Alphonsea glandulosa (Annonaceae), a new species from Yunnan, China

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Investigation of microvesicle uptake by mouse lung-marginated monocytes in vitro.

Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com

Antithrombotic therapy in patients with liver disease: population-based insights on variations in prescribing trends, adherence, persistence and impact on stroke and bleeding

Background: Patients with liver disease have complex haemostasis and due to such contraindications, landmark randomised controlled trials investigating antithrombotic medicines have often excluded these patients. As a result, there has been limited consensus on the safety, efficacy and monitoring practices of anticoagulant and antiplatelet therapy in patients with liver disease. This study aims to investigate prescribing prevalence, adherence, persistence and impact of adherence on bleeding and stroke risk in people with and without liver disease taking anticoagulants and antiplatelets. / Methods: We employed a population-based cohort consisting of person-level linked records from primary care, secondary care and the death registry. The cohort consisted of 3,929,596 adults aged ≥ 30 years during the study period of 1998 to 2020 and registered with an NHS general practitioner in England. The primary outcome was prescribing prevalence, adherence to and persistence with anticoagulant and antiplatelet therapy comparing patients with and without liver disease. Risk factors for non-adherence and non-persistence were analysed using multivariable logistic regression and Cox regression. Impact of adherence on bleeding and ischaemic stroke was assessed. / Findings: Among patients with any of the six liver diseases (ALD, autoimmune liver disease, cirrhosis, HBV, HCV and NAFLD), we identified 4,237 individuals with incident atrial fibrillation (indication for anticoagulants) and 4,929 individuals with incident myocardial infarction, transient ischaemic attack, unstable angina or peripheral arterial disease (indication for antiplatelets). Among patients without liver disease, 321,510 and 386,643 individuals were identified as having indications for anticoagulant and antiplatelet therapy, respectively. Among drug-naïve individuals, prescribing prevalence was lower in patients with liver disease compared with individuals without liver disease: anticoagulants (20.6% [806/3,921] vs. 33.5% [103,222/307,877]) and antiplatelets (56.2% [2,207/3,927] vs. 71.1% [249,258/350,803]). Primary non-adherence rates (stopping after one prescription) were higher in patients with liver disease, compared with those without liver disease: anticoagulants (7.9% [64/806] vs. 4.7% [4,841/103,222]) and antiplatelets (6.2% [137/2,207] vs. 4.4% [10,993/249,258]). Among individuals who were not primary non-adherent and had at least 12 months of follow-up, patients with liver disease however had a higher one-year adherence rate: anticoagulants (33.1% [208/628] vs. 29.4% [26,615/90,569]) and antiplatelets (40.9% [743/1,818] vs. 34.4% [76,834/223,154]). Likelihood of non-adherence was lower in apixaban and rivaroxaban (relative to warfarin) and lower in clopidogrel (relative to aspirin). Increased comorbidity burden (by CHA2DS2VASc score) was associated with decreased risk of non-adherence and non-persistence with anticoagulants. Overall rates of ‘non-adherent, non-persistent’ were highest in warfarin (compared with apixaban and rivaroxaban) and aspirin (compared with clopidogrel or dipyridamole) in patients with and without liver disease. Among patients without liver disease, not taking antithrombotic medications for >3 months was associated with a higher risk of stroke, however, adherence to these medications was also associated with a small increase in risk of bleeding. Patients with liver disease (when compared with those without liver disease) had higher risks of stroke, especially when they stopped taking antiplatelets for >3 months. Patients with liver disease who were adherent to antiplatelets, however, had a higher risk of bleeding compared with patients without liver disease. / Interpretation: Use of antithrombotic medicines in patients with and without liver disease is suboptimal with heterogeneity across medicines. As patients with liver disease are excluded from major randomised trials for these drugs, our results provide real-world evidence that may inform medicine optimisation strategies. We outline challenges and opportunities for tackling non-adherence, which begins with understanding patients’ views of medicines to help them make informed decisions about appropriate use. / Funding: AGL is supported by funding from the Wellcome Trust (204841/Z/16/Z), National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (BRC714/HI/RW/101440), NIHR Great Ormond Street Hospital Biomedical Research Centre (19RX02), the Health Data Research UK Better Care Catalyst Award (CFC0125) and the Academy of Medical Sciences (SBF006\1084). The funders have no role in the writing of the manuscript or the decision to submit it for publication

Late effects of cancer in children, teenagers and young adults: Population-based study on the burden of 183 conditions, in-patient and critical care admissions and years of life lost

