A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia.

Primary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity.

Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain.

Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders.

Identification of molecular subphenotypes in two cohorts of paediatric ARDS.

BACKGROUND: Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions. METHODS: We performed latent class analysis (LCA) separately on two cohorts using biomarkers as inputs. Subphenotypes were compared on clinical characteristics and outcomes. Finally, we assessed overlap with adult cohorts using parsimonious classifiers. FINDINGS: In two cohorts from the Children's Hospital of Philadelphia (n=333) and from a multicentre study based at the University of California San Francisco (n=293), LCA identified two subphenotypes defined by differential elevation of biomarkers reflecting inflammation and endotheliopathy. In both cohorts, hyperinflammatory subjects had greater illness severity, more sepsis and higher mortality (41% and 28% in hyperinflammatory vs 11% and 7% in hypoinflammatory). Both cohorts demonstrated overlap with adult subphenotypes when assessed using parsimonious classifiers. INTERPRETATION: We identified hypoinflammatory and hyperinflammatory subphenotypes of paediatric ARDS from two separate cohorts with utility for prognostic and potentially predictive, enrichment. Future paediatric ARDS trials should identify and leverage biomarker-defined subphenotypes in their analysis.

Awake versus Asleep Anesthesia in Deep Brain Stimulation Surgery for Parkinson's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Deep brain stimulation (DBS) is a well-established surgical therapy for patients with Parkinsons' Disease (PD). Traditionally, DBS surgery for PD is performed under local anesthesia, whereby the patient is awake to facilitate intraoperative neurophysiological confirmation of the intended target using microelectrode recordings. General anesthesia allows for improved patient comfort without sacrificing anatomic precision and clinical outcomes. METHODS: We performed a systemic review and meta-analysis on patients undergoing DBS for PD. Published randomized controlled trials, prospective and retrospective studies, and case series which compared asleep and awake techniques for patients undergoing DBS for PD were included. A total of 19 studies and 1,900 patients were included in the analysis. RESULTS: We analyzed the (i) clinical effectiveness - postoperative UPDRS III score, levodopa equivalent daily doses and DBS stimulation requirements. (ii) Surgical and anesthesia related complications, number of lead insertions and operative time (iii) patient's quality of life, mood and cognitive measures using PDQ-39, MDRS, and MMSE scores. There was no significant difference in results between the awake and asleep groups, other than for operative time, for which there was significant heterogeneity. CONCLUSION: With the advent of newer technology, there is likely to have narrowing differences in outcomes between awake or asleep DBS. What would therefore be more important would be to consider the patient's comfort and clinical status as well as the operative team's familiarity with the procedure to ensure seamless transition and care.

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling.

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

TIFA has dual functions in Helicobacter pylori-induced classical and alternative NF-κB pathways.

Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) via classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial cells. Tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA) was previously suggested to trigger classical NF-κB activation, but its role in alternative NF-κB activation remains unexplored. Here, we identify TRAF6 and TRAF2 as binding partners of TIFA, contributing to the formation of TIFAsomes upon H. pylori infection. Importantly, the TIFA/TRAF6 interaction enables binding of TGFß-activated kinase 1 (TAK1), leading to the activation of classical NF-κB signaling, while the TIFA/TRAF2 interaction causes the transient displacement of cellular inhibitor of apoptosis 1 (cIAP1) from TRAF2, and proteasomal degradation of cIAP1, to facilitate the activation of the alternative NF-κB pathway. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF-κB signaling in H. pylori-infected gastric epithelial cells.

A20 undermines alternative NF-κB activity and expression of anti-apoptotic genes in Helicobacter pylori infection.

A hallmark of infection by the pathogen Helicobacter pylori, which colonizes the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, underlying inflammation and cell survival. Here, we report that the classical NF-κB target gene product A20 contributes to the negative regulation of alternative NF-κB signaling in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesized A20 protein interacts with tumor necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) and thereby interferes with the association of TIFA with the NIK regulatory complex. We also show that alternative NF-κB activity contributes to the up-regulation of anti-apoptotic genes, such as baculoviral IAP repeat containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. Furthermore, the observed over-expression of RelB in human gastric biopsies with type B gastritis and RelB-dependent suppression of apoptotic cell death emphasize an important role of the alternative NF-κB pathway in H. pylori infection.

