Trajectories of depressive symptoms 10 years after stroke and associated risk factors: a prospective cohort study.

BACKGROUND: Previous studies have investigated the risk factors for post-stroke depression at only one timepoint, neglecting its dynamic nature. We aimed to identify trajectories of post-stroke depression from multiple assessments and explore their risk factors. METHODS: We did a population-based cohort study with the South London Stroke Register (1995-2019). All stroke patients with three or more measurements of the Hospital Anxiety and Depression Scale were included. We identified trajectories of post-stroke depression over a 10-year follow-up using group-based trajectory modelling. We determined the optimal number and shape of trajectories based on the lowest Bayesian information criterion, average posterior probability of assignment of each group over 0·70, and inclusion of at least 5% of participants within each group. We used multinomial logistic regression adjusted for age, sex, ethnicity, comorbidity, physical disability, stroke severity, history of depression and cognitive impairment to explore associations with different trajectories. FINDINGS: The analysis comprised 1968 participants (mean age 64·9 years [SD 13·8], 56·6% male and 43·4% female, 65·1% white ethnicity, 30·7% severe disability and 32·7% severe stroke). We identified four patterns of symptoms: no depressive symptoms (14·1%, n=277), low symptoms (41·7%, n=820), moderate symptoms and symptoms worsening early and then improving (34·6%, n=681), and high and increasing symptoms (9·7%, n=190). Compared with no depressive symptom trajectory, patients with severe disability, severe stroke, pre-stroke depression, and cognitive impairment were more likely to be in the moderate and high symptom groups (adjusted odds ratios [ORs] 2·26 [95% CI 1·56-3·28], 1·75 [1·19-2·57], 2·20 [1·02-4·74], and 2·04 [1·25-3·32], respectively). Female sex was associated with high depression (OR 1·65 [1·13-2·41]), while older age (≥65 years) was associated with moderate depression (OR 1·82 [1·36-2·45]). In men, the ORs for patients with severe disability, severe stroke, pre-stroke depression, and cognitive impairment being in the high depression group were 1·91 (1·01-3·60), 2·41 (1·26-4·60), 2·57 (0·84-7·88), and 2·68 (1·28-5·60), respectively. In women, the ORs were 1·08 (0·52-2·23), 1·30 (0·60-2·79), 19·2 (2·35-156·05), and 3·80 (1·44-10·01), respectively. INTERPRETATION: Female sex and older age were associated with distinct courses of depressive symptoms. In men, high depressive symptom trajectory was associated with severe stroke and severe disability, which was not the case in women. These findings were limited to patients with three or more assessments, who tended to have less severe disabilities than excluded patients and might not generalise to all stroke survivors. FUNDING: National Institute for Health and Care Research (NIHR).

Barriers and facilitators to early mobilisation and weight-bearing as tolerated after hip fracture surgery among older adults in Saudi Arabia: a qualitative study.

OBJECTIVE: To explore the practice of prescribing and implementing early mobilisation and weight-bearing as tolerated after hip fracture surgery in older adults and identify barriers and facilitators to their implementation. METHODS: Semi-structured interviews were conducted with 20 healthcare providers (10 orthopaedic surgeons and 10 physiotherapists) from Saudi Arabian government hospitals. Data were analysed using inductive thematic analysis. RESULTS: While early mobilisation and weight-bearing as tolerated were viewed as important by most participants, they highlighted barriers to the implementation of these practices. Most participants advocated for mobility within 48 h of surgery, aligning with international guidance; however, the implementation of weight-bearing as tolerated was varied. Some participants stressed the type of surgery undertaken as a key factor in weight-bearing prescription. For others, local protocols or clinician preference was seen as most important, the latter partially influenced by where they were trained. Interdisciplinary collaboration between orthopaedic surgeons and physiotherapists was seen as a crucial part of postoperative care and weight-bearing. Patient and family member buy-in was also noted as a key factor, as fear of further injury can impact a patient's adherence to weight-bearing prescriptions. Participants noted a lack of standardised postoperative protocols and the need for routine patient audits to better understand current practices and outcomes. CONCLUSION: This study contributes to national and global discussions on the prescription of early mobilisation and weight-bearing as tolerated. It highlights the necessity for a harmonised approach, incorporating standardised, evidence-based protocols with patient-specific care, robust healthcare governance and routine audits and monitoring for quality assurance and better patient outcomes.

