Predicting short- to medium-term care home admission risk in older adults: a systematic review of externally validated models.

INTRODUCTION: Predicting risk of care home admission could identify older adults for early intervention to support independent living but require external validation in a different dataset before clinical use. We systematically reviewed external validations of care home admission risk prediction models in older adults. METHODS: We searched Medline, Embase and Cochrane Library until 14 August 2023 for external validations of prediction models for care home admission risk in adults aged ≥65 years with up to 3 years of follow-up. We extracted and narratively synthesised data on study design, model characteristics, and model discrimination and calibration (accuracy of predictions). We assessed risk of bias and applicability using Prediction model Risk Of Bias Assessment Tool. RESULTS: Five studies reporting validations of nine unique models were included. Model applicability was fair but risk of bias was mostly high due to not reporting model calibration. Morbidities were used as predictors in four models, most commonly neurological or psychiatric diseases. Physical function was also included in four models. For 1-year prediction, three of the six models had acceptable discrimination (area under the receiver operating characteristic curve (AUC)/c statistic 0.70-0.79) and the remaining three had poor discrimination (AUC < 0.70). No model accounted for competing mortality risk. The only study examining model calibration (but ignoring competing mortality) concluded that it was excellent. CONCLUSIONS: The reporting of models was incomplete. Model discrimination was at best acceptable, and calibration was rarely examined (and ignored competing mortality risk when examined). There is a need to derive better models that account for competing mortality risk and report calibration as well as discrimination.

Performance of models for predicting 1-year to 3-year mortality in older adults: a systematic review of externally validated models.

Mortality prediction models support identifying older adults with short life expectancy for whom clinical care might need modifications. We systematically reviewed external validations of mortality prediction models in older adults (ie, aged 65 years and older) with up to 3 years of follow-up. In March, 2023, we conducted a literature search resulting in 36 studies reporting 74 validations of 64 unique models. Model applicability was fair but validation risk of bias was mostly high, with 50 (68%) of 74 validations not reporting calibration. Morbidities (most commonly cardiovascular diseases) were used as predictors by 45 (70%) of 64 of models. For 1-year prediction, 31 (67%) of 46 models had acceptable discrimination, but only one had excellent performance. Models with more than 20 predictors were more likely to have acceptable discrimination (risk ratio [RR] vs <10 predictors 1·68, 95% CI 1·06-2·66), as were models including sex (RR 1·75, 95% CI 1·12-2·73) or predicting risk during comprehensive geriatric assessment (RR 1·86, 95% CI 1·12-3·07). Development and validation of better-performing mortality prediction models in older people are needed.

Effectiveness of holistic assessment-based interventions for adults with multiple long-term conditions and frailty: an umbrella review of systematic reviews.

Holistic assessment-based interventions (HABIs) are effective in older people admitted to hospital, but it is unclear whether similar interventions are effective in adults with multiple long-term conditions or frailty in the community. We conducted an umbrella review to comprehensively evaluate the literature on HABIs for adults (aged ≥18 years) with multiple long-term conditions, and frailty. We searched eight databases for systematic reviews reporting on experimental or quasi-experimental studies. Of 9803 titles screened, we identified 29 eligible reviews (14 with meta-analysis) reporting on 14 types of HABIs. The evidence for the effectiveness of HABIs was largely inconsistent across different types of interventions, settings, and outcomes. We found evidence of no benefit from hospital HABIs on health-related quality of life (HRQoL) and emergency department re-attendance, and evidence of no benefit from community HABIs on overall health-care utilisation rates, emergency department attendance, nursing home admissions, and mortality. The best evidence of effectiveness was for hospital comprehensive geriatric assessment (CGA) on nursing home admissions, keeping patients alive and in their own homes. There was some evidence of benefit from community CGA on hospital admissions, and from CGA spanning community and hospital settings on HRQoL. Patient-centred medical homes had beneficial effects on HRQoL, mental health, self-management, and hospital admissions.

Duration of consultant experience and patient outcome following acute medical unit admission: an observational cohort study.

