A Branched SELEX Approach Identifies RNA Aptamers That Bind Distinct HIV-1 Capsid Structural Components.

The HIV-1 capsid protein (CA) assumes distinct structural forms during replication, each presenting unique, solvent-accessible surfaces that facilitate multifaceted functions and host factor interactions. However, functional contributions of individual CA structures remain unclear, as evaluation of CA presents several technical challenges. To address this knowledge gap, we identified CA-targeting aptamers with different structural specificities, which emerged through a branched SELEX approach using an aptamer library previously selected to bind the CA hexamer lattice. Subsets were either highly specific for the CA lattice or bound both the CA lattice and CA hexamer. We then evaluated four representatives to reveal aptamer regions required for binding, highlighting interesting structural features and challenges in aptamer structure determination. Further, we demonstrate binding to biologically relevant CA structural forms and aptamer-mediated affinity purification of CA from cell lysates without virus or host modification, supporting the development of structural form-specific aptamers as exciting new tools for the study of CA.

The use of natural language processing for the identification of ageing syndromes including sarcopenia, frailty and falls in electronic healthcare records: a systematic review.

BACKGROUND: Recording and coding of ageing syndromes in hospital records is known to be suboptimal. Natural Language Processing algorithms may be useful to identify diagnoses in electronic healthcare records to improve the recording and coding of these ageing syndromes, but the feasibility and diagnostic accuracy of such algorithms are unclear. METHODS: We conducted a systematic review according to a predefined protocol and in line with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Searches were run from the inception of each database to the end of September 2023 in PubMed, Medline, Embase, CINAHL, ACM digital library, IEEE Xplore and Scopus. Eligible studies were identified via independent review of search results by two coauthors and data extracted from each study to identify the computational method, source of text, testing strategy and performance metrics. Data were synthesised narratively by ageing syndrome and computational method in line with the Studies Without Meta-analysis guidelines. RESULTS: From 1030 titles screened, 22 studies were eligible for inclusion. One study focussed on identifying sarcopenia, one frailty, twelve falls, five delirium, five dementia and four incontinence. Sensitivity (57.1%-100%) of algorithms compared with a reference standard was reported in 20 studies, and specificity (84.0%-100%) was reported in only 12 studies. Study design quality was variable with results relevant to diagnostic accuracy not always reported, and few studies undertaking external validation of algorithms. CONCLUSIONS: Current evidence suggests that Natural Language Processing algorithms can identify ageing syndromes in electronic health records. However, algorithms require testing in rigorously designed diagnostic accuracy studies with appropriate metrics reported.

Nutritional Screening, Initial Management and Referral for Older People with Sarcopenia or Frailty - Results from a UK-Wide Survey.

Objectives: We surveyed healthcare staff working with older people to understand current practice in nutrition screening, initial management and referral for older people with sarcopenia and frailty. Methods: We conducted a UK-wide web-based survey of staff working with older people in both hospital and community settings. Surveys were distributed through professional organisation e-mail lists and social media channels. Descriptive data were generated from categorical responses and inductive thematic analysis was applied to free-text responses. Results: Data were analysed from 169 respondents (110 hospital, 59 community), representing 99 healthcare organisations. 91 (83%) hospital respondents and 24 (41%) community respondents reported that nutrition screening was performed on all patients with sarcopenia or frailty. The Malnutrition Universal Screening Tool was most commonly used to trigger referral to dietetics teams, but there was considerable variation in management before referral, referral thresholds and referral pathways. Themes derived from free-text responses included the need for training, issues of responsibility and ownership, inadequate resources (time, staff and equipment) and ineffective or inefficient processes for referral and management. Conclusions: Current UK nutritional care for older people with sarcopenia and frailty is heterogeneous. There are opportunities for better tools, processes, training and resources to improve current practice and pathways.

Innovations in Phenotyping and Diagnostics Create Opportunities for Improved Treatment and Genetic Counseling for Rare Diseases.

Genetic counseling and treatment options for rare developmental disabilities (DDs) have been revolutionized by the opportunities made possible by using massively parallel sequencing for diagnostic purposes [...].

Frailty progression in adults aged 40 years and older in rural Burkina Faso: a longitudinal, population-based study.

BACKGROUND: Little is known about ageing and frailty progression in low-income settings. We aimed to describe frailty changes over time in individuals living in rural Burkina Faso and to assess which sociodemographic, disability, and multimorbidity factors are associated with frailty progression and mortality. METHODS: This longitudinal, population-based study was conducted at the Nouna Health and Demographic Surveillance Systems (HDSS) site in northwestern Burkina Faso. Eligible participants were aged 40 years or older and had been primarily resident in a household within the HDSS area for at least the past 6 months before the baseline survey and were selected from the 2015 HDSS household census using a stratified random sample of adults living in unique households within the area. Participants were interviewed in their homes in 2018 (baseline), 2021 (follow-up), or both. We derived the Fried frailty score for each participant at each timepoint using data on grip strength, gait speed, self-reported weight loss, self-reported exhaustion, and physical activity, and described changes in frailty status (no frailty, pre-frailty, or frailty) between 2018 and 2021. We used multivariate regression models to assess factors (ie, sex, age, marital status, educational attainment, wealth quintile, WHO Disability Assessment Schedule (WHODAS) score, and multimorbidity) associated with frailty progression (either worsening frailty status or dying, compared with frailty status remaining the same or improving) and with mortality, and developed sequential models: unadjusted, adjusting for sociodemographic factors (sex, age, marital status, educational attainment, and wealth quintile), and adjusting for sociodemographic factors, disability, and multimorbidity. FINDINGS: Between May 25 and July 19, 2018, and between July 1 and Aug 22, 2021, 5952 individuals were invited to participate: 1709 (28·7%) did not consent, 1054 (17·8%) participated in 2018 only and were lost to follow-up, 1214 (20·4%) participated in 2021 only, and 1975 (33·2%) were included in both years or died between years. Of 1967 participants followed up with complete demographic data, 190 (9·7%) were frail or unable to complete the frailty assessment in 2018, compared with 77 (3·9%) in 2021. Between 2018 and 2021, frailty status improved in 567 (28·8%) participants and worsened in 327 (16·6%), and 101 (5·1%) participants died. The relative risk of frailty status worsening or of dying (compared with frailty impRoving or no change) increased with age and WHODAS score, whereas female sex appeared protective. After controlling for all sociodemographic factors, multimorbidity, and WHODAS score, odds of mortality were 1·07 (odds ratio 2·07, 95% CI 1·05-4·09) times higher among pre-frail individuals and 1·1 (2·21, 0·90-5·41) times higher among frail individuals than among non-frail individuals. INTERPRETATION: Frailty status was highly dynamic in this low-income setting and appears to be modifiable. Given the rapid increase in the numbers of older adults in low-income or middle-income countries, understanding the behaviour of frailty in these settings is of high importance for the development of policies and health systems to ensure the maintenance of health and wellbeing in ageing populations. Future work should focus on designing context-appropriate interventions to improve frailty status. FUNDING: Alexander Von Humboldt Foundation, Institute for Global Innovation, University of Birmingham, and Wellcome Trust.

Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.

BACKGROUND: Occurrence of squamous cell carcinoma (SCC) even in early-stage, untreated chronic lymphocytic leukemia (CLL) patients can be a significant morbidity issue with occasional transformation into metastatic skin lesions. METHODS: CLL cells and extracellular vesicles (EVs) from CLL patients' blood/plasma were purified and used. Expression/activation of AXL and its functions in normal keratinocytes (HEKa) were assessed in vitro co-culture system and in SCC tissues. RESULTS: We detected aberrant activation of AXL, AKT and ERK-1/2 in SCC cell lines compared to HEKa. We also detected increased expression of AXL in primary SCC tissues obtained from CLL patients. Increased activation of AXL, AKT, ERK-1/2 and Src was discernible in HEKa upon co-culturing with CLL cells. Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced expression of AXL, P-AKT, and EMT-associated markers leading to migration of the cells. Finally, pharmacologic inhibition of AXL induced cell death in SCC lines in a dose dependent manner. CONCLUSIONS: Our findings that CLL cells likely are involved in driving SCC progression, at least in part, via activation of the AXL signaling axis, indicating that AXL inhibition may be beneficial for our CLL patients with SCC.

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders.

The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). Biallelic variants of the phosphatidylinositol glycan (PIG) biosynthesis, type V (PIGV) gene identified in Mabry syndrome became evidence of the first in a phenotypic series that is numbered HPMRS1-6 in the order of discovery. HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. Similarly, HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. By contrast, HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4). The GPI biosynthesis disorders (GPIBDs) are currently numbered GPIBD1-21. Working with Dr. Mabry, in 2020, we were able to use improved laboratory diagnostics to complete the molecular diagnosis of patients he had originally described in 1970. We identified biallelic variants of the PGAP2 gene in the first reported HPMRS patients. We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry's patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

Kelp holdfast microclimates buffer invertebrate inhabitants from extreme temperatures.

Climate change is altering environmental conditions, with microclimates providing small-scale refuges within otherwise challenging environments. Durvillaea (southern bull kelp; rimurapa) is a genus of large intertidal fucoid algae, and some species harbour diverse invertebrate communities in their holdfasts. We hypothesised that animal-excavated Durvillaea holdfasts provide a thermal refuge for epibiont species, and tested this hypothesis using the exemplar species D. poha. Using a southern Aotearoa New Zealand population as a case-study, we found extreme temperatures outside the holdfast were 4.4 °C higher in summer and 6.9 °C lower in winter than inside the holdfast. A microclimate model of the holdfasts was built and used to forecast microclimates under 2100 conditions. Temperatures are predicted to increase by 2-3 °C, which may exceed the tolerances of D. poha. However, if D. poha or a similar congeneric persists, temperatures inside holdfasts will remain less extreme than the external environment. The thermal tolerances of two Durvillaea-associated invertebrates, the trochid gastropod Cantharidus antipodum and the amphipod Parawaldeckia kidderi, were also assessed; C. antipodum, but not P. kidderi, displayed metabolic depression at temperatures above and below those inside holdfasts, suggesting that they would be vulnerable outside the holdfast and with future warming. Microclimates, such as those within D. poha holdfasts or holdfasts of similar species, will therefore be important refuges for the survival of species both at the northern (retreating edge) and southern (expanding edge) limits of their distributions.

Treatment Outcomes of Stereotactic Ablative Body Radiotherapy on Extra-cranial Oligometastatic and Oligoprogressive Breast Cancer: Mature Results from a Single Institution Experience.

AIMS: Evidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. MATERIALS AND METHODS: A retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients' age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. RESULTS: 56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0-132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3-28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5-158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. CONCLUSION: There are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities.

Sarcopenia and sarcopenic obesity among community-dwelling Peruvian adults: A cross-sectional study.

INTRODUCTION: Sarcopenia and sarcopenic obesity (SO) have emerged as significant contributors to negative health outcomes in the past decade. We aimed to estimate the prevalence of probable sarcopenia, sarcopenia, and SO in a community-dwelling population of 1151 adults aged ≥55 years in Lima, Peru. METHODS: This cross-sectional study was conducted between 2018 and 2020. Sarcopenia was defined as the presence of low muscle strength (LMS) and low muscle mass (LMM) according to European (EWGSOP2), US (FNIH) and Asian (AWGS2) guidelines. We measured muscle strength by maximum handgrip strength and muscle mass using bioelectrical impedance analyzer. SO was defined as a body mass index ≥ 30 kg/m2 and sarcopenia. RESULTS: The study participants had a mean age of 66.2 years (SD 7.1), age range between 60 to 92 years old, of which 621 (53.9%) were men. Among the sample, 41.7% were classified as obese (BMI ≥30.0 kg/m²). The prevalence of probable sarcopenia was estimated to be 22.7% (95%CI: 20.3-25.1) using the EWGSOP2 criteria and 27.8% (95%CI: 25.2-30.4) using the AWGS2 criteria. Sarcopenia prevalence, assessed using skeletal muscle index (SMI), was 5.7% (95%CI: 4.4-7.1) according to EWGSOP2 and 8.3% (95%CI: 6.7-9.9) using AWGS2 criteria. The prevalence of sarcopenia based on the FNIH criteria was 18.1% (95%CI: 15.8-20.3). The prevalence of SO, considering different sarcopenia definitions, ranged from 0.8% (95%CI: 0.3-1.3) to 5.0% (95%CI: 3.8-6.3). CONCLUSION: Our findings reveal substantial variation in the prevalence of sarcopenia and SO, underscoring the necessity for context-specific cut-off values. Although the prevalence of SO was relatively low, this result may be underestimated. Furthermore, the consistently high proportion of probable sarcopenia and sarcopenia point to a substantial public health burden.

Improving care for patients with multiple long-term conditions admitted to hospital: challenges and potential solutions.

Increasing numbers of people live with multiple long-term conditions. These people are more likely to be admitted to hospital, experience adverse outcomes and receive poorer quality care than those with a single condition. Hospitals remain organised around a model of single-organ, disease-specific care which is not equipped to meet the needs of people living with multiple long-term conditions. This article considers these challenges and explores potential solutions. These include different service models to provide holistic, multidisciplinary inpatient and outpatient care across specialty boundaries, training a workforce to deliver high-quality hospital care for people living with multiple long-term conditions, and developing technological, financial and cultural enablers of change. Considerably more research is required to fully appreciate the shared risk factors, underlying mechanisms, patterns and consequences of multiple long-term conditions. This is essential to design and deliver better structures and processes of hospital care for people living with multiple long-term conditions.

G protein-coupled receptor (GPCR) gene variants and human genetic disease.

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other. GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling. Next generation sequencing has made it possible to identify variants of uncertain significance (VUS). We discuss variants in receptors known to result in disease and in silico strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping. Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism. Activating and inactivating variants of the calcium sensing receptor (CaSR) gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have enabled the development of calcimimetics and calcilytics. Next generation sequencing has continued to identify variants in GPCR genes, including orphan receptors, that contribute to human phenotypes and may have therapeutic potential. Variants of the CaSR gene, some encoding an arginine-rich region that promotes receptor phosphorylation and intracellular retention, have been linked to an idiopathic epilepsy syndrome. Agnostic strategies have identified variants of the pyroglutamylated RF amide peptide receptor gene in intellectual disability and G protein-coupled receptor 39 identified in psoriatic arthropathy. Coding variants of the G protein-coupled receptor L1 (GPR37L1) orphan receptor gene have been identified in a rare familial progressive myoclonus epilepsy. The study of the role of GPCR variants in monogenic, Mendelian phenotypes has provided the basis of modeling the significance of more common variants of pharmacogenetic significance.

Rising to the challenge of defining and operationalising multimorbidity in a UK hospital setting: the ADMISSION research collaborative.

PURPOSE: Greater transparency and consistency when defining multimorbidity in different settings is needed. We aimed to: (1) adapt published principles that can guide the selection of long-term conditions for inclusion in research studies of multimorbidity in hospitals; (2) apply these principles and identify a list of long-term conditions; (3) operationalise this list by mapping it to International Classification of Diseases 10th revision (ICD-10) codes. METHODS: Review by independent assessors and ratification by an interdisciplinary programme management group. RESULTS: Agreement was reached that when defining multimorbidity in hospitals for research purposes all conditions must meet the following four criteria: (1) medical diagnosis; (2) typically present for ≥ 12 months; (3) at least one of currently active; permanent in effect; requiring current treatment, care or therapy; requiring surveillance; remitting-relapsing and requiring ongoing treatment or care, and; (4) lead to at least one of: significantly increased risk of death; significantly reduced quality of life; frailty or physical disability; significantly worsened mental health; significantly increased treatment burden (indicated by an increased risk of hospital admission or increased length of hospital stay). Application of these principles to two existing lists of conditions led to the selection of 60 conditions that can be used when defining multimorbidity for research focused on hospitalised patients. ICD-10 codes were identified for each of these conditions to ensure consistency in their operationalisation. CONCLUSIONS: This work contributes to achieving the goal of greater transparency and consistency in the approach to the study of multimorbidity, with a specific focus on the UK hospital setting.

How far back do we need to look to capture diagnoses in electronic health records? A retrospective observational study of hospital electronic health record data.

OBJECTIVES: Analysis of routinely collected electronic health data is a key tool for long-term condition research and practice for hospitalised patients. This requires accurate and complete ascertainment of a broad range of diagnoses, something not always recorded on an admission document at a single point in time. This study aimed to ascertain how far back in time electronic hospital records need to be interrogated to capture long-term condition diagnoses. DESIGN: Retrospective observational study of routinely collected hospital electronic health record data. SETTING: Queen Elizabeth Hospital Birmingham (UK)-linked data held by the PIONEER acute care data hub. PARTICIPANTS: Patients whose first recorded admission for chronic obstructive pulmonary disease (COPD) exacerbation (n=560) or acute stroke (n=2142) was between January and December 2018 and who had a minimum of 10 years of data prior to the index date. OUTCOME MEASURES: We identified the most common International Classification of Diseases version 10-coded diagnoses received by patients with COPD and acute stroke separately. For each diagnosis, we derived the number of patients with the diagnosis recorded at least once over the full 10-year lookback period, and then compared this with shorter lookback periods from 1 year to 9 years prior to the index admission. RESULTS: Seven of the top 10 most common diagnoses in the COPD dataset reached >90% completeness by 6 years of lookback. Atrial fibrillation and diabetes were >90% coded with 2-3 years of lookback, but hypertension and asthma completeness continued to rise all the way out to 10 years of lookback. For stroke, 4 of the top 10 reached 90% completeness by 5 years of lookback; angina pectoris was >90% coded at 7 years and previous transient ischaemic attack completeness continued to rise out to 10 years of lookback. CONCLUSION: A 7-year lookback captures most, but not all, common diagnoses. Lookback duration should be tailored to the conditions being studied.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations. METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection. ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21. TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

Experiences of hospital care for people with multiple long-term conditions: a scoping review of qualitative research.

BACKGROUND: Multiple long-term conditions-the co-existence of two or more chronic health conditions in an individual-present an increasing challenge to populations and healthcare systems worldwide. This challenge is keenly felt in hospital settings where care is oriented around specialist provision for single conditions. The aim of this scoping review was to identify and summarise published qualitative research on the experiences of hospital care for people living with multiple long-term conditions, their informal caregivers and healthcare professionals. METHODS: We undertook a scoping review, following established guidelines, of primary qualitative research on experiences of hospital care for people living with multiple long-term conditions published in peer-reviewed journals between Jan 2010 and June 2022. We conducted systematic electronic searches of MEDLINE, CINAHL, PsycInfo, Proquest Social Science Premium, Web of Science, Scopus and Embase, supplemented by citation tracking. Studies were selected for inclusion by two reviewers using an independent screening process. Data extraction included study populations, study design, findings and author conclusions. We took a narrative approach to reporting the findings. RESULTS: Of 8002 titles and abstracts screened, 54 papers reporting findings from 41 studies conducted in 14 countries were identified as eligible for inclusion. The perspectives of people living with multiple long-term conditions (21 studies), informal caregivers (n = 13) and healthcare professionals (n = 27) were represented, with 15 studies reporting experiences of more than one group. Findings included poor service integration and lack of person-centred care, limited confidence of healthcare professionals to treat conditions outside of their specialty, and time pressures leading to hurried care transitions. Few studies explored inequities in experiences of hospital care. CONCLUSIONS: Qualitative research evidence on the experiences of hospital care for multiple long-term conditions illuminates a tension between the desire to provide and receive person-centred care and time pressures inherent within a target-driven system focussed on increasing specialisation, reduced inpatient provision and accelerated journeys through the care system. A move towards more integrated models of care may enable the needs of people living with multiple long-term conditions to be better met. Future research should address how social circumstances shape experiences of care.

The potential of suspended chitosan nanoparticles as a surgical irrigation fluid.