Improving Palivizumab Administration to High-Risk Infants with Heart Disease via a Communication-Based Quality Improvement Initiative.

To improve palivizumab administration in high-risk infants with congenital heart disease to 80% over 2 years at an academic children's heart center. A multidisciplinary team at our institution implemented a series of interventions over a 2-year prior. Pediatric cardiac patients were identified for palivizumab eligibility, and a baseline rate of administration was obtained. A series of communication and documentation-based interventions were implemented over the course of the next 2 years. Palivizumab eligible infants (n = 114) were determined based on guidelines after review of diagnosis code, oxygen saturation, and medications. Doses of palivizumab were tracked via the electronic health record. The primary outcome measures were the rate of monthly palivizumab doses administered per the number of eligible months and the percentage of infants who received at least 80% of eligible doses during the respiratory syncytial virus season. The rate of monthly palivizumab doses increased from 57.6% during the baseline period to 78.4% during the final year of the project (p = 0.02). The percentage of infants who received 80% of eligible doses increased from 42.1 to 60% but was not statistically significant (p = 0.20). Interventions focused on properly identifying and tracking infants eligible for palivizumab treatment significantly increased the rates of administration.

Prevalence and natural history of depression after stroke: A systematic review and meta-analysis of observational studies.

BACKGROUND: Depression is the most frequent psychiatric condition after stroke and is associated with negative health outcomes. We aim to undertake a systematic review and meta-analysis of the prevalence and natural history of depression after stroke. METHODS AND FINDINGS: Studies published up to 4 November 2022 on Medline, Embase, PsycINFO, and Web of Science Core Collection were searched. We included studies of adults with stroke, where depression was assessed at a prespecified time point. Studies excluding people with aphasia and history of depression are excluded. Critical Appraisal Skills Programme(CASP) cohort study tool was used to assess risk of bias. A total of 77 studies were included in the pooled estimates of the prevalence of poststroke depression (PSD). The overall prevalence of depression was 27% (95% CI 25 to 30). Prevalence of depression was 24% (95% CI 21 to 28) by clinical interview and 29% (95% CI 25 to 32) by rating scales. Twenty-four studies with more than one assessment time point reported the natural history of PSD. Among people who were depressed within 3 months of stroke, 53% (95% CI 47 to 59) experienced persistent depression, while 44% (95% CI 38 to 50) recovered. The incidence of later depression (3 to 12 months after stroke) was 9% (95% CI 7 to 12). The cumulative incidence during 1 year after stroke was 38% (95% CI 33 to 43), and the majority (71% (95% CI 65 to 76)) of depression had onset within 3 months after stroke. The main limitation of the present study is that excluding people in source studies with severe impairments may produce imprecise estimates of the prevalence of PSD. CONCLUSIONS: In this study, we observed that stroke survivors with early-onset depression (within 3 months after stroke) are at high risks for remaining depressed and make up two-thirds of the incident cases during 1 year after stroke. This highlights the need for ongoing clinical monitoring of patients depressed shortly after stroke. TRIAL REGISTRATION: PROSPERO CRD42022314146.

Cohort profile: The South London Stroke Register - a population-based register measuring the incidence and outcomes of stroke.