BACKGROUND: The effect of the duration of consultant experience on clinical outcomes in the acute medical unit (AMU) model remains unknown. METHODS: Unscheduled AMU admissions (n=66,929) admitted by 56 consultant physicians between 2017 and 2020 to two large teaching hospital AMUs in Lothian, Scotland were examined. The associations of consultant experience on AMU with patient discharge, mortality, readmission and postdischarge death were calculated adjusting for clinical acuity, pathology and comorbidity. RESULTS: Increasing consultant experience was associated with a continuous increase in likelihood of early AMU discharge (odds ratio (OR) 1.08; 95% confidence interval (CI) 1.07-1.10; p<0.001 per 5 years' experience), which persisted after adjustment for confounders (OR 1.06; 95% CI: 1.01-1.11; p=0.01). There was no association with early readmission, death after discharge or 30-day inpatient mortality. The marginal effect estimate translates into 31 (95% CI: 25-36), 41 (95% CI: 30-53) and 52 (95% CI: 35-71) additional safe discharges per 1,000 admissions for clinicians of 15, 20 and 25 years' experience, respectively compared with those recently completing training. CONCLUSIONS: Increasing consultant physician experience associates with early safe discharge after AMU admission. These data suggest that the support and retention of experienced clinicians is vital if escalating pressures on unscheduled medical care are to be addressed.

A case of Lemierre's syndrome causing panhypopituitarism, cavernous sinus thrombosis, ischaemic stroke and pulmonary embolism.

Infection is a rare cause of panhypopituitarism and has not been reported in the context of Lemierre's syndrome. We present the case of a previously well 19-year-old man, who presented acutely unwell with meningitis and sepsis. Fusobacterium necrophorum was isolated from peripheral blood cultures and identified on cerebrospinal fluid with 16S rDNA Polymerase Chain Reaction (PCR). Imaging demonstrated internal jugular vein thrombosis with subsequent cavernous venous sinus thrombosis. Pituitary function tests were suggestive of panhypopituitarism. The patient was diagnosed with Lemierre's syndrome complicated by meningitis, cavernous sinus thrombosis, base of skull osteomyelitis, ischaemic stroke and panhypopituitarism. He was treated with 13 weeks of intravenous antibiotics followed by 3 weeks of oral amoxicillin, and anticoagulated with dalteparin then apixaban. His panhypopituitarism was managed with hydrocortisone, levothyroxine and desmopressin.

Associations between glucagon prescribing, hospital admissions for hypoglycaemia and continuous glucose monitoring metrics in adults with type 1 diabetes.

AIMS: To assess features associated with glucagon prescribing and hospital admissions with hypoglycaemia in type one diabetes. METHODS: Observational study of 4462 adults. Outcome measures were features associated with glucagon prescriptions and predictors of hospital admissions with hypoglycaemia and high levels of glucagon prescribing. RESULTS: 74 % did not collect any glucagon prescriptions and 2.7 % collected >6 over 3.5 years. Hospital admission with hypoglycaemia (P = 0.032), impaired awareness (P = 0.049) and female sex (P < 0.001) were associated with glucagon collection. More frequent prescribing of glucagon was associated with diabetes duration (P < 0.001) and socioeconomic deprivation (P < 0.001). Higher average glucose (P = 0.047), higher time above 13.9 mM (P = 0.008) and higher SD (P = 0.002) were associated with glucagon prescribing. Diabetes duration (P < 0.001) and HbA1c (P < 0.001) were higher in people with hospitalised hypoglycaemia. Higher time above 13.9 mM (P = 0.004) and SD glucose (P < 0.001) were most clearly associated with hospitalised hypoglycaemia. CONCLUSIONS: A minority of people with type 1 diabetes have access to glucagon suggesting more could be done to better target this treatment. Individuals with risk factors and those with frequent glucagon prescriptions should be identified for interventions known to reduce hypoglycaemia.

Variation in general practice referral rate to acute medicine services and association with hospital admission. A retrospective observational study.

BACKGROUND: Variation in general practice (GP) referral rates to outpatient services is well described however variance in rates of referral to acute medical units is lacking. OBJECTIVE: To investigate variance in GP referral rate for acute medical assessment and subsequent need for hospital admission. METHODS: A retrospective cohort study of acute medical referrals from 88 GPs in Lothian, Scotland between 2017 and 2020 was performed using practice population size, age, deprivation, care home residence, and distance from hospital as explanatory variables. Patient-level analysis of demography, deprivation, comorbidity, and acuity markers was subsequently performed on referred and clinically assessed acute medical patients (n = 42,424) to examine how practice referral behaviour reflects clinical need for inpatient hospital care. RESULTS: Variance in GP referral rates for acute medical assessment was high (2.53-fold variation 1st vs. 4th quartile) and incompletely explained by increasing age and deprivation (adjusted R2 0.67, P < 0.001) such that significant variance remained after correction for confounders (2.15-fold). Patients from the highest referring quartile were significantly less likely to require hospital admission than those from the third, second, or lowest referring quartiles (adjusted odds ratio 1.28 [1.21-1.36, P < 0.001]; 1.30 [1.23-1.37, P < 0.001]; 1.53 [1.42-1.65, P < 0.001]). CONCLUSIONS: High variation in GP practice referral rate for acute medical assessment is incompletely explained by practice population socioeconomic factors and negatively associates with need for urgent inpatient care. Identifying modifiable factors influencing referral rate may provide opportunities to facilitate community-based care and reduce congestion on acute unscheduled care pathways.

