ABSTRACT
Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as ß-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation-a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.
Subject(s)
High-Throughput Screening Assays , Immunity, Innate , Small Molecule Libraries , Animals , Mice , High-Throughput Screening Assays/methods , Immunity, Innate/drug effects , Small Molecule Libraries/pharmacology , Mice, Inbred C57BL , Immunologic Memory/drug effects , Trained ImmunityABSTRACT
PURPOSE: Inherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large United Kingdom (UK) IRD patient cohort. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients with IRD who attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis was identified. METHODS: Genetic testing was undertaken via a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. Likely disease-causing variants were identified from entries within the genetics module of the hospital electronic patient record (OpenEyes Electronic Medical Record). Analysis was restricted to only genes listed in the Genomics England PanelApp R32 Retinal Disorders panel (version 3.24), which includes 412 genes associated with IRD. Manual curation ensured consistent variant annotation and included only plausible disease-associated variants. MAIN OUTCOME MEASURES: Detailed analysis was performed for variants in the 5 most frequent genes (ABCA4, USH2A, RPGR, PRPH2, and BEST1), as well as for the most common variants encountered in the IRD study cohort. RESULTS: We identified 4415 individuals from 3953 families with molecularly diagnosed IRD (variants in 166 genes). Of the families, 42.7% had variants in 1 of the 5 most common IRD genes. Complex disease alleles contributed to disease in 16.9% of affected families with ABCA4-associated retinopathy. USH2A exon 13 variants were identified in 43% of affected individuals with USH2A-associated IRD. Of the RPGR variants, 71% were clustered in the ORF15 region. PRPH2 and BEST1 variants were associated with a range of dominant and recessive IRD phenotypes. Of the 20 most prevalent variants identified, 5 were not in the most common genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1, and RP1. CONCLUSIONS: We describe the most common pathogenic IRD alleles in a large single-center multiethnic UK cohort and the burden of disease, in terms of families affected, attributable to these variants. Our findings will inform IRD diagnoses in future patients and help delineate the cohort of patients eligible for gene-directed therapies under development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Subject(s)
Genetic Testing , Retinal Diseases , Humans , United Kingdom/epidemiology , Retrospective Studies , Male , Female , Retinal Diseases/genetics , Retinal Diseases/diagnosis , Genetic Testing/methods , Mutation , Genetic Variation , Adult , Exome Sequencing/methods , Middle Aged , Pedigree , DNA/genetics , Genetic Predisposition to DiseaseABSTRACT
INTRODUCTION: Approval of adalimumab biosimilar ABP 501 (Amgevita®) for inflammatory bowel disease (IBD) was based upon the principle of extrapolation. Real-world experience of ABP 501 utilization in IBD can provide useful information to healthcare providers and patients. METHODS: Data were drawn from the 2020-2021 Adelphi IBD Disease Specific Programme™ conducted in five major European countries. Participating gastroenterologists completed a point-in-time survey to provide patient medical record data, and patients voluntarily completed questionnaires to report health-related quality of life (HRQoL). Descriptive analyses were conducted for "ABP 501 initiators" (received ABP 501 as first advanced therapy) and "RP-ABP 501 switchers" (switched to ABP 501 from reference product [RP; Humira®] as first advanced therapy). RESULTS: This analysis included 239 ABP 501 initiators and 136 RP-ABP 501 switchers. At consultation, initiators had been on ABP 501 treatment for a median of 7.5 months and switchers had received ABP 501 for a median of 7.7 months following the switch from a median of 14.0 months treatment with RP. About 74% of initiators and 89% of switchers were reported by their treating physicians as being in clinical remission. Physicians and patients reported satisfaction with ABP 501 in the range of 92-99% across both groups. Patient self-assessment, including EuroQol visual analogue scale, Short IBD Questionnaire, and Work Productivity and Activity Impairment scores, suggested minimal impairment of HRQoL while on ABP 501. The most common reason for RP to ABP 501 switch was lower healthcare costs. CONCLUSION: Both patients with IBD and treating physicians reported high levels of satisfaction with ABP 501 among initiators and switchers.
ABP 501 (Amgevita®) is the first approved biosimilar to adalimumab originator (Humira®), referred to here as the reference product. A biosimilar is a biological product that is highly similar to its reference product in terms of safety, purity, and effectiveness. ABP 501 has been approved for the treatment of certain chronic inflammatory diseases. The approval of ABP 501 for inflammatory disease is based upon the principle of extrapolation, with no clinical trial being conducted in patients with inflammatory bowel disease. Therefore, in this current study, we evaluated the utilization experience of biosimilar ABP 501 in the real-world setting from both physicians' and patients' perspectives. We reported that patients with inflammatory bowel disease who initiated ABP 501 as the first advanced therapy as well as patients who continued therapy on ABP 501 after a switch from the adalimumab reference product both had a high level of satisfaction when using the biosimilar ABP 501. Treating physicians also reported that most of their patients were in clinical remission while on treatment with ABP 501, and patients themselves reported minimal impairment of health-related quality of life.