PURPOSE: The South London Stroke Register (SLSR) is a population-based cohort study, which was established in 1995 to study the causes, incidence, and outcomes of stroke. The SLSR aims to estimate incidence, and acute and long term needs in a multi-ethnic inner-city population, with follow-up durations for some participants exceeding 20 years. PARTICIPANTS: The SLSR aims to recruit residents of a defined area within Lambeth and Southwark who experience a first stroke. More than 7700 people have been registered since inception, and >2750 people continue to be followed up. At the 2011 census, the source population was 357,308. FINDINGS TO DATE: The SLSR was instrumental in highlighting the inequalities in risk and outcomes in the UK, and demonstrating the dramatic improvements in care quality and outcomes in recent decades. Data from the SLSR informed the UK National Audit Office in its 2005 report criticising the poor state of stroke care in England. For people living in the SLSR area the likelihood of being treated in a stroke unit increased from 19% in 1995-7 to 75% in 2007-9. The SLSR has investigated health inequalities in stroke incidence and outcome. SLSR analyses have demonstrated that lower socioeconomic status was associated with poorer outcome, and that Black people and younger people have not experienced the same improvements in stroke incidence as other groups. FUTURE PLANS: As part of an NIHR Programme Grant for Applied Research, from April 2022 the SLSR has expanded to recruit ICD-11 defined stroke (including those with <24 h symptoms where there are neuroimaging findings), and have expanded the follow up interviews to collect more detailed information on quality of life, cognition, and care needs. Additional data items will be added over the Programme based on feedback from patients and other stakeholders.

Stroke Outcomes in Women: A Population-Based Cohort Study.

BACKGROUND: Limited data are available on sex-related disparities in long-term outcomes after stroke. We estimated sex differences in various stroke long-term outcomes among survivors after stroke in a prospective 25-year follow-up study. METHODS: Individuals recruited to the South London Stroke Register, an ongoing multi-ethnic urban-based population stroke register, from 1995 onward were included in the analyses (n=6687). The outcomes were death, subsequent stroke, activity of daily living, instrumental activity of daily living, cognitive impairment, depression, anxiety, and health-related quality of life. Kaplan-Meier curves were generated for mortality, stroke recurrence, and recurrence-free survival by sex and Cox proportional hazards model used to model sex differences up to 25 years. Generalized estimating equation were used to model sex differences in risk of self-reported stroke outcomes over 10 years poststroke outcomes, adjusting for age, preexisting activity of daily living, case-mix, stroke subtypes, and other potential confounding risk factors. RESULTS: There were 49% women (mean age, 72 years; SD, 15.6) and 51% men (mean age, 67 years; SD, 14.3) in 6687 participants. Compared with men, women had 9% (95% CI, 3%-15%) lower covariate-adjusted risk of death and 6% (0%-13%) lower risk of stroke recurrence or death. Generally, women had significantly poorer outcomes in activity of daily living and anxiety than men, and the sex differences persisted to up to 5 years after stroke. Women also had poorer health-related quality of life in physical (ß=-2.06 [95% CI, -3.01 to -1.10]) and mental domains (ß=-1.48 [95% CI, -2.44 to -0.52]). Although not significant, there was a suggestive trend for poorer outcomes in cognitive impairment and depression in women. No significant difference in stroke recurrence were found between men and women. CONCLUSIONS: Female patients with stroke tended to have better covariate-adjusted survival but poorer outcomes among survivors than male patients, with deficits persisting to up to 5 years poststroke.

Do changes in outcomes following primary and revision hip replacement differ and relate to markers of socioeconomic status? A 1-year population-based cohort study.

