Th2 cell clonal expansion at diagnosis in human type 1 diabetes.

Soon after diagnosis with type 1 diabetes (T1D), many patients experience a period of partial remission. A longer partial remission is associated with a better response to treatment, but the mechanism is not known. The frequency of CD4+CD25+CD127hi (127-hi) cells, a cell subset with an anti-inflammatory Th2 bias, correlates positively with length of partial remission. The purpose of this study was to further characterize the nature of the Th2 bias in 127-hi cells. Single cell RNA sequencing paired with TCR sequencing of sorted 127-hi memory cells identifies clonally expanded Th2 clusters in 127-hi cells from T1D, but not from healthy donors. The Th2 clusters express GATA3, GATA3-AS1, PTGDR2, IL17RB, IL4R and IL9R. The existence of 127-hi Th2 cell clonal expansion in T1D suggests that disease factors may induce clonal expansion of 127-hi Th2 cells that prolong partial remission and delay disease progression.

Deaths at home, area-based deprivation and the effect of the Covid-19 pandemic: An analysis of mortality data across four nations.

BACKGROUND: The number and proportion of home deaths in the UK increased during the Covid-19 pandemic. It is not known whether these changes were experienced disproportionately by people from different socioeconomic groups. AIM: To examine the association between home death and socioeconomic position during the Covid-19 pandemic, and how this changed between 2019 and 2020. DESIGN: Retrospective cohort study using population-based individual-level mortality data. SETTING/PARTICIPANTS: All registered deaths in England, Wales, Scotland and Northern Ireland. The proportion of home deaths between 28th March and 31st December 2020 was compared with the same period in 2019. We used Poisson regression models to evaluate the association between decedent's area-based level of deprivation and risk of home death, as well as the interaction between deprivation and year of death, for each nation separately. RESULTS: Between the 28th March and 31st December 2020, 409,718 deaths were recorded in England, 46,372 in Scotland, 26,410 in Wales and 13,404 in Northern Ireland. All four nations showed an increase in the adjusted proportion of home deaths between 2019 and 2020, ranging from 21 to 28%. This increase was lowest for people living in the most deprived areas in all nations, with evidence of a deprivation gradient in England. CONCLUSIONS: The Covid-19 pandemic exacerbated a previously described socioeconomic inequality in place of death in the UK. Further research to understand the reasons for this change and if this inequality has been sustained is needed.

Researching minoritised communities in palliative care: An agenda for change.

BACKGROUND: Palliative care access, experiences and outcomes of care disadvantage those from ethnically diverse, Indigenous, First nation and First people communities. Research into this field of inquiry raises unique theoretical, methodological, and moral issues. Without the critical reflection of methods of study and reporting of findings, researchers may inadvertently compromise their contribution to reducing injustices and perpetuating racism. AIM: To examine key evidence of the place of minoritised communities in palliative care research to devise recommendations that improve the precision and rigour of research and reporting of findings. METHODS: Narrative review of articles identified from PubMed, CINAHL and Google Scholar for 10 years augmented with supplementary searches. RESULTS: We identified and appraised 109 relevant articles. Four main themes were identified (i) Lack of precision when working with a difference; (ii) 'black box epidemiology' and its presence in palliative care research; (iii) the inclusion of minoritised communities in palliative care research; and (iv) the potential to cause harm. All stymie opportunities to 'level up' health experiences and outcomes across the palliative care spectrum. CONCLUSIONS: Based on the findings of this review palliative care research must reflect on and justify the classification of minoritised communities, explore and understand intersectionality, optimise data quality, decolonise research teams and methods, and focus on reducing inequities to level up end-of-life care experiences and outcomes. Palliative care research must be forthright in explicitly indentifying instances of structural and systemic racism in palliative care research and engaging in non-judgemental debate on changes required.

The association between socioeconomic position and the symptoms and concerns of hospital inpatients seen by specialist palliative care: Analysis of routinely collected patient data.