Subject(s)
Biosimilar Pharmaceuticals , Inflammatory Bowel Diseases , Humans , Adalimumab/adverse effects , Biosimilar Pharmaceuticals/therapeutic use , Quality of Life , Inflammatory Bowel Diseases/drug therapy , Europe , Treatment OutcomeABSTRACT
INTRODUCTION: Bowel urgency (BU) is among the most disruptive of inflammatory bowel disease (IBD) symptoms. However, data on its prevalence and association with disease activity are limited. This real-world study of Japanese patients with IBD evaluated BU prevalence and compared clinical outcomes and health-related quality of life (HRQoL) between patients with and without BU. METHODS: Data were drawn from the Adelphi IBD Disease Specific Programme™, a cross-sectional survey of physicians and their patients with ulcerative colitis (UC) and Crohn's disease (CD). Physicians reported demographic and clinical data, including disease activity measures (Mayo score and CD Activity Index [CDAI]), for consulting patients, who voluntarily completed a patient-reported questionnaire, including HRQoL measures (Short IBD Questionnaire [SIBDQ] and EQ-5D-5L). Outcomes were compared between patients with and without BU using t-, Fisher exact and Mann-Whitney U tests as appropriate. RESULTS: Of 120 UC patients, 27.5% (n = 33) self-reported BU; physicians were unaware of BU in 54.5% (n = 18) of these patients. Patients with BU had higher mean Mayo scores (p < 0.01) and lower mean SIBDQ scores (47.9 vs 56.6, p < 0.01) than patients without BU, with mean EQ-5D-5L scores 0.83 and 0.87, respectively (p = 0.06). Physicians were satisfied with treatment but believed better control could be achieved for 39.4% of patients with BU and 35.6% without. Of 114 CD patients, 17.5% (n = 20) self-reported BU; physicians were unaware of BU in 75.0% (n = 15) of these patients. Patients with BU had higher mean CDAI scores (p < 0.01) and lower mean SIBDQ (48.7 vs 56.2, p < 0.01) and EQ-5D-5L scores (0.81 vs 0.88, p < 0.01) than patients without BU. Physicians were satisfied but believed better control could be achieved for 40.0% of patients with BU vs 19.1% without. CONCLUSIONS: Patients with BU have worse clinical outcomes and HRQoL than patients without, underlining the need for improved physician-patient communication regarding BU and new IBD therapeutic options.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Fecal Incontinence , Inflammatory Bowel Diseases , Humans , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Cross-Sectional Studies , Japan/epidemiology , Quality of LifeABSTRACT
OBJECTIVE: Although dosing regimens of targeted therapies (TT) for ulcerative colitis (UC) and Crohn's disease (CD) are guided by market authorizations and clinical guidelines, little is known about clinical guideline adherence or outcomes in patients receiving escalated doses of TT due to lack of response. This real-world study explored the prevalence of dose escalation and compared outcomes between patients receiving standard and escalated TT doses. METHODS: Data were from the 2020-2021 Adelphi Disease Specific Programme for inflammatory bowel disease, a cross-sectional survey of gastroenterologists and their UC and CD patients across five European countries and the US. Physicians provided retrospective data collection of patient demographics, clinical characteristics, treatment history, and satisfaction; patients reported quality-of-life and work productivity. Patients were grouped by TT maintenance dose; standard and escalated dose groups were compared. Outcomes were adjusted for time on current TT and severity at current TT initiation using regression analyses. RESULTS: Of 1,241 UC and 1,477 CD patients, 19.1% and 24.1%, respectively, received escalated TT doses. Despite escalation, a substantial proportion of patients had not achieved remission, had moderate or severe disease activity, or were flaring. Most physicians were not fully satisfied with treatment in the escalated dose group and were more likely to switch patients to another treatment regimen than patients on standard dose. CONCLUSION: Dose escalation is not always an effective approach to resolve inadequate or loss of response in UC and CD, highlighting a need for more therapeutic options or alternative treatment strategies in patients unresponsive to TT.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Humans , Retrospective Studies , Cross-Sectional Studies , Colitis, Ulcerative/epidemiology , Crohn Disease/drug therapy , Crohn Disease/epidemiology , Inflammatory Bowel Diseases/drug therapyABSTRACT
BACKGROUND: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. METHODS: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. RESULTS: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling. CONCLUSIONS: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.