BACKGROUND AND PURPOSE: There is little evidence on improvement after revision total hip replacement (THR). Moreover, improvements may be associated with socioeconomic status (SES). We investigated whether changes in Harris Hip Score (HHS) differ among patients undergoing primary and revision THR, and their association with markers of SES. PATIENTS AND METHODS: We conducted a populationbased cohort study on 16,932 patients undergoing primary and/or revision THR from 1995 to 2018 due to hip osteoarthritis. The patients were identified in the Danish Hip Arthroplasty Registry. Outcome was defined as mean change in HHS (0-100) from baseline to 1-year follow-up, and its association with SES markers (education, cohabiting, and wealth) was analyzed using multiple linear regression adjusting for sex, age, comorbidities, and baseline HHS. RESULTS: At 1-year follow-up, HHS improved clinically relevant for patients undergoing both primary THR: mean 43 (95% CI 43-43) and revision THR: mean 31 (CI 29-33); however, the increase was 12 points (CI 10-14) higher for primary THR. For primary THR, improvements were 0.9 points (CI 0.4-1.5) higher for patients with high educational level compared with low educational level, 0.4 points (CI 0.0-0.8) higher for patients cohabiting compared with living alone, and 2.6 points higher (CI 2.1-3.0) for patients with high wealth compared with low wealth. INTERPRETATION: Patients undergoing primary THR achieve higher improvements on HHS than patients undergoing revision THR, and the improvements are negatively related to markers of low SES. Health professionals should be aware of these characteristics and be able to identify patients who may benefit from extra rehabilitation to improve outcomes after THR to ensure equality in health.

Diabetes As an Independent Risk Factor for Stroke Recurrence in Ischemic Stroke Patients: An Updated Meta-Analysis.

INTRODUCTION: Stroke and its recurrence and diabetes will increase in incidence as the population ages globally. This study explores the relationship between diabetes and stroke recurrence to understand if diabetes is an independent predictor for stroke recurrence in ischemic stroke (IS) patients. METHODS: We conducted a systematic review and meta-analysis of studies on the effect of diabetes on stroke recurrence among patients with IS. We searched population-based studies published before 15th February 2021 in PubMed and EMBASE following PRISMA guidelines. Random-effects estimates of the pooled hazard ratio (HR) and 95% confidence intervals (CIs) of each study were generated. A funnel plot and an Egger test were performed to evaluate publication bias. All statistical analyses were conducted in the R software 4.0.1 and Stata 16.0. RESULTS: The search identified 3,121 citations, of which 27 studies met inclusion criteria. Diabetes was associated with a significant risk of stroke recurrence in all IS patients (pooled HR, 1.50; 95% CI: 1.36-1.65; I2 = 61.0%). Similar results were found in lacunar stroke patients with diabetes (pooled HR, 1.65; 95% CI: 1.41-1.92; I2 = 22.0%). Moreover, we found that the risk of recurrent IS among patients of IS with diabetes was higher than that in those without diabetes (pooled HR, 1.53; 95% CI: 1.30-1.81; I2 = 74.0%). CONCLUSION: Diabetes is an independent risk factor for stroke recurrence among patients with IS.

Associations between cognitive function, actigraphy-based and self-reported sleep in older community-dwelling adults: Findings from the Irish Longitudinal Study on Ageing.

OBJECTIVE: Cognitive impairment is prevalent in older ages. Associations with sleep are well established; however, ambiguity remains in which sleep characteristics contribute to this impairment. We examined cross-sectional associations between both self-reported and actigraphy-based sleep and cognitive performance across a number of domains in community-dwelling older adults. METHODS: 1520 participants aged 50 and older with self-reported and actigraphy-based total sleep time (TST) (≤5, 6, 7-8, 9 and ≥10 h) and self-reported sleep problems were analysed. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency, immediate and delayed recall memory, colour trails tests, and choice reaction tests (CRT). Associations between sleep and cognition were modelled using linear and negative binomial regression. RESULTS: Negative associations were found between ≥10 h of self-reported TST and MoCA error rate (incidence rate ratio [IRR] = 1.42; 95% confidence interval [CI] = 1.18, 1.71; p < 0.001); verbal fluency (beta [B] = -2.32 words; 95% CI = -4.00, -0.65; p < 0.01); and delayed recall (B = -0.91 words; 95% CI = -1.58, -0.25; p < 0.05) compared to 7-8 h. Significant associations with actigraphy-based TST were limited to MoCA error rate in ≤5 h (IRR = 1.22; 95% CI = 1.02, 1.45; p < 0.05) compared to 7-8 h. Higher numbers of sleep problems were associated with slower performance in CRT cognitive response time (IRR = 1.02; 95% CI = 1.00, 104; p < 0.05) and total response time (IRR = 1.02; 95% CI = 1.00, 1.04; p < 0.05). CONCLUSIONS: Self-reported long sleep duration was consistently associated with worse cognitive performance across multiple domains. Marginal associations between cognition and both actigraphy-based sleep and self-reported sleep problems were also apparent. These results further affirm poor sleep as a risk factor for cognitive impairment.