BACKGROUND: Understanding how socioeconomic position influences the symptoms and concerns of patients approaching the end of life is important for planning more equitable care. Data on this relationship is lacking, particularly for patients with non-cancer conditions. AIM: To analyse the association between socioeconomic position and the symptoms and concerns of older adult patients seen by specialist palliative care. DESIGN: Secondary analysis of cross-sectional, routinely collected electronic patient data. We used multivariable linear regression with robust standard errors, to predict scores on the three subscales of the Integrated Palliative care Outcome Scale (IPOS; physical symptoms, emotional symptoms and communication and practical concerns) based on patient level of deprivation, measured using Index of Multiple Deprivation. SETTING/PARTICIPANTS: Consecutive inpatients aged 60 years and over, seen by specialist palliative care at two large teaching hospitals in London between 1st January 2016 and 31st December 2019. RESULTS: Seven thousand eight hundred and sixty patients were included, 38.3% had cancer. After adjusting for demographic and clinical characteristics, patients living in the most deprived areas had higher (worse) predicted mean scores on the communication and practical subscale than patients living in the least deprived areas, 5.38 (95% CI: 5.10, 5.65) compared to 4.82 (4.62, 5.02) respectively. This effect of deprivation diminished with increasing age. Deprivation was not associated with scores on the physical or emotional symptoms subscales. CONCLUSIONS: Targetting resources to address practical and communication concerns could be a strategy to reduce inequalities. Further research in different hospitals and across different settings using patient centred outcome measures is needed to examine inequalities.

Exploratory Study of Parenting Differences for Autism Spectrum Disorder and Attachment Disorder.

The current study explored similarities and differences in parenting stress (PSI) and behaviours in parent reports of autism spectrum disorder (ASD) and attachment disorder (AD). 155 parents whose children had developmental delays and disorders completed the social communication questionnaire, Randolph attachment questionnaire, strengths and difficulties questionnaire, PSI, and parent-child relationship inventory. Parents of children with AD reported greater levels of PSI than parents of children with ASD. Parents of children reaching criteria for both disorders reported the greatest levels of PSI. Limit setting was poorest in parents of children with both classifications, followed by parents of children with AD, and then ASD. Limit setting mediated the relationship between PSI and child behaviour problems for parents of children with ASD < but not for parents of children with AD. These findings suggest different areas of difficulty for parents of children with these conditions, which may be of help in designing interventions.

Brief Report: Differential Persistence of Primary Reflexes for Children with Autism Spectrum Disorder: A Systematic Replication.

Primary reflexes are highly stereotypical, automatic movements comprising much of the motor repertoire of newborns. The current study examined rates of presence of five primary reflexes (snout, visual rooting, sucking, tactile rooting, and grasp) and variables predictive of their persistence for children with ASD (n = 35), developmental disability (n = 30), and typically developing children matched to participants with ASD on chronological age (n = 30). There was a higher prevalence of snout and visual rooting reflex among children with ASD. These data suggest that the persistence of primary reflexes holds promise as a biomarker for autism spectrum disorder (ASD).

Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.

Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.

Communication failures contributing to patient injury in anaesthesia malpractice claims☆.

BACKGROUND: Communication amongst team members is critical to providing safe, effective medical care. We investigated the role of communication failures in patient injury using the Anesthesia Closed Claims Project database. METHODS: Claims associated with surgical/procedural and obstetric anaesthesia and postoperative pain management for adverse events from 2004 or later were included. Communication was defined as transfer of information between two or more parties. Failure was defined as communication that was incomplete, inaccurate, absent, or not timely. We classified root causes of failures as content, audience, purpose, or occasion with inter-rater reliability assessed by kappa. Claims with communication failures contributing to injury (injury-related communication failures; n=389) were compared with claims without any communication failures (n=521) using Fisher's exact test, t-test, or Mann-Whitney U-tests. RESULTS: At least one communication failure contributing to patient injury occurred in 43% (n=389) out of 910 claims (κ=0.885). Patients in claims with injury-related communication failures were similar to patients in claims without failures, except that failures were more common in outpatient settings (34% vs 26%; P=0.004). Fifty-two claims had multiple communication failures for a total of 446 injury-related failures, and 47% of failures occurred during surgery, 28% preoperatively, and 23% postoperatively. Content failures (insufficient, inaccurate, or no information transmitted) accounted for 60% of the 446 communication failures. CONCLUSIONS: Communication failure contributed to patient injury in 43% of anaesthesia malpractice claims. Patient/case characteristics in claims with communication failures were similar to those without failures, except that failures were more common in outpatient settings.

Key considerations to inform operational EU-specific protection goals: An example for non-target terrestrial plants.

