Poor sleep quality and progression of gait impairment in an incident Parkinson’s disease cohort

Abnormal sleep may associate with cognitive decline in Parkinson's disease (PD). Furthermore, sleep dysfunction may associate with worse motor outcome. We hypothesised that PD patients with poor quality sleep would have greater progression in gait dysfunction, due to structural and functional overlap in networks subserving sleep and gait regulation. 12 PD patients and 12 age-matched controls completed longitudinal follow-up over 36 months. Poor sleep efficiency and greater sleep fragmentation correlated significantly with progression of step-width variability, a gait characteristic mediated by postural control, providing evidence that poor sleep in PD is associated with a more rapid deterioration in gait

Does inbreeding contribute to pregnancy loss in Thoroughbred horses?

Background: Excessive inbreeding increases the probability of uncovering homozygous recessive genotypes and has been associated with an increased risk of retained placenta and lower semen quality. No genomic analysis has investigated the association between inbreeding levels and pregnancy loss. Objectives: This study compared genetic inbreeding coefficients (F) of naturally occurring Thoroughbred Early Pregnancy Loss (EPLs), Mid and Late term Pregnancy Loss (MLPL), and Controls. The F value was hypothesised to be higher in cases of pregnancy loss (EPLs and MLPLs) than Controls. Study design: Observational case-control study. Methods: Allantochorion and fetal DNA from EPL (n=37, gestation age 14-65 days), MLPL (n=94, gestational age 70 days–24 hours post parturition) and Controls (n=58) were genotyped on the Axiom Equine 670K SNP Genotyping Array. Inbreeding coefficients using Runs Of Homozygosity (FROH) were calculated using PLINK software. ROHs were split into size categories to investigate the recency of inbreeding. Results: MLPLs had significantly higher median number of ROH (188 interquartile range (IQR), 180.8-197.3), length of ROH (3.10, IQR 2.93-3.33), and total number of ROH (590.8, IQR 537.3-632.3), and FROH (0.26, IQR 0.24-0.28) when compared with the Controls and the EPLs (p<0.05). There was no significant difference in any of the inbreeding indices between the EPLs and Controls. The MLPLs had a significantly higher proportion of long (>10 Mb) ROH (2.5%, IQR 1.6-3.6) than the Controls (1.7%, IQR 0.6-2.5), p=0.001. No unique ROHs were found in the EPL or MLPL populations. Limitations: SNP-array data does not allow analysis of every base in the sequence. Conclusions: This first study of the effect of genomic inbreeding levels on pregnancy loss showed that inbreeding is a contributor to MLPL, but not EPL in the UK Thoroughbred population. Mating choices remain critical, because inbreeding may predispose to MLPL by increasing the risk of homozygosity for specific lethal allele(s)

The effect of increasing temperature on crop photosynthesis: From enzymes to ecosystems

As global land surface temperature continues to rise and heatwave events increase in frequency, duration, and/or intensity, our key food and fuel cropping systems will likely face increased heat-related stress. A large volume of literature exists on exploring measured and modelled impacts of rising temperature on crop photosynthesis, from enzymatic responses within the leaf up to larger ecosystem-scale responses that reflect seasonal and interannual crop responses to heat. This review discusses (i) how crop photosynthesis changes with temperature at the enzymatic scale within the leaf; (ii) how stomata and plant transport systems are affected by temperature; (iii) what features make a plant susceptible or tolerant to elevated temperature and heat stress; and (iv) how these temperature and heat effects compound at the ecosystem scale to affect crop yields. Throughout the review, we identify current advancements and future research trajectories that are needed to make our cropping systems more resilient to rising temperature and heat stress, which are both projected to occur due to current global fossil fuel emissions

Outcome trends in people with heart failure, type 2 diabetes mellitus and chronic kidney disease in the UK over twenty years