The state of loneliness and social isolation research: current knowledge and future directions.

In this editorial, we consider the current state of loneliness and social isolation research around the world, including knowledge gaps in the empirical literature.

Early Postoperative Volume Overload is a Predictor of 1-Year Post-Transplant Mortality in Pediatric Heart Transplant Recipients.

Fluid restriction and diuretic management are mainstays in the postoperative management of cardiac patients, at risk of volume overload and its deleterious effects on primary cardiac function and multi-organ systems. The importance of fluid homeostasis is further emphasized among orthotopic heart transplant recipients (OHT). We sought to investigate the relationship between postoperative volume overload, mortality, and allograft dysfunction among pediatric OHT recipients within 1-year of transplantation. This is a retrospective cohort study from a single pediatric OHT center. Children under 21 years undergoing cardiac transplantation between 2010 and 2018 were included. Cumulative fluid overload (cFO) was assessed as percent fluid accumulation adjusted for preoperative body weight. Greater than 10% cFO defined those with postoperative cFO and a comparison of postoperative cFO vs. no postoperative cFO (< 5%) is reported. 102 pediatric OHT recipients were included. Early cFO at 72 h post-OHT occurred in 14% and overall cFO at 1-week post-OHT occurred in 23% of patients. Risk factors for cFO included younger age, lower weight, and postoperative ECMO. Early cFO was associated with postoperative mortality at 1-year, OR 8.6 (95% CI 1.4, 51.6), p = 0.04, independent of age and weight. There was no significant relationship between cFO and allograft dysfunction, measured by rates of clinical rejection and cardiopulmonary filling pressures within 1-year of transplant. Early postoperative volume overload is prevalent and associated with increased risk of death at 1-year among pediatric OHT recipients. It may be an important postoperative marker of transplant survival, and this relationship warrants further clinical investigation.

Beyond the Alveolar Epithelium: Plasma Soluble Receptor for Advanced Glycation End Products Is Associated With Oxygenation Impairment, Mortality, and Extrapulmonary Organ Failure in Children With Acute Respiratory Distress Syndrome.

OBJECTIVES: Soluble receptor for advanced glycation end products is a known plasma marker of alveolar epithelial injury. However, RAGE is also expressed on cell types beyond the lung, and its activation leads to up-regulation of pro-inflammatory mediators. We sought to examine the relationship between plasma soluble receptor for advanced glycation end products and primary pulmonary dysfunction, extrapulmonary organ dysfunction, and mortality in pediatric acute respiratory distress syndrome patients at two early time points following acute respiratory distress syndrome diagnosis and compare these results to plasma surfactant protein-D, a marker of pure alveolar epithelial injury. DESIGN: Prospective observational study. SETTING: Five academic PICUs. PATIENTS: Two hundred fifty-eight pediatric patients 30 days to 18 years old meeting Berlin Criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected for soluble receptor for advanced glycation end products and surfactant protein-D measurements within 24 hours (day 1) and 48 to 72 hours (day 3) after acute respiratory distress syndrome diagnosis. Similar to surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with a higher oxygenation index (p < 0.01) and worse lung injury score (p < 0.001) at the time of acute respiratory distress syndrome diagnosis. However, unlike surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with worse extrapulmonary Pediatric Logistic Organ Dysfunction score during ICU stay (day 3; p < 0.01) and positively correlated with plasma levels of interleukin-6 (p < 0.01), tumor necrosis factor-α (p < 0.01), and angiopoietin-2 (p < 0.01). Among children with indirect lung injury, plasma soluble receptor for advanced glycation end products was associated with mortality independent of age, sex, race, cancer/bone marrow transplant, and Pediatric Risk of Mortality score (day 3; odds ratio, 3.14; 95% CI, 1.46-6.75; p < 0.01). CONCLUSIONS: Unlike surfactant protein-D, which is primarily localized to the alveolar epithelium plasma soluble receptor for advanced glycation end products is systemically expressed and correlates with markers of inflammation, extrapulmonary multiple organ dysfunction, and death in pediatric acute respiratory distress syndrome with indirect lung injury. This suggests that unlike surfactant protein-D, soluble receptor for advanced glycation end products is a multifaceted marker of alveolar injury and increased inflammation and that receptor for advanced glycation end products activation may contribute to the pathogenesis of multiple organ failure among children with indirect acute respiratory distress syndrome.