Background: Children, teenagers and young adults who survived cancer are prone to developing late effects. The burden of late effects across a large number of conditions, in-patient hospitalisation and critical care admissions have not been described using a population-based dataset. We aim to systematically quantify the cumulative burden of late effects across all cancer subtypes, treatment modalities and chemotherapy drug classes. // Methods: We employed primary care records linked to hospitals, the death registry and cancer registry from 1998–2020. CTYA survivors were 25 years or younger at the time of cancer diagnosis had survived ≥5 years post-diagnosis. Year-of-birth and sex-matched community controls were used for comparison. We considered nine treatment types, nine chemotherapy classes and 183 physical and mental health late effects. Cumulative burden was estimated using mean cumulative count, which considers recurring events. Multivariable logistic regression was used to investigate the association between treatment exposures and late effects. Excess years of life lost (YLL) attributable to late effects were estimated. // Findings: Among 4,063 patients diagnosed with cancer, 3,466 survived ≥ 5 years (85%); 13,517 matched controls were identified. The cumulative burden of late effects at age 35 was the highest in survivors of leukaemia (23.52 per individual [95% CI:19.85–29.33]) and lowest in survivors of germ cell tumours (CI:6.04 [5.32–6.91]). In controls, the cumulative burden was 3.99 (CI:3.93–4.08) at age 35 years. When survivors reach age 45, the cumulative burden for immunological conditions and infections was the highest (3.27 [CI:3.01–3.58]), followed by cardiovascular conditions (3.08 [CI:1.98–3.29]). Survivors who received chemotherapy and radiotherapy had the highest disease burden compared to those who received surgery only. These patients also had the highest burden of hospitalisation (by age 45: 10.43 [CI:8.27–11.95]). Survivors who received antimetabolite chemotherapy had the highest disease and hospitalisation burden, while the lowest burden is observed in those receiving antitumour antibiotics. Regression analyses revealed that survivors who received only surgery had lower odds of developing cardiovascular (adjusted odds ratio 0.73 [CI:0.56–0.94]), haematological (aOR 0.51 [CI:0.37–0.70]), immunology and infection (aOR 0.84 [CI:0.71–0.99]) and renal (aOR 0.51 [CI:0.39–0.66]) late effects. By contrast, the opposite trend was observed in survivors who received chemo-radiotherapy. High antimetabolite chemotherapy cumulative dose was associated with increased risks of subsequent cancer (aOR 2.32 [CI:1.06–4.84]), metastatic cancer (aOR 4.44 [CI:1.29–11.66]) and renal (aOR 3.48 [CI:1.36–7.86]) conditions. Patients who received radiation dose of ≥50 Gy experienced higher risks of developing metastatic cancer (aOR 5.51 [CI:2.21–11.86]), cancer (aOR 3.77 [CI:2.22–6.34]), haematological (aOR 3.43 [CI:1.54–6.83]) and neurological (aOR 3.24 [CI:1.78–5.66]) conditions. Similar trends were observed in survivors who received more than three teletherapy fields. Cumulative burden analyses on 183 conditions separately revealed varying dominance of different late effects across cancer types, socioeconomic deprivation and treatment modalities. Late effects are associated with excess YLL (i.e., the difference in YLL between survivors with or without late effects), which was the most pronounced among survivors with haematological comorbidities. // Interpretation: To our knowledge, this is the first study to dissect and quantify the importance of late morbidities on subsequent survival using linked electronic health records from multiple settings. The burden of late effects is heterogeneous, as is the risk of premature mortality associated with late effects. We provide an extensive knowledgebase to help inform treatment decisions at the point of diagnosis, future interventional trials and late-effects screening centred on the holistic needs of this vulnerable population

An investigation of working memory deficits in depression using the n-back task: A systematic review and meta-analysis

Background: Depression is associated with cognitive deficits across multiple domains, including working memory. The n-back task, a convenient psychometric tool capable of computerised delivery and concurrent use with neuroimaging, can provide enhanced insight into working memory dysfunction in depression. This meta-analysis sought to investigate the n-back task under varying cognitive load conditions (i.e. different levels of ‘n’) to clarify the pattern of working memory deficits in depression. Methods: We conducted a systematic review and meta-analysis of studies involving unipolar depressed participants and matched controls utilising the n-back task. Meta-analyses were performed for accuracy and response times at four levels of cognitive load (0-, 1-, 2-, and 3-back). Results: 31 studies (total 1,666 participants) met inclusion criteria and were included for quantitative analyses. Depressed individuals had significantly reduced accuracy compared to controls for 1-, 2-, and 3-back tasks, but not the attentional 0-back task. Likewise, response latencies were prolonged for all task levels (0-, 1-, 2-, and 3-back). Additional meta-regression analyses indicated that participant age and clinical status (i.e. inpatient/outpatient) may exacerbate working memory deficits associated with depression. Limitations: Our results indicate high levels of heterogeneity between studies, particularly for response times. Conclusions: Accuracy impairments were worse at higher levels of n, with the largest effect size obtained on the 2-back task, suggesting deficits to higher executive functions. Response times were consistently prolonged at all cognitive loads in agreement with a pattern of generalised psychomotor retardation