Managing the populations need for urgent medical care is challenge in many healthcare systems and overcrowding of urgent medical services negatively affects patient experience and can affect timely treatment. In the United Kingdom, the primary sources of patients attending for acute medical care are self-attendance to the hospital or by way of referral by a primary care physician (general practitioner). These data for the first time demonstrate high variation in referral rates for acute medical assessment between general practices which is incompletely explained by factors such as the age, deprivation, distance to the hospital or care home residence status of the care home population. Analysis of over 40,000 of these referrals for urgent medical care was subsequently undertaken to further investigate this variation. After adjusting for important clinical factors, patients referred from "high referring" practices were over 50% less likely to require inpatient hospital care than patients from lower referring practices. This suggests that the threshold for referral varies greatly between individual primary care clinicians, practices, or practice populations and many of these patients may have been suitable for less urgent community-based care. Identification of modifiable factors that account for this unexplained variation may facilitate community-based care and improve patient experience by reducing unnecessary attendance and congestion in already busy emergency care services.

Higher clinical acuity and 7-day hospital mortality in non-COVID-19 acute medical admissions: prospective observational study.

OBJECTIVES: To understand the effect of COVID-19 lockdown measures on severity of illness and mortality in non-COVID-19 acute medical admissions. DESIGN: A prospective observational study. SETTING: 3 large acute medical receiving units in NHS Lothian, Scotland. PARTICIPANTS: Non-COVID-19 acute admissions (n=1682) were examined over the first 31 days after the implementation of the COVID-19 lockdown policy in the UK on 23 March 2019. Patients admitted over a matched interval in the previous 5 years were used as a comparator cohort (n=14 954). MAIN OUTCOME MEASURES: Patient demography, biochemical markers of clinical acuity and 7-day hospital inpatient mortality. RESULTS: Non-COVID-19 acute medical admissions reduced by 44.9% across all three sites in comparison with the mean of the preceding 5 years (p<0.001). Patients arriving during this period were more likely to be male, of younger age and to arrive by emergency ambulance transport. Non-COVID-19 admissions during lockdown had a greater incidence of acute kidney injury, lactic acidaemia and an increased risk of hospital death within 7 days (4.2% vs 2.5%), which persisted after adjustment for confounders (OR 1.87, 95% CI 1.43 to 2.41, p<0.001). CONCLUSIONS: These data demonstrate a significant reduction in non-COVID-19 acute medical admissions during the early weeks of lockdown. Patients admitted during this period were of higher clinical acuity with a higher incidence of early inpatient mortality.

A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis. Following induction of macrovesicular steatosis in hepatocyte-like cells using lactate, pyruvate, and octanoate (LPO), respirometry and transcriptomic analyses revealed compromised electron transport chain activity. 13C isotopic tracing studies revealed enhanced TCA cycle anaplerosis, with concomitant development of a compensatory purine nucleotide cycle shunt leading to excess generation of fumarate. This model of hepatic steatosis is reproducible, scalable, and overcomes the challenges of studying mitochondrial metabolism in currently available models.

Socioeconomic deprivation, technology use, C-peptide, smoking and other predictors of glycaemic control in adults with type 1 diabetes.