This paper complements recent considerations of specific protection goals (SPG) to inform risk assessments for non-target terrestrial plants (NTTP) in the European Union. The SPG options in-field appear to be of the most disruptive potential from agronomic perspective and are therefore investigated in more detail. Overarching prerequisites have been identified that need to be accounted for to ensure that any of the potential SPG options remain operational in a sustainable agricultural context. As soon as crop production is considered a desired ecosystem service for the in-field, its specific requirements in the context of sustainable agriculture have to be factored in. Good agricultural practices (GAPs), potential ecosystem disservices (e.g. weeds, pests and diseases) and supporting and regulating services need to be considered to ensure a successful and sustainable delivery of the ecosystem service crop production. Concerning in-field SPG options for NTTP specifically GAPs related to integrated weed management (IWM) require detailed assessment, as they individually and in combination have the purpose of weed control. Therefore, they result in specific implications to the environment, ecosystem services and biodiversity within the context of sustainable agricultural production. When diverging in-field ecosystem services are considered for the same context, the protection goals options require an additional assessment of synergies and trade-offs between the relevant ecosystem services (e.g. crop production, climate regulation and aesthetic values), a corresponding weighing and prioritization. Similarly, for biodiversity conservation, the trade-offs and synergies between sustainable crop production and specific habitat requirements need to be accounted for. Consequently, an interdisciplinary approach can ensure that SPG are operational by integrating a broad understanding of cropping systems, the environmental impact of the tools a farmer uses and the link between habitat availability, the impact of any of the applied tools on habitat quality and the broader landscape context. Integr Environ Assess Manag 2021;17:905-910. © 2021 Bayer AG, BASF SE and Syngenta. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Indications and patterns of use of benzodiazepines and opioids in severe interstitial lung disease: a population-based longitudinal study.

BACKGROUND: Despite evidence that opioids might relieve chronic breathlessness, physicians may still be reluctant to prescribe them due to safety concerns. By contrast, benzodiazepine (BDZ) prescribing often seeks to reduce chronic breathlessness despite no evidence of net benefit. Prescribing patterns and indications for these medications in severe interstitial lung disease (ILD) are unknown. Here, our objective was to evaluate the indications, medications and temporal patterns of BDZ and opioid prescriptions in people with oxygen-dependent ILD. METHODS: This was an observational, population-based, longitudinal study of adults starting long-term oxygen therapy (LTOT) for ILD between 2005 and 2014 in the Swedish National Registry for Respiratory Failure (Swedevox). People dispensed BDZs (n=2000) and opioids (n=2000) from 6 months before start of LTOT throughout follow-up (first of death or study end) were analysed. RESULTS: Of 1635 included patients, 651 (39.8%) received BDZs and 710 (43.4%) received opioids during the study period; 373 (22.8%) patients received both. The most frequently prescribed BDZs and opioids were oxazepam (85.6%) and oxycodone (28.7%), respectively. Indications for breathlessness were uncommon for BDZs (1.4%) and opioids (6.4%). During the last year of life, opioid indications for breathlessness increased from 2.5% (12-10 months before death) to 10.2% in the last 3 months of life (p=0.048). CONCLUSIONS: In oxygen-dependent ILD, opioids are rarely prescribed for breathlessness even in the last months of life, when chronic breathlessness often increases in prevalence and intensity.

Socioeconomic position and use of hospital-based care towards the end of life: a mediation analysis using the English Longitudinal Study of Ageing.

BACKGROUND: Many patients prefer to avoid hospital-based care towards the end of life, yet hospitalisation is common and more likely for people with low socioeconomic position. The reasons underlying this socioeconomic inequality are not well understood. This study investigated health, service access, and social support as potential mediating pathways between socioeconomic position and receipt of hospital-based care towards the end of life. METHODS: For this observational cohort study, we included deceased participants from the nationally representative English Longitudinal Study of Ageing of people aged 50 years or older in England. We used a multiple mediation model with age-adjusted and gender-adjusted probit regression to estimate the direct effect of socioeconomic position (measured by wealth and education) on death in hospital and three or more hospital admissions in the last 2 years of life, and the indirect effects of socioeconomic position via three mediators: health and function, access to health-care services, and social support. FINDINGS: 737 participants were included (314 [42·6%] female, 423 [57·4%] male), with a median age at death of 78 years (IQR 71-85). For death in hospital, higher wealth had a direct negative effect (probit coefficient -0·16, 95% CI -0·25 to -0·06), which was not mediated by any of the pathways tested. For frequent hospital admissions, health and function mediated the effect of wealth (-0·04, -0·08 to -0·01), accounting for 34·6% of the total negative effect of higher wealth (-0·13, -0·23 to -0·02). Higher wealth was associated with better health and function (0·25, 0·18 to 0·33). Education was associated with the outcomes only indirectly via wealth. INTERPRETATION: Our findings suggest that worse health and function could partly explain why people with lower wealth have more hospital admissions, highlighting the importance of socioeconomically driven health differences in explaining patterns of hospital use towards the end of life. The findings should raise awareness about the related risk factors of low wealth and worse health for patients approaching the end of life, and strengthen calls for resource allocation to be made on the basis of health need and socioeconomic profile. FUNDING: Dunhill Medical Trust Fellowship Grant (RTF74/0116).