Identifying a therapeutic target for vancomycin against staphylococci in young infants.

OBJECTIVES: To determine the therapeutic target of vancomycin in young infants with staphylococcal infections. METHODS: Retrospective data were collected for infants aged 0 to 90 days with CoNS or MRSA bacteraemia over a 4 year period at the Royal Children's Hospital Melbourne, Australia. Vancomycin broth microdilution MICs were determined. A published pharmacokinetic model was externally validated using the study dataset and a time-to-event (TTE) pharmacodynamic model developed to link the AUC of vancomycin with the event being the first negative blood culture. Simulations were performed to determine the trough vancomycin concentration that correlates with a 90% PTA of the target AUC24. RESULTS: Thirty infants, 28 with CoNS and 2 with MRSA bacteraemia, who had 165 vancomycin concentrations determined were included. The vancomycin broth microdilution MIC was determined for 24 CoNS and 1 MRSA isolate, both with a median MIC of 1 mg/L (CoNS range = 0.5-4.0). An AUC0-24 target of ≥300 mg/L·h or AUC24-48 of ≥424 mg/L·h. increased the chance of bacteriological cure by 7.8- and 7.3-fold, respectively. However, AUC0-24 performed best in the pharmacokinetic-pharmacodynamic model. This correlates with 24 to 48 h trough concentrations of >15-18 mg/L and >10-15 mg/L for 6- and 12-hourly dosing, respectively, and can be used to guide vancomycin therapy in this population. CONCLUSIONS: An AUC0-24 ≥300 mg/L·h or AUC24-48 ≥424 mg/L·h was associated with an increase in bacteriological cure in young infants with staphylococcal bloodstream infections.

Psychometric assessment of scales for measuring loneliness and social isolation: an analysis of the household, income and labour dynamics in Australia (HILDA) survey.

BACKGROUND: Loneliness and social isolation are increasingly recognised as global public health threats, meaning that reliable and valid measures are needed to monitor these conditions at a population level. We aimed to determine if robust and practical scales could be derived for conditions such as loneliness and social isolation using items from a national survey. METHODS: We conducted psychometric analyses of ten items in two waves of the Household, Income and Labour Dynamics in Australia Survey, which included over 15,000 participants. We used the Hull method, exploratory structural equation modelling, and multidimensional item response theory analysis in a calibration sample to determine the number of factors and items within each factor. We cross-validated the factor structure using confirmatory factor analysis in a validation sample. We assessed construct validity by comparing the resulting sub-scales with measures for psychological distress and mental well-being. RESULTS: Calibration and cross-validation consistently revealed a three-factor model, with sub-scales reflecting constructs of loneliness and social isolation. Sub-scales showed high reliability and measurement invariance across waves, gender, and age. Construct validity was supported by significant correlations between the sub-scales and measures of psychological distress and mental health. Individuals who met threshold criteria for loneliness and social isolation had consistently greater odds of being psychologically distressed and having poor mental health than those who did not. CONCLUSIONS: These derived scales provide robust and practical measures of loneliness and social isolation for population-based research.

The impact of loneliness and social isolation on health state utility values: a systematic literature review.

BACKGROUND: Loneliness and social isolation are recognised as social problems and denote a significant health burden. The aim of this study was to conduct a systematic literature review to explore the health state utility values (HSUVs) associated with loneliness and/or social isolation. METHOD: Peer-reviewed journals published in English language that reported both HSUVs along with loneliness and/or social isolation scores were identified through five databases. No restrictions were made relating to the population, study design or utility estimation method used. RESULTS: In total, 19 papers were included; 12 included a measure of loneliness, four studies included a measure of social isolation and three studies considered both loneliness and social isolation. All studies focused on individuals with pre-existing health conditions-where the EQ-5D-3L instrument was most frequently used to assess HSUVs. HSUVs ranged from 0.5 to 0.95 in those who reported not being lonely, 0.42 to 0.97 in those who experienced some level of loneliness, 0.3 to 0.87 in those who were socially isolated and 0.63 to 0.94 in those who were not socially isolated. CONCLUSION: There was significant variation in HSUVs complicated by the presence of co-morbidities, population heterogeneity, variations in methods used to derive utility scores and differences in the measurement of loneliness and/or social isolation. Nevertheless, the lower HSUVs observed should be considered to significantly impact quality of life, though we also note the need for further research to explore the unique impact of loneliness and social isolation on HSUVs that can be used in the future economic evaluations.