In this study, we sought to synthesize chitosan nanoparticles (CS-NPs) and characterize their morphology, efficacy in inhibiting bacterial attachment, and efficacy in eradicating bacteria established on implantable hardware. CS-NPs possess desirable properties, including antibacterial properties in biofilm-mediated infections. CS-NPs were produced using ionic gelation and characterized via scanning electron microscope imaging. Staphylococcus aureus was incubated with CS-NPs at various concentrations and compared to a 1% povidone-iodine with 1% H2 O2 control in 24-well plates. Stainless steel bone screws were placed in six-well plates and inoculated with S. aureus. After 24 h, the screws were transferred to one of three solutions (saline, 40 mg/mL CS-NP, or 1% povidone-iodine with 1% H2 O2 ). Four screws from each group were vortexed in saline and plated. The remaining screw from each group was prepped and imaged to map the location of persistent bacteria. Synthesized CS-NPs had a mean diameter of 0.39 ± 0.13 µm and circularity of 0.87 ± 0.05. The percent inhibition of bacterial attachment was 73% at 20 mg/mL, 73% at 30 mg/mL, 75% at 40 mg/mL, 79% at 50 mg/mL, and 78% at 60 mg/mL. When compared to saline, the 40 mg/mL CS-NP solution reduced bacteria on the screws by 76%. No bacteria were retrieved from the 1% povidone-iodine with 1% H2 O2 group. This study demonstrated that CS-NP solution effectively inhibited S. aureus bacterial attachment and was more effective than saline in eradicating bacteria from orthopedic hardware, suggesting that CS-NPs have the potential for prevention and treatment of musculoskeletal infections as a component of an intraoperative surgical irrigation solution.

Why are older adults living with the complexity of multiple long-term conditions, frailty and a recent deterioration in health under-served by research? A narrative synthesis review of the literature.

Older adults living with the complexity of multiple long-term conditions (MLTC), frailty and a recent deterioration in health are under-served by research. As a result, current treatment guidelines are often based on data from studies of younger and less frail participants, and often single disease focused. The aims of this review were (i) to identify why older adults living with the complexity of MLTC, frailty and a recent deterioration in health are under-served by research and (ii) to identify strategies for increasing their recruitment and retention. Although a range of factors have been suggested to affect the participation of older adults with MLTC and frailty in research, this review shows that much less is known about the inclusion of older adults living with the complexity of MLTC, frailty and a recent deterioration in health. Researchers should focus on strategies that minimise participation burden for these patients, maintaining an adaptive and flexible approach, to increase their recruitment and retention. Future research should include qualitative interviews to provide further insights into how best to design and conduct research to suit the needs of this population group.

Topological data analysis reveals a core gene expression backbone that defines form and function across flowering plants.

Since they emerged approximately 125 million years ago, flowering plants have evolved to dominate the terrestrial landscape and survive in the most inhospitable environments on earth. At their core, these adaptations have been shaped by changes in numerous, interconnected pathways and genes that collectively give rise to emergent biological phenomena. Linking gene expression to morphological outcomes remains a grand challenge in biology, and new approaches are needed to begin to address this gap. Here, we implemented topological data analysis (TDA) to summarize the high dimensionality and noisiness of gene expression data using lens functions that delineate plant tissue and stress responses. Using this framework, we created a topological representation of the shape of gene expression across plant evolution, development, and environment for the phylogenetically diverse flowering plants. The TDA-based Mapper graphs form a well-defined gradient of tissues from leaves to seeds, or from healthy to stressed samples, depending on the lens function. This suggests that there are distinct and conserved expression patterns across angiosperms that delineate different tissue types or responses to biotic and abiotic stresses. Genes that correlate with the tissue lens function are enriched in central processes such as photosynthetic, growth and development, housekeeping, or stress responses. Together, our results highlight the power of TDA for analyzing complex biological data and reveal a core expression backbone that defines plant form and function.

Spotlight on the academic multidisciplinary team: proposals from the 3rd NIHR Newcastle BRC Academic Geriatric Medicine Workshop.

High-quality care for older people is best delivered by multidisciplinary teams involving a range of professions. Similarly, if research evidence is to effectively inform practice, it needs to be designed and executed by teams that are both multidisciplinary and multiprofessional. Here, we summarise the discussions from a 1-day workshop convened by the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre in Spring 2021, which focussed on multidisciplinary academic teams. Barriers to success include small numbers of clinical academic researchers across all professions focussing on older people, and lack of career pathways, role models and support for non-medical clinical researchers. The workshop identified strengths in the tradition of multidisciplinary working in the care of older people, research questions that lend themselves naturally to multidisciplinary working, increasing interest from funders in multidisciplinary research, and untapped opportunities for greater commercial engagement. Initiatives to improve engagement of students and trainees, mentorship, career pathways, networking across research centres and possibly developing a national School of Older People's Care Research are all ways that we can ensure the growth of multidisciplinary research to best serve older people's health and social care in the future.