Background: Heart failure (HF) together with type 2 diabetes (T2D) and chronic kidney disease (CKD) are major pandemics of the twenty first century. It is not known in people with new onset HF, what the distinct and combined associations are between T2D and CKD comorbidities and cause-specific hospital admissions and death, over the past 20 years. Methods: An observational study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics in England (1998-2017). Participants were people aged >= 30 years with new onset HF. Exposure groups were HF with: (i) no T2D and no CKD (reference group); (ii) CKD-only (estimated glomerular filtration rate (eGFR) Findings: In 87,709 HF patients (mean age, 78 years; 49% female), 40% had CKD-only, 12% T2D-only, and 16% both. Age-standardised first-year CVD hospitalisation rates were significantly higher in HF patients with CKD-only (46.4; 95% CI 44.9,47.9 per 100 person years) and T2D-only (49.2; 46.7,58.8) than in the reference group (35.1; 34.0,36.1); the highest rate was in patients with T2D-CKD-5: 89.1 (65.8,112.4). Similar patterns were observed for non-CVD hospitalisations and deaths. Group differences remained significant after adjustment for potential confounders. Median survival was highest in the reference (4.4 years) and HF-T2D-only (4.1 years) groups, compared to HF-CKD-only (2.2 years). HF-T2D-CKD group survival ranged from 2.8 (CKD-3a) to 0.7 years (CKD-5). Over time, CVD hospitalisation rates significantly increased for HF-CKD-only (+26%) and reduced (-24%) for HF-T2D-only groups; no reductions were observed in any of the HF-T2D-CKD groups. Trends were similar for non-CVD hospitalisations and death: whilst death rates significantly reduced for HF-T2D-only (-37%), improvement was not observed in any of the T2D-CKD groups. Interpretation: In a cohort of people with new onset HF, hospitalisations and deaths are high in patients with T2D or CKD, and worst in those with both comorbidities. Whilst outcomes have improved over time for patients with HF and comorbid T2D, similar trends were not seen in those with comorbid CKD. Strategies to prevent and manage CKD in people with HF are urgently needed. [reference: NIHR 30011] (C) 2021 The Author(s). Published by Elsevier Ltd

Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson's Disease: The ICICLE-PD Study.

BACKGROUND: Cognitive decline is a frequent complication of Parkinson's disease (PD) and the identification of predictive biomarkers for it would help in its management. OBJECTIVE: Our aim was to analyse whether senescence markers (telomere length, p16 and p21) or their change over time could help to better predict cognitive and motor progression of newly diagnosed PD patients. We also compared these senescence markers to previously analysed markers of inflammation for the same purpose. METHODS: This study examined the association of blood-derived markers of cell senescence and inflammation with motor and cognitive function over time in an incident PD cohort (the ICICLE-PD study). Participants (154 newly diagnosed PD patients and 99 controls) underwent physical and cognitive assessments over 36 months of follow up. Mean leukocyte telomere length and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Additionally, we selected five inflammatory markers from existing baseline data. RESULTS: We found that PD patients had shorter telomeres at baseline and 18 months compared to age-matched healthy controls which also correlated to dementia at 36 months. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months in PD cases, while a simple inflammatory summary score at baseline best predicted cognitive score over this same time period in PD patients. CONCLUSION: Our study suggests that both inflammatory and senescence markers (p16) are valuable predictors of clinical progression in PD patients.This study was supported by a Newcastle upon Tyne Hospital Trust (Brain Research Unit PD0612) grant to GS. ICICLE-PD is funded by Parkinson’s UK (grant no J-0802, G-1301) and supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre in Ageing and Chronic Disease and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (CM-R) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (146281). This work was also supported by grants from the Academy of Medical Sciences, UK, the Rosetrees Trust, and the Stevenage Biosciences Catalyst. CHWG is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1). RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and is supported by the WT/MRC Stem Cell Institute (203151/Z/16/Z

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment

Association Between Diabetes, Chronic Kidney Disease, and Outcomes in People With Heart Failure From Asia

Background: Diabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF) are pathophysiologically linked and increasing in prevalence in Asian populations, but little is known about the interplay of DM and CKD on outcomes in HF. Objectives: This study sought to investigate outcomes in patients with heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF) in relation to the presence of DM and CKD. Methods: Using the multinational ASIAN-HF registry, we investigated associations between DM only, CKD only, and DM+CKD with: 1) composite of 1-year mortality or HF hospitalization; and 2) Kansas City Cardiomyopathy Questionnaire scores, according to HF subtype. Results: In 5,239 patients with HF (74.6% HFrEF, 25.4% HFpEF; mean age 63 years; 29.1% female), 1,107 (21.1%) had DM only, 1,087 (20.7%) had CKD only, and 1,400 (26.7%) had DM+CKD. Compared with patients without DM nor CKD, DM+CKD was associated with 1-year all-cause mortality or HF hospitalization in HFrEF (adjusted HR: 2.07; 95% CI: 1.68-2.55) and HFpEF (HR: 2.37; 95% CI: 1.40-4.02). In HFrEF, DM only and CKD only were associated with 1-year all-cause mortality or HF hospitalization (both HRs: 1.43; 95% CI: 1.14-1.80), while in HFpEF, CKD only (HR: 2.54; 95% CI: 1.46-4.41) but not DM only (HR: 1.01; 95% CI: 0.52-1.95) was associated with increased risk (interaction P &lt; 0.01). Adjusted Kansas City Cardiomyopathy Questionnaire scores were lower in patients with DM+CKD (HFrEF: mean 60.50, SEM 0.77, HFpEF: mean 70.10, SEM 1.06; P &lt; 0.001) than with no DM or CKD (HFrEF: mean 66.00, SEM 0.65; and HFpEF: mean 75.80, SEM 0.99). Conclusions: Combined DM and CKD adversely effected outcomes independently of HF subtype, with CKD a consistent predictor of worse outcomes. Strategies to prevent and treat DM and CKD in HF are urgently required.</p