Behavioural and neurophysiological differences in working memory function of depressed patients and healthy controls

Objective: Major depressive disorder (MDD) is associated with deficits in working memory. Several cognitive subprocesses interact to produce working memory, including attention, encoding, maintenance and manipulation. We sought to clarify the contribution of functional deficits in these subprocesses in MDD by varying cognitive load during a working memory task. Methods: 41 depressed participants and 41 age and gender-matched healthy controls performed the n-back working memory task at three levels of difficulty (0-, 1-, and 2-back) in a pregistered study. We assessed response times, accuracy, and event-related electroencephalography (EEG), including P2 and P3 amplitudes, and frontal theta power (4–8 Hz). Results: MDD participants had prolonged response times and more positive frontal P3 amplitudes (i.e., Fz) relative to controls, mainly in the most difficult 2-back condition. Working memory accuracy, P2 amplitudes and frontal theta event-related synchronisation did not differ between groups at any level of task difficulty. Conclusions: Depression is associated with generalized psychomotor slowing of working memory processes, and may involve compensatory hyperactivity in frontal and parietal regions. Significance: These findings provide insights into MDD working memory deficits, indicating that depressed individuals dedicate greater levels of cortical processing and cognitive resources to achieve comparable working memory performance to controls

Evaluating the impacts of school garden-based programmes on diet and nutrition-related knowledge, attitudes and practices among the school children: a systematic review

Background Previous evidence suggests that school garden-based programmes (SGBP) may be a promising yet cost-effective intervention to improve children’s knowledge, attitudes and practices (KAP) on healthy eating. This review aimed to summarise and evaluate the evidence available on the impacts of SGBP in addressing diet and nutrition-related KAP among school-aged children. Methods Five databases including PubMed, Embase, Cochrane, Web of Science and Scopus were searched until February 2021. Randomised, non-randomised controlled and pre-post intervention studies investigating the impacts of SGBP on at least one of the outcomes of interest including diet and nutrition-related knowledge, attitudes towards fruits and vegetables (F&V), food diversity and dietary practice among school-aged children were included. Study selection and data extraction were performed by one reviewer and checked for accuracy by the other two reviewers in accordance with PRISMA guideline. Quality appraisal for studies included was assessed using American Dietetic Association Quality Criteria Checklist. Results A total of 10,836 records were identified, and 35 studies that met the inclusion and exclusion criteria were included. This includes 25,726 students from 341 schools and 8 nurseries from 12 countries. Intervention duration ranged from 6 weeks to 4 years with 18 studies involving a varied degree of parental participation. SGBP, which majorly includes school gardening activities, cooking lessons and nutrition education, demonstrated beneficial effects on children’s nutritional knowledge, their attitudes and acceptability towards fruits and vegetables and children’s dietary practices including the actual F&V consumption and dietary diversity. However, the impacts of SGBP on such outcomes were highly influenced by various social and environmental factors including the activities/components and duration of the intervention, parental involvement, sample size, and the age of children when interventions were first introduced. Conclusion These findings suggest that SGBP may be effective in promoting children’s nutritional knowledge, attitudes and acceptability towards vegetables, however, the impacts may vary by the type, the extent, and the length of the programmes, and other factors such as parent involvement. Future SGBP is suggested to implement using a combined multidisciplinary approach targeting the children, parents, and community to effectively promote healthy eating among the children and prevent childhood obesity

Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. METHODS: Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. RESULTS: Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. CONCLUSIONS: The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.Stroke Association (Grant ID: TSA2008/10), British Heart Foundation (Grant ID: PG/13/30/30005), Stroke Association/British Heart Foundation (Grant ID: TSA BHF 2010/01), Agency for Science, Technology and Research, Singapore, National Institute for Health Research (Senior Investigator award), Cambridge University Hospital Comprehensive National Institute for Health Research Biomedical Research UnitThis is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1161/STROKEAHA.116.01376

Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients.

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode