Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study.

BACKGROUND AND AIMS: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. APPROACH AND RESULTS: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p  = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. CONCLUSIONS: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

Frailty scoring in vascular and endovascular surgery: A systematic review.

One in 10 independently living adults aged 65 years old and older is considered frail, and frailty is associated with poor postoperative outcomes. This systematic review aimed to examine the association between frailty assessments and postoperative outcomes in patients with vascular disease. Electronic databases - MEDLINE, Embase, and the Cochrane Library - were searched from inception until January 2022, resulting in 648 articles reviewed for potential inclusion and 16 studies selected. Demographic data, surgery type, frailty measure, and postoperative outcomes predicted by frailty were extracted from the selected studies. The risk of bias was assessed using the Newcastle-Ottawa Scale. The selected studies (mean age: 56.1-76.3 years) had low-to-moderate risk of bias and included 16 vascular (elective and nonelective) surgeries and eight frailty measures. Significant associations (p < 0.05) were established between mortality (30-day, 90-day, 1-year, 5-year), 30-day morbidity, nonhome discharge, adverse events, failure to rescue, patient requiring care after discharge, and amputation following critical limb ischaemia. The strongest evidence was found between 30-day mortality and frailty. Composite 30-day morbidity and mortality, functional status at discharge, length of stay, spinal cord deficit, and access site complications were found to be nonsignificantly associated with frailty. With frailty being significantly associated with several adverse postoperative outcomes, preoperative frailty assessments can potentially be clinically useful in helping practitioners predict and guide the pre-, peri-, and postoperative management of frail with vascular disease.

Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer.

PURPOSE: Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS: Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.

Proportion of medical admissions that may be hospitalised at home and their service utilisation patterns: a single-centre, descriptive retrospective cohort study in Singapore.

OBJECTIVES: For eligible patient groups, hospital-at-home (HaH) programmes have been shown to deliver equivalent patient outcomes with cost reduction compared with standard care. This study aims to establish a benchmark of inpatient admissions that could potentially be substituted by HaH services. DESIGN: Descriptive retrospective cohort study. SETTING: Academic tertiary hospital in Singapore. PARTICIPANTS: 124 253 medical admissions over 20 months (January 2016 to August 2017). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary measure was the proportion of hospitalised patients who may be eligible for HaH, based on eligibility criteria adapted for the Singapore context. The secondary measures were the utilisation patterns and outcomes of these patients. RESULTS: Applying generalised eligibility criteria to the retrospective dataset showed that 53.0% of 124 253 medical admissions fitted the eligibility criteria for HaH based on administrative data. 46.8% of such patients had a length of stay <48 hours ('short-stay') and 53.1% had a length of stay ≥48 hours ('medium-stay'). The mortality rate and the 30-day readmission rate were lower in the 'short-stay' cohort (0.6%, 12.8%) compared with the 'medium-stay' cohort (0.7%, 20.3%). The key services used by both groups were: parenteral drug administration, blood investigations, imaging procedures and consultations with allied health professionals. CONCLUSIONS: Up to 53.0% of medical admissions receive care elements that HaH programmes could provide. Applying estimates of functional limitations and patient preferences, we propose a target of ~18% of inpatient medical admissions to be substituted by HaH services. The methodology adopted in this paper is a reproducible approach to characterise potential patients and service utilisation requirements when developing such programmes.

Sustainability and impact of the implementation of a frailty checklist for the acute medical unit: experience from a tertiary public hospital in Singapore.

