Stroke Survivors Who Score below Threshold on Standard Depression Measures May Still Have Negative Cognitions of Concern

Background and Purpose— There has been an increase in screening for depression in the physically ill. We explored whether important negative cognitions may be missed by conventional approaches to screening for depression in 2 independently conducted stroke studies with similar methods. Methods— The Auckland Regional Community Stroke (ARCOS) study was a prospective, population-based stroke incidence study conducted in Auckland, New Zealand, for 12 months in 2002 to 2003. The Stroke Outcomes Study was a prospective, hospital cohort study conducted in Leeds and Bradford, United Kingdom, for 33 months in 2002 to 2005. Symptoms of abnormal mood were assessed at 6 months in ARCOS with a single simple question, “Do you often feel sad and depressed?” and the 28-item General Health Questionnaire administered as part of a structured interview and in the Stroke Outcomes Study with the 28-item General Health Questionnaire and a single question about depressed mood taken from the Present State Examination. Results— Mood data were available at 6 months from 770 ARCOS and 492 Stroke Outcomes Study participants. A significant proportion (up to 28%) of people who did not meet study criteria for depression reported important negative cognitions such as hopelessness, worthlessness, or suicidality. People who were older, dependent in activities of daily living, or not partnered were more likely to report negative cognitions. Conclusions— Important negative cognitions, including suicidal thoughts, may be missed when people are screened for depression after stroke. Screening alone is not an adequate substitute for a sensitive exploration of the psychological impact of stroke on the survivor

Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Background: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. Methods: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). Findings: Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80). Interpretation: Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care. Funding: The National Health and Medical Research Council of Australia

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.United States. National Institutes of Health (R01GM107536)Alex's Lemonade Stand FoundationHoward Hughes Medical InstituteBoston Children's Hospital. Manton Center for Orphan Disease ResearchNational Institute of General Medical Sciences (U.S.) (T32GM007753

Klinefelters Syndrome: Change in T-Scores with Testosterone, Bisphosphonate, and Vitamin D Treatment over 6 Years

Background: Klinefelter's syndrome (KS) is characterized by extra X chromosomes and features of primary hypogonadism including osteopenia and osteoporosis. Testosterone therapy (TTh) is widely used to treat men with KS and low serum testosterone/hypogonadal symptoms, though studies on its efficacy in improving bone density show varied outcomes. Materials and Methods: We studied the effects of TTh, bisphosphonates, and vitamin D/calcium in 38 men with KS and low testosterone, hypogonadal symptoms, and T-scores consistent with osteoporosis. Our aim was to investigate at the end of follow-up (median: 87 months, range: 27-147 months), associations between age, baseline total testosterone, and T-scores, and change in T-scores after treatment. Results: At final assessment, all men had T-score values outside the osteoporotic range (-1.1 standard deviation [SD],-1.8 SD). Baseline age but not median baseline testosterone appeared associated with change in T-score and T-score at final assessment. All men had dual-energy X-ray absorptiometry every 6 months and demonstrated continued improvement in T-scores after 3 months and up to 72 months. Baseline age and T-scores (stratified by median) were associated with change in T-score at final assessment. Compared with men ≥51 years, those aged <51 years showed significantly greater improvement in T-scores between 6 and 30 months. Men with worse T-score values (<3.7 SD) showed significantly greater improvement at every time point up to 36 months. Our results indicate that TTh, bisphosphonates, and vitamin D/calcium improve osteoporosis although there is a need to better understand the effects of the individual therapies, age, and baseline T-score on treatment efficacy

Testosterone undecanoate is associated with improved ageing male symptoms score in men with type 2 diabetes and adult-onset testosterone deficiency: re-analyzed results from a randomised controlled trial