CD4+CD25+CD127hi cell frequency predicts disease progression in type 1 diabetes.

Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain ß cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, ß cell survival, and response to antiinflammatory immunotherapy.

Correction: Socioeconomic position and use of healthcare in the last year of life: A systematic review and meta-analysis.

[This corrects the article DOI: 10.1371/journal.pmed.1002782.].

Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study.

BACKGROUND: Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4+ precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti-cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer. METHODS: The frequency of circulating CD4+ and CD8+ naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real-time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one-repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual-energy X-ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses. RESULTS: Our data show significant correlations between (i) higher frequencies of CD8+ naïve (P = 0.02) and effector memory (P = 0.003) T cells and lower frequencies of CD8+ central memory T cells (P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index (P = 0.04), (iii) lower frequency of CD8+ T cells that express CD95 with greater stair climb power (P = 0.003), (iv) higher frequency of T cells that co-express CD197 and CD45RA and greater one-repetition maximum knee extension strength (P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment (P = 0.004) in people with cancer. CONCLUSIONS: We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow-up study with a larger cohort to test the validity of the findings.

Socioeconomic position and use of healthcare in the last year of life: A systematic review and meta-analysis.

BACKGROUND: Low socioeconomic position (SEP) is recognized as a risk factor for worse health outcomes. How socioeconomic factors influence end-of-life care, and the magnitude of their effect, is not understood. This review aimed to synthesise and quantify the associations between measures of SEP and use of healthcare in the last year of life. METHODS AND FINDINGS: MEDLINE, EMBASE, PsycINFO, CINAHL, and ASSIA databases were searched without language restrictions from inception to 1 February 2019. We included empirical observational studies from high-income countries reporting an association between SEP (e.g., income, education, occupation, private medical insurance status, housing tenure, housing quality, or area-based deprivation) and place of death, plus use of acute care, specialist and nonspecialist end-of-life care, advance care planning, and quality of care in the last year of life. Methodological quality was evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS). The overall strength and direction of associations was summarised, and where sufficient comparable data were available, adjusted odds ratios (ORs) were pooled and dose-response meta-regression performed. A total of 209 studies were included (mean NOS quality score of 4.8); 112 high- to medium-quality observational studies were used in the meta-synthesis and meta-analysis (53.5% from North America, 31.0% from Europe, 8.5% from Australia, and 7.0% from Asia). Compared to people living in the least deprived neighbourhoods, people living in the most deprived neighbourhoods were more likely to die in hospital versus home (OR 1.30, 95% CI 1.23-1.38, p < 0.001), to receive acute hospital-based care in the last 3 months of life (OR 1.16, 95% CI 1.08-1.25, p < 0.001), and to not receive specialist palliative care (OR 1.13, 95% CI 1.07-1.19, p < 0.001). For every quintile increase in area deprivation, hospital versus home death was more likely (OR 1.07, 95% CI 1.05-1.08, p < 0.001), and not receiving specialist palliative care was more likely (OR 1.03, 95% CI 1.02-1.05, p < 0.001). Compared to the most educated (qualifications or years of education completed), the least educated people were more likely to not receive specialist palliative care (OR 1.26, 95% CI 1.07-1.49, p = 0.005). The observational nature of the studies included and the focus on high-income countries limit the conclusions of this review. CONCLUSIONS: In high-income countries, low SEP is a risk factor for hospital death as well as other indicators of potentially poor-quality end-of-life care, with evidence of a dose response indicating that inequality persists across the social stratum. These findings should stimulate widespread efforts to reduce socioeconomic inequality towards the end of life.