BACKGROUND: Accelerated population ageing is associated with an increasing prevalence of frailty. International guidelines call for systematic assessment and timely interventions for older persons requiring acute care. Checklists have been applied successfully in healthcare settings. OBJECTIVE: This study describes the implementation of a safety checklist for frailty in the acute medical unit (AMU) of a tertiary public hospital in Singapore. We explored the sustainability of processes up to 6 months after initial implementation. Additionally, we investigated process and system outcome benefits following the implementation of the checklist. METHODS: This retrospective observational study used case notes review of patients admitted to the AMU of a tertiary public hospital in Singapore from February to August 2019. Process outcomes measured to include compliance with AMU frailty checklist assessments and interventions at 24 hours of hospital admission. System and patient outcomes studied to include the length of hospital stay; 30-day emergency department reattendance rate; 30-day hospital readmission rate and inpatient mortality. Propensity scores were used to create balanced cohorts for comparison between those with complete and incomplete compliance with the checklist. Logistic regression was used to adjust for known confounders. RESULTS: Average weekly (all-or-nothing) compliance with the frailty checklist (14.7%) was sustained for 6 months. Where assessments detected high risk, appropriate interventions were appropriately triggered (44%-97.4%). While trends to benefit systems and patient outcomes were present, these were not statistically significant. Contextual patterns are discussed. CONCLUSION: A safety checklist for frailty was feasibly implemented in the AMU. The checklist was a complex intervention. Full compliance with the checklist was challenging to achieve. Further research assessing optimal patient selection criteria and how checklists may shift team behaviour is a priority.

A G-quadruplex stabilizer, CX-5461 combined with two immune checkpoint inhibitors enhances in vivo therapeutic efficacy by increasing PD-L1 expression in colorectal cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration. RESULTS: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-ß secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. CONCLUSIONS: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.

Inflammatory phenotypes may be more important than age and comorbidities in predicting clinical outcomes in hospitalised patients with COVID-19.

Objectives: In critically ill patients with COVID-19, distinct hyperinflammatory and hypoinflammatory phenotypes have been described, with different outcomes and responses to therapy. We investigated if similar phenotypes exist in non-severe illness. Methods: Consecutive patients with polymerase chain reaction (PCR) confirmed SARS-CoV-2 were examined. Baseline demographics and laboratory investigations were tabulated, including serum C-reactive protein. Patients were divided into those who were hyperinflammatory (defined as C-reactive protein >17 mg/l) or hypoinflammatory. Adverse outcomes, defined as requiring oxygenation, intensive care, or death, were recorded during the hospital stay. Clinical characteristics and outcomes were compared. Results: Of the 1781 patients examined, 276 (15.5%) had a hyperinflammatory phenotype. They were older (51.8 ± 17.2 vs 40.3 ± 13.8 years, P <0.001), had a lower PCR cycle threshold (PCR cycle threshold value 19.3 ± 6.3 vs 22.7 ± 15.4, P = 0.025) at presentation, and more medical comorbidities. The hyperinflammatory phenotype was independently associated with adverse clinical outcomes, even after adjusting for age, medical history and viral load on multivariable analyses (adjusted odds ratio 5.78, 95% confidence interval 2.86-11.63). Conclusion: Even in non-severe COVID-19, there are distinct hyper- and hypoinflammatory phenotypes, with the hyperinflammatory phenotype strongly associated with adverse clinical outcomes, that could be distinguished with a simple biomarker.

Gender Differences in Body Composition in Pre-Frail Older Adults With Diabetes Mellitus.

BACKGROUND & AIMS: Ageing is a risk factor for diabetes mellitus (DM) and frailty. It is associated with body composition changes including increase in fat mass (FM), central fat distribution, decrease in fat free mass (FFM) and skeletal muscle which are risk factors for DM. This study aims to evaluate gender differences in body composition in pre-frail diabetics and association with physical performance, cognitive function and perceived health. In addition, we aim to explore the association of obesity, sarcopenia, sarcopenic obesity, and body composition in pre-frail older adults to DM status. METHODS: Cross-sectional study of 192 pre-frail community dwelling older adults (≥ 65 years). Data was collected on demographics, physical function, cognition, frailty, sarcopenia, perceived health and body composition using the InBody S10. Univariate and multivariate logistic regression were undertaken to explore the association of sarcopenic obesity, obesity, sarcopenia and body composition measures to DM status. RESULTS: There were insignificant within-gender differences for physical function, cognition and body composition, except for a higher prevalence of obesity defined by body mass index (BMI) and body fat percentage (BF%), increased fat mass index(FMI) and fat free mass index(FFMI) in females with DM. There were significant between-gender differences for those with DM where females overall had lower education levels, lower perceived health, higher prevalence of depression and low mental vitality, lower overall physical function (low short physical performance battery scores, low gait speed and hand grip strength), lower cognitive scores, lower muscle mass and muscle quality with higher FMI, FM/FFM and visceral fat area(VFA). BMI, VFA>100 cm2, FMI and FFMI were found to be independently associated with DM status after multivariable adjustment. CONCLUSION: Within pre-frail DM vs non-DM, there were insignificant differences in body composition, physical function, cognition and perceived health within gender except for FMI, BF% and FFMI in females. There were significant differences between gender in pre-frail DM in muscle mass, quality, functional, cognitive and mental status. Further longitudinal studies are required to understand the pathogenesis, trajectory of DM and protective role of oral hypoglycemics in pre-frail older adults.

Meeting today's healthcare needs: Medicine at the interface.

The demographic of Singapore has undergone dramatic change. Historically, younger patients with communicable diseases predominated, whereas patients are now older with chronic multimorbidity and functional impairment. This shift challenges existing health and social care systems in Singapore, which must pivot to meet the changing need. The consequences of mismatched health and social care to patient needs are the fragmentation of care, dysfunctional acute care utilisation and increasing care costs. In Singapore and internationally, there is an inexorable rise in acute care utilisation, with patients facing the greatest point of vulnerability at transitions between acute and chronic care. Recently, innovative care models have developed to work across the boundaries of traditional care interfaces. These "Interface Medicine" models aim to provide a comprehensive and integrated approach to meet the healthcare needs of today and optimise value with our finite resources. These models include Acute Medical Units, Ambulatory Emergency Care, Extensivist-Comprehensivist Care, Virtual Wards, Hospital-at-Home and Acute Frailty Units. We describe these models of care across the acute care chain and explore how they may apply to the Singapore setting. We discuss how these models have evolved, appraise the evidence for clinical effectiveness, point out gaps in knowledge for further study and make recommendations for future progress.

Variation in coded frailty syndromes in secondary care administrative data: an international retrospective exploratory study.

OBJECTIVES: Challenges with manual methodologies to identify frailty, have led to enthusiasm for utilising large-scale administrative data, particularly standardised diagnostic codes. However, concerns have been raised regarding coding reliability and variability. We aimed to quantify variation in coding frailty syndromes within standardised diagnostic code fields of an international dataset. SETTING: Pooled data from 37 hospitals in 10 countries from 2010 to 2014. PARTICIPANTS: Patients ≥75 years with admission of >24 hours (N=1 404 671 patient episodes). PRIMARY AND SECONDARY OUTCOME MEASURES: Frailty syndrome groups were coded in all standardised diagnostic fields by creation of a binary flag if the relevant diagnosis was present in the 12 months leading to index admission. Volume and percentages of coded frailty syndrome groups by age, gender, year and country were tabulated, and trend analysis provided in line charts. Descriptive statistics including mean, range, and coefficient of variation (CV) were calculated. Relationship to in-hospital mortality, hospital readmission and length of stay were visualised as bar charts. RESULTS: The top four contributors were UK, US, Norway and Australia, which accounted for 75.4% of the volume of admissions. There were 553 595 (39.4%) patient episodes with at least one frailty syndrome group coded. The two most frequently coded frailty syndrome groups were 'Falls and Fractures' (N=3 36 087; 23.9%) and 'Delirium and Dementia' (N=221 072; 15.7%), with the lowest CV. Trend analysis revealed some coding instability over the frailty syndrome groups from 2010 to 2014. The four countries with the lowest CV for coded frailty syndrome groups were Belgium, Australia, USA and UK. There was up to twofold, fourfold and twofold variation difference for outcomes of length of stay, 30-day readmission and inpatient mortality, respectively, across the countries. CONCLUSIONS: Variation in coding frequency for frailty syndromes in standardised diagnostic fields are quantified and described. Recommendations are made to account for this variation when producing risk prediction models.

Treating acutely ill patients at home: Data from Singapore.

INTRODUCTION: Hospital-at-home programmes are well described in the literature but not in Asia. We describe a home-based inpatient substitutive care programme in Singapore, with clinical and patient-reported outcomes. METHODS: We conducted a retrospective cohort study of patients admitted to a hospital-at-home programme from September 2020 to September 2021. Suitable patients, who otherwise required hospitalisation, were admitted to the programme. They were from inpatient wards, emergency department and community nursing teams in the western part of Singapore, where a multidisciplinary team provided hospital-level care at home. Electronic health record data were extracted from all patients admitted to the programme. Patient satisfaction surveys were conducted post-discharge. RESULTS: A total of 108 patients enrolled. Mean age was 67.9 (standard deviation 16.7) years, and 46% were male. The main diagnoses were skin and soft tissue infections (35%), urinary tract infections (29%) and fluid overload (18%). Median length of stay was 4 (interquartile range 3-7) days. Seven patients were escalated back to the hospital, of whom 2 died after escalation. One patient died at home. There was 1 case of adverse drug reaction and 1 fall at home, and no cases of hospital-acquired infections. Patient satisfaction rates were high and 94% of contactable patients would choose to participate again. CONCLUSION: Hospital-at-home programmes appear to be safe and feasible alternatives to inpatient care in Singapore. Further studies are warranted to compare clinical outcomes and cost to conventional inpatient care.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

Acute medical units during the first wave of the COVID-19 pandemic: a cross-national exploratory study of impact and responses.

BACKGROUND: The COVID-19 pandemic represents one of the greatest ever challenges for healthcare. In the UK and beyond, acute medical units (AMUs) are the first point of assessment and care for the majority of medical inpatients. By their design and systems, they inevitably played an important role in the COVID-19 response but to date little has been published on how the COVID-19 pandemic has affected how AMUs have reorganised their resources, processes and structure. METHODS: This retrospective study in August 2020 of 10 AMUs across Europe and Australasia used a standardised questionnaire to investigate existing practice and structure of AMUs, the national context of local hospital experience, changes to practice during the COVID-19 pandemic and views regarding future practice. RESULTS: Changes to AMU structure, process and organisation are described in two contexts: preventing and controlling the spread of COVID-19 and adding value to the patient's acute care journey in the local context. We describe novel practices that have arisen and highlight areas of concern. CONCLUSIONS: The AMUs were able to adapt to meet the demands of acute care delivery during the first wave of the COVID-19 pandemic. Operational planning and prioritisation of resources must be optimised to ensure sustainability of these services for future waves.

Asian Attitudes and Perceptions Toward Hospital-At-Home: A Cross-Sectional Study.

Introduction: Hospital-at-Home (HaH) programmes are well-established in Australia, Europe, and the United States. However, there is limited experience in Asia, where the hospital is traditionally seen as a safe and trusted space for healing. This cross-sectional study aimed to explore attitudes and perceptions among patients and caregivers in Singapore toward this care model. Methods: A quantitative study design was adopted to collect data among patients and their caregivers from medical wards within two acute hospitals in Singapore. Using a series of closed-ended and open-ended questions, the investigator-administered survey aimed to explore barriers and facilitators determining patients' and caregivers' responses. The study questionnaire was pretested and validated. Data were summarised using descriptive statistics, and logistic regression was performed to determine key factors influencing patients' decisions to enrol in such programmes. Results: Survey responses were collected from 120 participants (101 patients, 19 caregivers; response rate: 76%), of which 87 respondents (72.5%) expressed willingness to try HaH if offered. Many respondents valued non-quantifiable programme benefits, including perceived gains in quality of life. Among them, reasons cited for acceptance included preference for the comfort of their home environment, presence of family members, and confidence toward remote monitoring modalities. Among respondents who were unwilling to accept HaH, a common reason indicated was stronger confidence toward hospital care. Discussion: Most patients surveyed were open to having acute care delivered in their home environment, and concerns expressed may largely be addressed by operational considerations. The findings provide useful insights toward the planning of HaH programmes in Singapore.

Relationship of Fat Mass Index and Fat Free Mass Index With Body Mass Index and Association With Function, Cognition and Sarcopenia in Pre-Frail Older Adults.

Background: Body mass index (BMI) is an inadequate marker of obesity, and cannot distinguish between fat mass, fat free mass and distribution of adipose tissue. The purpose of this study was twofold. First, to assess cross-sectional relationship of BMI with fat mass index (FMI), fat free mass index (FFMI) and ratio of fat mass to fat free mass (FM/FFM). Second, to study the association of FMI, FFMI and FM/FFM with physical function including sarcopenia, and cognition in pre-frail older adults. Methods: Cross-sectional study of 191 pre-frail participants ≥ 65 years, 57.1% females. Data was collected on demographics, cognition [Montreal Cognitive Assessment (MoCA)], function, frailty, calf circumference, handgrip strength (HGS), short physical performance battery (SPPB) and gait speed. Body composition was measured using InBody S10. FMI, FFMI and FM/FFM were classified into tertiles (T1, T2, T3) with T1 classified as lowest and T3 highest tertile respectively and stratified by BMI. Results: Higher FFMI and lower FM/FFM in the high BMI group were associated with better functional outcomes. Prevalence of low muscle mass was higher in the normal BMI group. FMI and FM/FFM were significantly higher in females and FFMI in males with significant gender differences except for FFMI in ≥ 80 years old. Small calf circumference was significantly less prevalent in the highest tertile of FMI, FM/FMI and FFMI. Prevalence of sarcopenic obesity and low physical function (HGS, gait speed and SPPB scores) were significantly higher in the highest FMI and FM/FFM tertile. Highest FFMI tertile group had higher physical function, higher MoCA scores, lower prevalence of sarcopenic obesity and sarcopenia, After adjustment, highest tertile of FFMI was associated with lower odds of sarcopenia especially in the high BMI group. Highest tertile of FM/FFM was associated with higher odds of sarcopenia. Higher BMI was associated with lower odds of sarcopenia. Conclusion: FFMI and FM/FFM may be a better predictor of functional outcomes in pre-frail older adults than BMI. Cut-off values for healthy BMI values and role of calf circumference as a screening tool for sarcopenia need to be validated in larger population. Health promotion intervention should focus on FFMI increment.

Validating a methodology to measure frailty syndromes at hospital level utilising administrative data.

BACKGROUND: Identifying older people with clinical frailty, reliably and at scale, is a research priority. We measured frailty in older people using a novel methodology coding frailty syndromes on routinely collected administrative data, developed on a national English secondary care population, and explored its performance of predicting inpatient mortality and long length of stay at a single acute hospital. METHODOLOGY: We included patient spells from Secondary User Service (SUS) data for those ≥65 years with attendance to the emergency department or admission to West Middlesex University Hospital between 01 July 2016 to 01 July 2017. We created eight groups of frailty syndromes using diagnostic coding groups. We used descriptive statistics and logistic regression to explore performance of diagnostic coding groups for the above outcomes. RESULTS: We included 17,199 patient episodes in the analysis. There was at least one frailty syndrome present in 7,004 (40.7%) patient episodes. The resultant model had moderate discrimination for inpatient mortality (area under the receiver operating characteristic curve (AUC) 0.74; 95% confidence interval (CI) 0.72-0.76) and upper quartile length of stay (AUC 0.731; 95% CI 0.722-0.741). There was good negative predictive value for inpatient mortality (98.1%). CONCLUSIONS: Coded frailty syndromes significantly predict outcomes. Model diagnostics suggest the model could be used for screening of elderly patients to optimise their care.