XPG-related nucleases are hierarchically recruited for double-stranded rDNA break resection.

dsDNA breaks (DSBs) are resected in a 5'→3' direction, generating single-stranded DNA (ssDNA). This promotes DNA repair by homologous recombination and also assembly of signaling complexes that activate the DNA damage checkpoint effector kinase Chk1. In fission yeast (Schizosaccharomyces pombe), genetic screens have previously uncovered a family of three xeroderma pigmentosum G (XPG)-related nucleases (XRNs), known as Ast1, Exo1, and Rad2. Collectively, these XRNs are recruited to a euchromatic DSB and are required for ssDNA production and end resection across the genome. Here, we studied why there are three related but distinct XRN enzymes that are all conserved across a range of species, including humans, whereas all other DSB response proteins are present as single species. Using S. pombe as a model, ChIP and DSB resection analysis assays, and highly efficient I-PpoI-induced DSBs in the 28S rDNA gene, we observed a hierarchy of recruitment for each XRN, with a progressive compensatory recruitment of the other XRNs as the responding enzymes are deleted. Importantly, we found that this hierarchy reflects the requirement for different XRNs to effect efficient DSB resection in the rDNA, demonstrating that the presence of three XRN enzymes is not a simple division of labor. Furthermore, we uncovered a specificity of XRN function with regard to the direction of transcription. We conclude that the DSB-resection machinery is complex, is nonuniform across the genome, and has built-in fail-safe mechanisms, features that are in keeping with the highly pathological nature of DSB lesions.

Initiation of DNA damage responses through XPG-related nucleases.

Lesion-specific enzymes repair different forms of DNA damage, yet all lesions elicit the same checkpoint response. The common intermediate required to mount a checkpoint response is thought to be single-stranded DNA (ssDNA), coated by replication protein A (RPA) and containing a primer-template junction. To identify factors important for initiating the checkpoint response, we screened for genes that, when overexpressed, could amplify a checkpoint signal to a weak allele of chk1 in fission yeast. We identified Ast1, a novel member of the XPG-related family of endo/exonucleases. Ast1 promotes checkpoint activation caused by the absence of the other XPG-related nucleases, Exo1 and Rad2, the homologue of Fen1. Each nuclease is recruited to DSBs, and promotes the formation of ssDNA for checkpoint activation and recombinational repair. For Rad2 and Exo1, this is independent of their S-phase role in Okazaki fragment processing. This XPG-related pathway is distinct from MRN-dependent responses, and each enzyme is critical for damage resistance in MRN mutants. Thus, multiple nucleases collaborate to initiate DNA damage responses, highlighting the importance of these responses to cellular fitness.

DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics.