Development of reconstructed intestinal micronucleus cytome (RICyt) assay in 3D human gut model for genotoxicity assessment of orally ingested substances.

The micronucleus (MN) assay is widely used as part of a battery of tests applied to evaluate the genotoxic potential of chemicals, including new food additives and novel food ingredients. Micronucleus assays typically utilise homogenous in vitro cell lines which poorly recapitulate the physiology, biochemistry and genomic events in the gut, the site of first contact for ingested materials. Here we have adapted and validated the MN endpoint assay protocol for use with complex 3D reconstructed intestinal microtissues; we have named this new protocol the reconstructed intestine micronucleus cytome (RICyt) assay. Our data suggest the commercial 3D microtissues replicate the physiological, biochemical and genomic responses of native human small intestine to exogenous compounds. Tissues were shown to maintain log-phase proliferation throughout the period of exposure and expressed low background MN. Analysis using the RICyt assay protocol revealed the presence of diverse cell types and nuclear anomalies (cytome) in addition to MN, indicating evidence for comprehensive DNA damage and mode(s) of cell death reported by the assay. The assay correctly identified and discriminated direct-acting clastogen, aneugen and clastogen requiring exogenous metabolic activation, and a non-genotoxic chemical. We are confident that the genotoxic response in the 3D microtissues more closely resembles the native tissues due to the inherent tissue architecture, surface area, barrier effects and tissue matrix interactions. This proof-of-concept study highlights the RICyt MN cytome assay in 3D reconstructed intestinal microtissues is a promising tool for applications in predictive toxicology.

The Relationship between AKI and CKD in Patients with Type 2 Diabetes: An Observational Cohort Study.

BACKGROUND: There are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population. METHODS: In this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline. RESULTS: We followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD. CONCLUSIONS: Patients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.

Lived experience of loneliness in psychosis: A qualitative approach.

BACKGROUND: Loneliness impedes recovery from mental illness. Despite increased interest in loneliness in psychosis, qualitative methods are underused in clinical research on this topic. AIMS: We used qualitative interviews to explore loneliness among persons with schizophrenia spectrum disorders (SSDs). We examined which aspects of living with psychosis were associated with the experience of loneliness, including symptomatology, social relationships, and disruptions in school/work. METHODS: Sixteen participants diagnosed with SSDs engaged in semi-structured, qualitative interviews about loneliness. Participants commented on current activities and social relationships, including their perceptions of the quantity, quality and types of relationships. Important demographic and clinical information was acquired through communication with participants and/or through medical record review. Thematic analysis was used to examine interview content. RESULTS: Our analyses revealed four key topic areas and several sub-themes related to loneliness across participants, including aspects of the physical environment (e.g. financial limitations), social context (e.g. lacking a romantic partner), and psychological functioning (e.g. psychotic/symptoms) that impact lonely feelings. Participants commented on coping strategies to manage loneliness and provided suggestions for possible interventions. CONCLUSIONS: Persons diagnosed with SSDs report significant and impactful feelings of loneliness. This study highlights the need for novel and effective treatments targeting loneliness in this population.

CHANS-Law: preventing the next pandemic through the integration of social and environmental law.