Reasons for readmission after hospital discharge in patients with chronic diseases-Information from an international dataset.

BACKGROUND: Chronic diseases are increasingly prevalent in Western countries. Once hospitalised, the chance for another hospitalisation increases sharply with large impact on well-being of patients and costs. The pattern of readmissions is very complex, but poorly understood for multiple chronic diseases. METHODS: This cohort study of administrative discharge data between 2009-2014 from 21 tertiary hospitals (eight USA, five UK, four Australia, four continental Europe) investigated rates and reasons of readmissions to the same hospital within 30 days after unplanned admission with one of the following chronic conditions; heart failure; atrial fibrillation; myocardial infarction; hypertension; stroke; chronic obstructive pulmonary disease (COPD); bacterial pneumonia; diabetes mellitus; chronic renal disease; anaemia; arthritis and other cardiovascular disease. Proportions of readmissions with similar versus different diseases were analysed. RESULTS: Of 4,901,584 admissions, 866,502 (17.7%) were due to the 12 chronic conditions. In-hospital, 43,573 (5.0%) patients died, leaving 822,929 for readmission analysis. Of those, 87,452 (10.6%) had an emergency 30-day readmission, rates ranged from 2.8% for arthritis to 18.4% for COPD. One third were readmitted with the same condition, ranging from 53% for anaemia to 11% for arthritis. Reasons for readmission were due to another chronic condition in 10% to 35% of the cases, leaving 30% to 70% due to reasons other than the original 12 conditions (most commonly, treatment related complications and infections). The chance of being readmitted with the same cause was lower in the USA, for female patients, with increasing age, more co-morbidities, during study period and with longer initial length of stay. CONCLUSION: Readmission in chronic conditions is very common and often caused by diseases other than the index hospitalisation. Interventions to reduce readmissions should therefore focus not only on the primary condition but on a holistic consideration of all the patient's comorbidities.

CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer.

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

Dr Foster global frailty score: an international retrospective observational study developing and validating a risk prediction model for hospitalised older persons from administrative data sets.

OBJECTIVES: This study aimed to examine the prevalence of frailty coding within the Dr Foster Global Comparators (GC) international database. We then aimed to develop and validate a risk prediction model, based on frailty syndromes, for key outcomes using the GC data set. DESIGN: A retrospective cohort analysis of data from patients over 75 years of age from the GC international administrative data. A risk prediction model was developed from the initial analysis based on seven frailty syndrome groups and their relationship to outcome metrics. A weighting was then created for each syndrome group and summated to create the Dr Foster Global Frailty Score. Performance of the score for predictive capacity was compared with an established prognostic comorbidity model (Elixhauser) and tested on another administrative database Hospital Episode Statistics (2011-2015), for external validation. SETTING: 34 hospitals from nine countries across Europe, Australia, the UK and USA. RESULTS: Of 6.7 million patient records in the GC database, 1.4 million (20%) were from patients aged 75 years or more. There was marked variation in coding of frailty syndromes between countries and hospitals. Frailty syndromes were coded in 2% to 24% of patient spells. Falls and fractures was the most common syndrome coded (24%). The Dr Foster Global Frailty Score was significantly associated with in-hospital mortality, 30-day non-elective readmission and long length of hospital stay. The score had significant predictive capacity beyond that of other known predictors of poor outcome in older persons, such as comorbidity and chronological age. The score's predictive capacity was higher in the elective group compared with non-elective, and may reflect improved performance in lower acuity states. CONCLUSIONS: Frailty syndromes can be coded in international secondary care administrative data sets. The Dr Foster Global Frailty Score significantly predicts key outcomes. This methodology may be feasibly utilised for case-mix adjustment for older persons internationally.