Cohesin is one of three multi-protein structural maintenance of chromosome (SMC) complexes that regulate eukaryotic chromosome dynamics. It forms a ring-shaped structure that embraces sister chromatids through interphase to promote their pairing. In preparation for mitosis, most cohesin is stripped from the chromosome arms in prophase by a poorly defined process that is associated with cohesin phosphorylation. In the fission yeast Schizosaccharomyces pombe this prophase pathway is dependent on the cohesin-related Smc5/6 complex, and this requirement is heightened in Smc5/6 hypomorphs by DNA damage, replication stress and Topoisomerase II (Top2) dysfunction. Cohesin interacts with chromosomes immediately upon mitotic exit and becomes cohesive coincident with DNA replication. Cohesiveness is promoted by acetylation of the Smc3 subunit by an acetyltransferase, known as Eso1 in the S. pombe, which counteracts the anti-cohesive function(s) of the cohesin regulators Pds5 and Wpl1. We recently showed that Eso1 and Smc5/6 antagonize each other, and concurrent inactivation restores sister chromatid separation following genotoxic stress. Here, we have investigated the relationship between Top2 and Eso1 in successful completion of mitosis. We observe that partial inactivation of both results in a synthetic lethal mitotic block, but this is not overcome by deleting pds5 or wpl1. However, analysis of both acetyl-blocking and mimetic mutations in Smc3 indicates that the cycling of cohesin acetyl-regulation is more important than acetyl-status per se, highlighting the non-linear nature of the cohesin cycle.

Sub-clinical orthostatic hypotension is associated with greater subjective memory impairment in older adults.

INTRODUCTION: Orthostatic blood pressure (BP) is a measure of cardiovascular autonomic function. Orthostatic BP dysregulation may lie on the causal pathway to dementia. Subjective memory impairment (SMI) is commonly reported by older people some of whom may progress to dementia. We hypothesised that sub-clinical orthostatic hypotension would be associated with SMI and explored these associations according to sex. METHODS: Cross-sectional analysis of data from 4340 participants aged 50 and over collected during the first wave (2009-2011) of the cohort study, The Irish Longitudinal Study on Ageing. Subjective memory was rated according to a 5-point scale ranging from 'poor' to 'excellent'. BP was measured during orthostatic stress using continuous non-invasive beat-to-beat recording over 2 min. RESULTS: 2% reported 'poor' subjective memory, 12.3% 'fair' , 38% 'good', 33% 'very good' and 14.6% 'excellent'. After controlling for several potential confounding factors including cardiovascular risk, objective cognition, and depressive symptoms mean systolic orthostatic BP was lowest in those with poor subjective memory: 92.2 mmHg (CI95% = 87.1, 97.3) versus excellent 99.3 mmHg (CI95% = 97.4, 101.2); p = 0.011. Further adjustment for supine systolic BP suggested that men with poor subjective memory reached the lowest average systolic orthostatic BP and had the greatest impairment in systolic orthostatic BP stabilisation to baseline levels at 10 s post-stand (-6.64 mmHg; CI95% = -11.49, -1.79; p = 0.007). CONCLUSIONS: Sub-clinical orthostatic hypotension is associated with SMI, and there are sex-specific relationships evident in this population-based cohort. Subtle cardiovascular autonomic dysfunction may represent a modifiable risk marker at an early stage of cognitive decline in older adults. Copyright © 2016 John Wiley & Sons, Ltd.

Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: In this report, we provide the first normative reference data and prevalence estimates of impaired orthostatic blood pressure (BP) stabilization, initial orthostatic hypotension, and orthostatic hypotension based on beat-to-beat blood pressure methods in a population-representative sample. METHODS AND RESULTS: Participants were recruited from a nationally representative cohort study (≥50 years). Beat-to-beat systolic BP, diastolic BP, and heart rate records were analyzed among those who underwent an active stand test (n=4475). Normograms were estimated by use of generalized additive models for location, shape, and scale with Box-Cox power exponential distribution. Prevalence estimates of impaired BP stabilization, initial orthostatic hypotension, and orthostatic hypotension are reported. Orthostatic BP responses in adults aged 50 to 59 years stabilized within 30 seconds of standing, with older groups taking 30 seconds or longer. The total prevalence of impaired BP stabilization was 15.6% (95% confidence interval [CI], 14.1%-17.1%), increasing with age to 41.2% (95% CI, 30.0%-52.4%) in people ≥80 years old. Initial orthostatic hypotension occurred in 32.9% (95% CI, 31.2%-34.6%) of the population aged ≥50 years, with no age gradient evident. The prevalence of orthostatic hypotension was 6.9% (95% CI, 5.9%-7.8%) in the total population, increasing to 18.5% (95% CI, 9.0%-28.0%) in those aged ≥80 years old. CONCLUSIONS: Significant age-related differences exist in the time course of postural BP responses, with abnormal responses taking longer than 30 seconds to stabilize. Impaired BP stabilization is more common as we age, affecting more than two-fifths of the population aged ≥80 years, and may play a future role in the management of falls and syncope.

Functional interplay between cohesin and Smc5/6 complexes.

Chromosomes are subjected to massive reengineering as they are replicated, transcribed, repaired, condensed, and segregated into daughter cells. Among the engineers are three large protein complexes collectively known as the structural maintenance of chromosome (SMC) complexes: cohesin, condensin, and Smc5/6. As their names suggest, cohesin controls sister chromatid cohesion, condensin controls chromosome condensation, and while precise functions for Smc5/6 have remained somewhat elusive, most reports have focused on the control of recombinational DNA repair. Here, we focus on cohesin and Smc5/6 function. It is becoming increasingly clear that the functional repertoires of these complexes are greater than sister chromatid cohesion and recombination. These SMC complexes are emerging as interrelated and cooperating factors that control chromosome dynamics throughout interphase. However, they also release their embrace of sister chromatids to enable their segregation at anaphase, resetting the dynamic cycle of SMC-chromosome interactions.

Higher orthostatic heart rate predicts mortality: The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Orthostatic hemodynamic signals may predict adverse outcomes in elders. AIMS: To study the association between orthostatic hemodynamics and incident mortality in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Wave 1 subjects underwent an active stand with non-invasive beat-to-beat blood pressure monitoring. We compared wave 1 active stands, dead vs alive in wave 2. RESULTS: Compared to the 4,415 participants who had not died, the 53 who had died had a higher baseline heart rate [HR mean of 69 vs 65 beats per minute (bpm)] and a higher mean orthostatic HR, especially between 30 and 60 s post-stand (mean of 79 vs 73 bpm). After adjusting for age, sex, baseline HR, mini-mental state examination score and cardiovascular comorbidities and medications, the mean HR between 30 and 60 s post-stand independently predicted mortality (baseline HR did not). DISCUSSION: Higher early orthostatic HR may be an independent risk marker. Further validation is required.

Brc1-dependent recovery from replication stress.

BRCT-containing protein 1 (Brc1) is a multi-BRCT (BRCA1 carboxyl terminus) domain protein in Schizosaccharomyces pombe that is required for resistance to chronic replicative stress, but whether this reflects a repair or replication defect is unknown and the subject of this study. We show that brc1Δ cells are significantly delayed in recovery from replication pausing, though this does not activate a DNA damage checkpoint. DNA repair and recombination protein Rad52 is a homologous recombination protein that loads the Rad51 recombinase at resected double-stranded DNA (dsDNA) breaks and is also recruited to stalled replication forks, where it may stabilize structures through its strand annealing activity. Rad52 is required for the viability of brc1Δ cells, and brc1Δ cells accumulate Rad52 foci late in S phase that are potentiated by replication stress. However, these foci contain the single-stranded DNA (ssDNA) binding protein RPA, but not Rad51 or γH2A. Further, these foci are not associated with increased recombination between repeated sequences, or increased post-replication repair. Thus, these Rad52 foci do not represent sites of recombination. Following the initiation of DNA replication, the induction of these foci by replication stress is suppressed by defects in origin recognition complex (ORC) function, which is accompanied by loss of viability and severe mitotic defects. This suggests that cells lacking Brc1 undergo an ORC-dependent rescue of replication stress, presumably through the firing of dormant origins, and this generates RPA-coated ssDNA and recruits Rad52. However, as Rad51 is not recruited, and the checkpoint effector kinase Chk1 is not activated, these structures must not contain the unprotected primer ends found at sites of DNA damage that are required for recombination and checkpoint activation.