Availability of data and materials: The datasets that support the findings of this study are available from Professor Sudarshan Ramachandran upon reasonable request.Aim: To evaluate changes in quality of life via the ageing male symptom scale (AMSS) and somatic, psychological, and sexual sub-scales following testosterone undecanoate (TU) or placebo (P) treatment in men with type 2 diabetes mellitus (T2DM) and adult-onset testosterone deficiency (TD) via a re-analysis of the BLAST (Burntwood, Lichfield, Atherstone, Sutton Coldfield, and Tamworth) randomised controlled trial (RCT). Methods: Analysis of data from the BLAST RCT in men with T2DM and adult-onset TD was performed. Summation baseline and study-end AMSS data were available in 170 men (94: P; 76: TU) with subscale data available in 82 men. Rank-sum and sign-rank tests determined inter/intra-group differences, whilst linear/multiple regression models identified predictors of AMSS change. Results: AMSS improved significantly in P [–2 (median), p = 0.010] and TU [–6 (median), p 49. In the cohort with subscale AMSS data, TU was associated with improvements in somatic, psychological, and sexual subscales, whilst improvement was limited to the somatic subscale in the men on P. TU (reference: P) and higher baseline AMSS were significantly and independently associated with AMSS improvement. The improvement in summation AMSS associated with TU (reference: P) was only evident in men with mild depression and no anxiety (based on baseline Hospital Anxiety and Depression Scale data). Conclusions: TU appeared associated with improved AMSS (summation and subscales) in men with T2DM and adult-onset TD demonstrating symptoms (AMSS ≥ 27) with this benefit mediated by levels of depression and anxiety (European Union Clinical Trials Register, EudraCT 2008-000931-16).The practice expenses (BLAST RCT) of the research are supported by a grant from Bayer plc [BSP-SOP-040]

A Simple PCR Method for Rapid Genotype Analysis of the TH-MYCN Transgenic Mouse

BACKGROUND: The TH-MYCN transgenic mouse is the most widely used murine model of human neuroblastoma, in which a human MYCN oncogene is targeted to neuroectodermal cells of developing mice under the influence of the rat tyrosine hydroxylase promoter. So far, homozygous transgenic mice have been identified by either Southern blot or quantitative real-time PCR. PRINCIPAL FINDINGS: To establish a simple and reliable genotyping method by conventional PCR, we confirmed the integration of the transgene in the TH-MYCN transgenic mouse by Southern blot and inverse PCR analyses. Our results showed that either five or six copies were found to be inserted in a head-to-tail tandem configuration at a single locus. The MYCN transgene/host DNA junction was sequenced and the integration site was identified at chromosome 18qE4. Finally, we succeeded in designing rapid, simple and reliable genotyping method by common PCR using primers flanking the integrated TH-MYCN transgene. CONCLUSION: We established a simple and reliable genotyping PCR method for determining the integration site of the TH-MYCN transgene that enables all possible genotypes to be distinguished within several hours. TH-MYCN mice are excellent model for human neuroblastoma study, thus our results will largely be useful for facilitating the pace of neuroblastoma study, including in the study of the tumourigenic process, and in the development of therapies to treat patients suffering from neuroblastoma

Towards a Processual Microbial Ontology

types: ArticleStandard microbial evolutionary ontology is organized according to a nested hierarchy of entities at various levels of biological organization. It typically detects and defines these entities in relation to the most stable aspects of evolutionary processes, by identifying lineages evolving by a process of vertical inheritance from an ancestral entity. However, recent advances in microbiology indicate that such an ontology has important limitations. The various dynamics detected within microbiological systems reveal that a focus on the most stable entities (or features of entities) over time inevitably underestimates the extent and nature of microbial diversity. These dynamics are not the outcome of the process of vertical descent alone. Other processes, often involving causal interactions between entities from distinct levels of biological organisation, or operating at different time scales, are responsible not only for the destabilisation of pre-existing entities, but also for the emergence and stabilisation of novel entities in the microbial world. In this article we consider microbial entities as more or less stabilised functional wholes, and sketch a network-based ontology that can represent a diverse set of processes including, for example, as well as phylogenetic relations, interactions that stabilise or destabilise the interacting entities, spatial relations, ecological connections, and genetic exchanges. We use this pluralistic framework for evaluating (i) the existing ontological assumptions in evolution (e.g. whether currently recognized entities are adequate for understanding the causes of change and stabilisation in the microbial world), and (ii) for identifying hidden ontological kinds, essentially invisible from within a more limited perspective. We propose to recognize additional classes of entities that provide new insights into the structure of the microbial world, namely ‘‘processually equivalent’’ entities, ‘‘processually versatile’’ entities, and ‘‘stabilized’’ entities.Economic and Social Research Council, U

