections. Visual cortical regions interacted mainly with one another and with somatosensory cortical regions. Among a set of distributed cortical regions exhibiting greater spatial selectivity in early blind compared to late blind individuals, the age of complete blindness was predicted by activity in a subset of frontoparietal regions and by the weight of a path from the right lateral occipital complex to right occipitopolar cortex. Thus, many aspects of neural processing during tactile microspatial discrimination differ between the blind and sighted, with some of the key differences reflecting visual cortical engagement in the blind.

Effect of prefrontal cortex damage on resolving lexical ambiguity in text.

The function of suppression of context-inappropriate meanings during lexical ambiguity resolution was examined in 25 adults with prefrontal cortex damage (PFCD) localized to the left (N=8), right (N=6), or bilaterally (N=11); and 21 matched Controls. Results revealed unexpected inverse patterns of suppression between PFCD and Control groups, with measures suggesting decreased interference across time in the PFCD group and increased interference in the Control group. The PFCD group, however, had significantly lower accuracy rates for the context-inappropriate condition. Results suggest a loss of the control aspects of inhibitory processes in lexical ambiguity resolution following PFCD. An aging effect on suppression function is also suggested.