Natural history of depression up to 18 years after stroke: a population-based South London Stroke Register study.

Background: Current evidence on the long-term natural history of post-stroke depression (PSD) is limited. We aim to determine the prevalence, incidence, duration and recurrence rates of depression to 18-years after stroke and assess differences by onset-time and depression severity. Methods: Data were from the South London Stroke Register (1995-2019, N = 6641 at registration). Depression was defined using the Hospital Anxiety and Depression scale (scores > 7 = depression) at 3-months, then annually to 18-years after stroke. We compared early- (3-months post-stroke) vs late-onset depression (1-year) and initial mild (HADS scores > 7) vs severe depression (scores > 10). Findings: 3864 patients were assessed for depression at any time-points during the follow-up (male:55.4% (2141), median age: 68.0 (20.4)), with the number ranging from 2293 at 1-year to 145 at 18-years after stroke. Prevalence of PSD ranged from 31.3% (28.9-33.8) to 41.5% (33.6-49.3). The cumulative incidence of depression was 59.4% (95% CI 57.8-60.9), of which 87.9% (86.5-89.2) occurred within 5-years after stroke. Of patients with incident PSD at 3-months after stroke, 46.6% (42.1-51.2) recovered after 1 year. Among those recovered, 66.7% (58.0-74.5) experienced recurrent depression and 94.4% (87.5-98.2) of recurrences occurred within 5-years since recovery. Similar estimates were observed in patients with PSD at 1-year. 34.3% (27.9-41.1) of patients with severe depression had recovered at the next time-point, compared to 56.7% (50.5-62.8) with mild depression. Recurrence rate at 1-year after recovery was higher in patients with severe depression (52.9% (35.1-70.2)) compared to mild depression (23.5% (14.1-35.4)) (difference: 29.4% (7.6-51.2), p = 0.003). Interpretation: Long-term depressive status may be established by 5-years post-onset. Early- and late-onset depression presented similar natural history, while severe depression had a longer duration and quicker recurrence than mild depression. These estimates were limited to alive patients completing the depression assessment, who tended to have less severe stroke than excluded patients, so may be underestimated and not generalizable to all stroke survivors. Funding: National Institute for Health and Care Research (NIHR202339).

Histone H3 lysine 14 acetylation is required for activation of a DNA damage checkpoint in fission yeast.

Histone lysine acetylation has emerged as a key regulator of genome organization. However, with a few exceptions, the contribution of each acetylated lysine to cellular functions is not well understood because of the limited specificity of most histone acetyltransferases and histone deacetylases. Here we show that the Mst2 complex in Schizosaccharomyces pombe is a highly specific H3 lysine 14 (H3K14) acetyltransferase that functions together with Gcn5 to regulate global levels of H3K14 acetylation (H3K14ac). By analyzing the effect of H3K14ac loss through both enzymatic inactivation and histone mutations, we found that H3K14ac is critical for DNA damage checkpoint activation by directly regulating the compaction of chromatin and by recruiting chromatin remodeling protein complex RSC.

Smc5/6 maintains stalled replication forks in a recombination-competent conformation.

The Smc5/6 structural maintenance of chromosomes complex is required for efficient homologous recombination (HR). Defects in Smc5/6 result in chromosome mis-segregation and fragmentation. By characterising two Schizosaccharomyces pombe smc6 mutants, we define two separate functions for Smc5/6 in HR. The first represents the previously described defect in processing recombination-dependent DNA intermediates when replication forks collapse, which leads to increased rDNA recombination. The second novel function defines Smc5/6 as a positive regulator of recombination in the rDNA and correlates mechanistically with a requirement to load RPA and Rad52 onto chromatin genome-wide when replication forks are stably stalled by nucleotide depletion. Rad52 is required for all HR repair, but Rad52 loading in response to replication fork stalling is unexpected and does not correlate with damage-induced foci. We propose that Smc5/6 is required to maintain stalled forks in a stable recombination-competent conformation primed for replication restart.