AIMS: Intensive glycaemic control is associated with substantial health benefits in people with type 1 diabetes. We sought to examine clinical and demographic factors associated with meeting glycaemic targets in type 1 diabetes. METHODS: We conducted a cross-sectional analysis of 4594 individuals with type 1 diabetes. The primary outcome of the study was assessing factors associated with meeting HbA1c targets. Secondary endpoints included factors associated with continuous subcutaneous insulin infusion (CSII) use and persistent C-peptide secretion. RESULTS: Socioeconomic deprivation was strongly associated with a lower likelihood of achieving an HbA1c <58 mmol/mol (7.5%) (20% in the most deprived quintile vs. 40% in the least deprived, p < 0.001). In multivariate analysis, absence of smoking history (OR 3.06, p < 0.001), flash monitoring (OR 1.49, p < 0.001), CSII (1.43, p = 0.022) and longer diabetes duration (OR 1.02 per year, p = 0.004) were independently associated with achieving HbA1c <58 mmol/mol (7.5%), whereas increasing age (OR 0.99 per year, p = 0.004) and C-peptide <50 pM (OR 0.58, p < 0.001) were associated with a lower likelihood of meeting this target. Low C-peptide (<50 pM) was less likely in men (OR 0.55, p < 0.001) and never smokers (0.44, p < 0.001) in multivariate analysis. CONCLUSIONS: Lower levels of deprivation, non-smoking, higher C-peptide, technology use, lower BMI and male gender were all associated with a higher likelihood of meeting HbA1c targets. Access to proven diabetes treatments is lower in the most deprived individuals. Urgent efforts are required to provide treatments which are effective across the socioeconomic gradient.

Non-alcoholic fatty liver disease (NAFLD) is associated with dynamic changes in DNA hydroxymethylation.

Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of liver disease in developed countries affecting 25-33% of the general population and up to 75% of those with obesity. Recent data suggest that alterations in DNA methylation may be related to NAFLD pathogenesis and progression and we have previously shown that dynamic changes in the cell lineage identifier 5-hydroxymethylcytosine (5hmC) may be important in the pathogenesis of liver disease. We used a model of diet-induced obesity, maintaining male mice on a high-fat diet (HFD) to generate hepatic steatosis. We profiled hepatic gene expression, global and locus-specific 5hmC and additionally investigated the effects of weight loss on the phenotype. HFD led to increased weight gain, fasting hyperglycaemia, glucose intolerance, insulin resistance and hepatic periportal macrovesicular steatosis. Diet-induced hepatic steatosis associated with reversible 5hmC changes at a discrete number of functionally important genes. We propose that 5hmC profiles are a useful signature of gene transcription and a marker of cell state in NAFLD and suggest that 5hmC profiles hold potential as a biomarker of abnormal liver physiology.

Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An in vitro NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear. Additionally, the epigenetic mark 5-hydroxymethylcytosine (5hmC), a cell lineage identifier, is rapidly lost during cell culture, alongside expression of the Ten-eleven-translocation (TET) methylcytosine dioxygenase enzymes, restricting meaningful epigenetic analysis. Hepatocyte-like cells (HLCs) derived from human embryonic stem cells can provide a non-neoplastic, renewable model for liver research. Here, we have developed a model of NAFLD using HLCs exposed to lactate, pyruvate and octanoic acid (LPO) that bear all the hallmarks, including 5hmC profiles, of liver functionality. We exposed HLCs to LPO for 48 h to induce lipid accumulation. We characterized the transcriptome using RNA-seq, the metabolome using ultra-performance liquid chromatography-mass spectrometry and the epigenome using 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) sequencing. LPO exposure induced an NAFLD phenotype in HLCs with transcriptional and metabolomic dysregulation consistent with those present in human NAFLD. HLCs maintain expression of the TET enzymes and have a liver-like epigenome. LPO exposure-induced 5hmC enrichment at lipid synthesis and transport genes. HLCs treated with LPO recapitulate the transcriptional and metabolic dysregulation seen in NAFLD and additionally retain TET expression and 5hmC. This in vitro model of NAFLD will be useful for future mechanistic and therapeutic studies.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD.

Background: Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.              Methods: Adult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD. Results: Compared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases ( Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC. Conclusions: This study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level.

Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer.

Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations that occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, selected CGIs underwent hypo-hydroxymethylation prior to hypermethylation, while retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprograming of DNA methylation at silent CGI during progression. Cancer Res; 76(10); 3097-108. ©2016 AACR.

Recombinant Laminins Drive the Differentiation and Self-Organization of hESC-Derived Hepatocytes.

Stem cell-derived somatic cells represent an unlimited resource for basic and translational science. Although promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes that are the product of using undefined components in the differentiation process. This serves as a significant barrier to scale-up and application. To tackle this issue, we designed a defined differentiation process using recombinant laminin substrates to provide instruction. We demonstrate efficient hepatocyte specification, cell organization, and significant improvements in cell function and phenotype. This is driven in part by the suppression of unfavorable gene regulatory networks that control cell proliferation and migration, pluripotent stem cell self-renewal, and fibroblast and colon specification. We believe that this represents a significant advance, moving stem cell-based hepatocytes closer toward biomedical application.