Zoonotic viruses have sacrificed hundreds of millions of people throughout human history. There are currently 1.7 million unidentified viruses estimated to be circulating in mammal and bird populations. It is foreseeable that in the near future, another of these will transmit to people, heralding the start of the next pandemic-one potentially more deadly than COVID-19. At the core of this article is a call for pre-emptive protection of the natural environment and its regenerative systems as the first fundamental step in the prevention of future epidemics and pandemics. While zoonoses originate in nature, the predominant legal discipline, managing these crises, is international health law which is invoked reactively once an outbreak has been reported. In this paper, we identify the need for a legal shift in epidemic and pandemic responses. In particular, we call for the incorporation of international environmental agreements to prevent the initial viral spillover from animal to human populations. We propose a strategy of strengthening existing agreements and a coupling of legal disciplines, such as health and environmental law, emphasizing the need for synergies across legal disciplines to enhance the emergence and management of future pandemics and epidemics. We introduce Coupled Human and Natural Systems (CHANS) Law to frame the required integration across legal instruments to regulate inextricably human-nature connections and advocate for the development of a Convention on Epidemics and Pandemics.

The prevalence of pain among patients with chronic kidney disease using systematic review and meta-analysis.

Pain is a common but often undertreated symptom in patients with chronic kidney disease (CKD) with a much higher prevalence than in the general population. The aim of this systematic review was to synthesize all available quantitative evidence, in order to gain a better understanding of pain prevalence and pain types in patients with CKD. Four databases and the grey literature were searched until 15th January 2021. Random-effect meta-analyses were conducted with multiple subgroup analyses and meta-regressions to further explore the between-study heterogeneity. The quality of studies included was assessed using the Newcastle-Ottawa scale and the level of evidence was determined using the GRADE approach. One hundred sixteen studies reported data on 40,678 individuals. Results from meta-analyses yielded an overall prevalence of 60% (95% confidence interval 56-64) for pain, 48% (42-55) for chronic pain and 10% (6-15) for neuropathic pain. The prevalence of pain was lower among kidney transplant recipients 46% (37-56) compared with patients undergoing dialysis 63% (57-68) and those with non-dialysis CKD 63% (55-70). Musculoskeletal pain appeared to be the most common pain symptom among patients with CKD managed conservatively 42% (28-56) or receiving dialysis 45% (36-55) whilst abdominal pain was most prevalent in kidney transplant recipients 41% (7-86). Thus, all subgroups of patients with CKD suffer from a high burden of pain. Hence, greater awareness and recognition of this issue is vital to inform policy and service provision in this area.

Dynamic expression of tRNA-derived small RNAs define cellular states.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell-state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs. differentiated states revealed a differentiation-dependent enrichment of 5'-tsRNAs. We report the identification of a set of 5'-tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Notably, interactome studies with differentially enriched 5'-tsRNAs revealed a switch in their association with "effector" RNPs and "target" mRNAs in different cell states. We demonstrate that specific 5'-tsRNAs can preferentially interact with the RNA-binding protein, Igf2bp1, in the RA-induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency-promoting factor, c-Myc, thus providing a mechanistic basis for how 5'-tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 5'-tsRNAs in defining distinct cell states.

A randomised controlled trial of the Nextdoor Kind Challenge: a study protocol.

BACKGROUND: Community interventions are often promoted as a way of reducing loneliness and social isolation in our neighbourhoods. However, those community interventions are rarely examined within rigorous study designs. One strategy that holds the potential to reduce loneliness and can promote health and wellbeing is doing acts of kindness. The current study involves evaluating the impact of kindness acts on loneliness in community-dwelling individuals using an online social networking platform. METHODS: This study is made up of three randomised controlled trials conducted in three countries. Each randomised controlled trial has two arms (intervention vs waitlist control) and is designed to compare the effectiveness of the KIND challenge, which involves doing at least one act of kindness per week within a four-week period. This study will recruit users of an online community, be randomised online, and will be conducted using online assessments. We will first explore the effects of the intervention on the primary outcome of loneliness, followed by secondary outcomes, social isolation, neighbour relationship quality and contact, mental health symptoms, stress, quality of life, and positive affect. Further, we will assess the feasibility, acceptability, and safety of the KIND Challenge. DISCUSSION: This study, designed to evaluate the impact of kindness on the community, will be the first large scale randomised control trial conducted across three countries, Australia, UK, and USA. It will examine the potential of community-led interventions to reduce loneliness, improve social isolation, and promote neighbourhood cohesion, health, and wellbeing, which is especially crucial during the COVID-19 public health crisis. TRIAL REGISTRATION: Clinical Trials Registry. NCT04398472 . Registered 21st May 2020.