Obesity, chronic disease, age, and in-hospital mortality in patients with covid-19: analysis of ISARIC clinical characterisation protocol UK cohort.

BACKGROUND: Although age, obesity and pre-existing chronic diseases are established risk factors for COVID-19 outcomes, their interactions have not been well researched. METHODS: We used data from the Clinical Characterisation Protocol UK (CCP-UK) for Severe Emerging Infection developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC). Patients admitted to hospital with COVID-19 from 6th February to 12th October 2020 were included where there was a coded outcome following hospital admission. Obesity was determined by an assessment from a clinician and chronic disease by medical records. Chronic diseases included: chronic cardiac disease, hypertension, chronic kidney disease, chronic pulmonary disease, diabetes and cancer. Mutually exclusive categories of obesity, with or without chronic disease, were created. Associations with in-hospital mortality were examined across sex and age categories. RESULTS: The analysis included 27,624 women with 6407 (23.2%) in-hospital deaths and 35,065 men with 10,001 (28.5%) in-hospital deaths. The prevalence of chronic disease in women and men was 66.3 and 68.5%, respectively, while that of obesity was 12.9 and 11.1%, respectively. Association of obesity and chronic disease status varied by age (p < 0.001). Under 50 years of age, obesity and chronic disease were associated with in-hospital mortality within 28 days of admission in a dose-response manner, such that patients with both obesity and chronic disease had the highest risk with a hazard ratio (HR) of in-hospital mortality of 2.99 (95% CI: 2.12, 4.21) in men and 2.16 (1.42, 3.26) in women compared to patients without obesity or chronic disease. Between the ages of 50-69 years, obesity and chronic disease remained associated with in-hospital COVID-19 mortality, but survival in those with obesity was similar to those with and without prevalent chronic disease. Beyond the age of 70 years in men and 80 years in women there was no meaningful difference between those with and without obesity and/or chronic disease. CONCLUSION: Obesity and chronic disease are important risk factors for in-hospital mortality in younger age groups, with the combination of chronic disease and obesity being particularly important in those under 50 years of age. These findings have implications for targeted public health interventions, vaccination strategies and in-hospital clinical decision making

Obesity, Ethnicity, and Risk of Critical Care, Mechanical Ventilation, and Mortality in Patients Admitted to Hospital with COVID-19: Analysis of the ISARIC CCP-UK Cohort.

OBJECTIVE: The aim of this study was to investigate the association of obesity with in-hospital coronavirus disease 2019 (COVID-19) outcomes in different ethnic groups. METHODS: Patients admitted to hospital with COVID-19 in the United Kingdom through the Clinical Characterisation Protocol UK (CCP-UK) developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) were included from February 6 to October 12, 2020. Ethnicity was classified as White, South Asian, Black, and other minority ethnic groups. Outcomes were admission to critical care, mechanical ventilation, and in-hospital mortality, adjusted for age, sex, and chronic diseases. RESULTS: Of the participants included, 54,254 (age = 76 years; 45.0% women) were White, 3,728 (57 years; 41.1% women) were South Asian, 2,523 (58 years; 44.9% women) were Black, and 5,427 (61 years; 40.8% women) were other ethnicities. Obesity was associated with all outcomes in all ethnic groups, with associations strongest for black ethnicities. When stratified by ethnicity and obesity status, the odds ratios for admission to critical care, mechanical ventilation, and mortality in black ethnicities with obesity were 3.91 (3.13-4.88), 5.03 (3.94-6.63), and 1.93 (1.49-2.51), respectively, compared with White ethnicities without obesity. CONCLUSIONS: Obesity was associated with an elevated risk of in-hospital COVID-19 outcomes in all ethnic groups, with associations strongest in Black ethnicities