Leaky doors: private captivity as a prominent source of bird introductions in Australia

The international pet trade is a major source of emerging invasive vertebrate species. We used online resources as a novel source of information for accidental bird escapes, and we investigated the factors that influence the frequency and distribution of bird escapes at a continental scale. We collected information on over 5,000 pet birds reported to be missing on animal websites during the last 15 years in Australia. We investigated whether variables linked to pet ownership successfully predicted bird escapes, and we assessed the potential distribution of these escapes. Most of the reported birds were parrots (> 90%), thus, we analysed factors associated with the frequency of parrot escapes. We found that bird escapes in Australia are much more frequent than previously acknowledged. Bird escapes were reported more frequently within, or around, large Australian capital cities. Socio-economic factors, such as the average personal income level of the community, and the level of human modification to the environment were the best predictors of bird escapes. Cheaper parrot species, Australian natives, and parrot species regarded as peaceful or playful were the most frequently reported escapees. Accidental introductions have been overlooked as an important source of animal incursions. Information on bird escapes is available online in many higher income countries and, in Australia, this is particularly apparent for parrot species. We believe that online resources may provide useful tools for passive surveillance for non-native pet species. Online surveillance will be particularly relevant for species that are highly reported, such as parrots, and species that are either valuable or highly commensal.Miquel Vall-llosera, Phillip Casse

Testosterone replacement therapy: association with mortality in high-risk patient subgroups

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.[Correction added on 12 January 2024, after first online publication: Figure 1 updated in this version.]Copyright © 2023 The Authors. Objectives: We describe studies determining the association between testosterone therapy (TTh) and mortality. Materials & methods: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. Results: During a median follow-up interquartile range (IQR) of 114 (84–132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14–0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the “law of initial value,” where greater improvements are evident following treatment in patients with worse baseline values. Conclusions: This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.North Staffordshire Medical Institute. Grant Number: PID-200078

Testosterone Replacement Therapy: Effects on Blood Pressure in Hypogonadal Men

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.Purpose: While testosterone therapy can improve the various pathologies associated with adult-onset testosterone deficiency (TD), Summary of Product Characteristics (SPC) of five testosterone preparations caution that treatment may be associated with hypertension. This paper evaluates the impact of testosterone undecanoate (TU) on blood pressure (BP) in men with adult-onset TD. Materials and Methods: Of 737 men with adult-onset TD in an on-going, observational, prospective, cumulative registry, we studied changes in BP using non-parametric sign-rank tests at final assessment and fixed time points. We used multiple regression analysis to establish factors (baseline BP, age, change/baseline waist circumference [WC] and hematocrit [HCT] and follow-up) potentially associated with BP change in men on TU. Results: TU was associated with significant reductions in systolic, diastolic BP and pulse pressure, regardless of antihypertensive therapy (at baseline or during follow-up), larger reductions were seen with concurrent antihypertensive therapy. In men never on antihypertensive agents, median changes (interquartile range [IQR]) in systolic BP, diastolic BP and pulse pressure were -12.5 (-19.0, -8.0), -8.0 (-14.0, -3.0), and -6.0 (-10.0, -1.0) mmHg, respectively at final assessment, with only baseline BP values inversely associated with these changes (HCT and WC were not significantly associated). In men not on TU, systolic BP, diastolic BP, and pulse pressure significantly increased. In the TU treated men only 1 of the 152 men (not on antihypertensive agents at baseline) were started on antihypertensives during follow-up. In contrast 33 of the 202 men on antihypertensives (at baseline or follow-up) had the antihypertensive agent discontinued by the end of the follow-up. Conclusions: TU was associated with lowering of BP during follow-up irrespective of antihypertensive therapy, with greater reductions in men with higher baseline BP. In the context of SPC warnings, our long-term data provide reassurance on the effect of TU on BP.North Staffordshire Medical Institute, Grant/Award Number: PID-200078