Subject(s)
Cyclins , Pulmonary Arterial Hypertension , Humans , Mice , Animals , Cyclins/metabolism , Pulmonary Arterial Hypertension/metabolism , Cysteine/metabolism , Endothelial Cells/metabolism , Cell Proliferation , Pulmonary Artery/metabolism , Phosphorylation , Cell Cycle Checkpoints , Cyclin D/metabolism , Cells, Cultured , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolismABSTRACT
OBJECTIVE: Vedolizumab is an antibody targeting α4ß7 integrin used in the treatment of ulcerative colitis (UC). Patients are commonly prescribed higher-than-standard doses if treatment response is inadequate, but little is known about the drivers and impact of increased dosing. Our objective was to use real-world data to describe vedolizumab dosages in current clinical practice, patient characteristics, physicians' reasons for prescribing vedolizumab, and physician treatment satisfaction. METHODS: Data were derived from the Adelphi Real World UC vedolizumab Chart Review, a cross-sectional survey of gastroenterologists and their UC patients, conducted in France, Germany, Italy, Spain, and the United Kingdom between December 2022 and March 2023. Gastroenterologists provided data on patient demographics, clinical characteristics, treatment and vedolizumab dosage history, reasons for dose choice, and treatment satisfaction. RESULTS: Data were returned on 448 patients by 112 gastroenterologists. Overall, 83.5% of patients were on a standard vedolizumab dose and 10.3% were on a higher-than-standard dose. The worsening of symptoms was the most cited reason for higher doses. Most reported symptoms at survey were fatigue, abdominal distention or pain, diarrhea, and bowel urgency, with the latter particularly in higher-than-standard dose patients. Patients on higher-than-standard dose had high rates of mild (37.0%) or moderate (26.1%) disease, and low rates of remission (33.8%). Physicians were dissatisfied with treatment control for 2.7% of standard and 26.1% of higher-than-standard dose patients. CONCLUSIONS: Over 10% of patients were receiving a higher-than-standard dose of vedolizumab, but despite this were found to have suboptimal clinical outcomes and low physician satisfaction.
Subject(s)
Colitis, Ulcerative , Humans , Colitis, Ulcerative/drug therapy , Cross-Sectional Studies , Antibodies, Monoclonal, Humanized/therapeutic use , Europe , Gastrointestinal Agents/therapeutic use , Treatment OutcomeABSTRACT
INTRODUCTION: Despite availability of advanced therapies (ATs) for ulcerative colitis (UC), many patients fail to respond to treatment. This study examined real-world clinical and humanistic outcomes associated with current treatments in patients with UC. METHODS: This cross-sectional study used US data from the Adelphi Real World Disease Specific Programme for inflammatory bowel disease from before (2017-2018) and during the COVID-19 pandemic (2020-2021). Physicians (gastroenterologists) seeing > 5 patients/month reported patients' disease characteristics, current symptoms and treatments, and reasons for treatment choices for their next seven consecutive patients aged ≥ 18 years with moderately to severely active UC before current treatment. Patients were asked to complete the EQ-5D-5L health-related quality of life (HRQoL) measure. ATs included tumor necrosis factor inhibitors (TNFis), integrin receptor antagonists, interleukin-12/23 antagonists, and Janus kinase inhibitors. Patients were classified as AT-naïve or AT-experienced based on current treatment received for ≥ 8 weeks and further classified as responders or non-responders based on symptoms, disease flare status, and remission. Descriptive analyses are presented. RESULTS: The 2017-2018 cohort included 92 physicians and 539 patients (208 [38.6%] AT-experienced). The 2020-2021 cohort included 73 physicians and 448 patients (349 [77.9%] AT-experienced). TNFis were the most common ATs. In 2017-2018, 195 (58.9%) AT-naïve and 113 (54.3%) AT-experienced patients were non-responders; in 2020-2021 this was 57 (57.6%) and 182 (52.1%). Efficacy and induction of remission were physicians' most common reasons for AT choice. Dislike of injections/infusions was the most common reason for eligible patients not receiving biologic therapy. Numerically, non-responders (both AT-naïve and AT-experienced) had more symptoms, overall pain and fatigue, and lower HRQoL scores than responders. CONCLUSIONS: Before (2017-2018) and during the pandemic (2020-2021), over half of patients with UC did not respond to AT. Non-responders carried a high burden of disease. Alternative therapies are urgently needed to treat UC.
Subject(s)
COVID-19 , Colitis, Ulcerative , Humans , United States/epidemiology , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/drug therapy , Quality of Life , Cross-Sectional Studies , PandemicsABSTRACT
BACKGROUND: Ethnic and socioeconomic inequalities in obstetric outcomes are well established. However, the role of induction of labour (IOL) to reduce these inequalities is controversial, in part due to insufficient evidence. This national cohort study aimed to identify adverse perinatal outcomes associated with IOL with birth at 39 weeks of gestation ("IOL group") compared to expectant management ("expectant management group") according to maternal characteristics in women with low-risk pregnancies. METHODS AND FINDINGS: All English National Health Service (NHS) hospital births between January 2018 and March 2021 were examined. Using the Hospital Episode Statistics (HES) dataset, maternal and neonatal data (demographic, diagnoses, procedures, labour, and birth details) were linked, with neonatal mortality data from the Office for National Statistics (ONS). Women with a low-risk pregnancy were identified by excluding pregnancies with preexisting comorbidities, previous cesarean section, breech presentation, placenta previa, gestational diabetes, or a baby with congenital abnormalities. Women with premature rupture of membranes, placental abruption, hypertensive disorders of pregnancy, amniotic fluid abnormalities, or antepartum stillbirth were excluded only from the IOL group. Adverse perinatal outcome was defined as stillbirth, neonatal death, or neonatal morbidity, the latter identified using the English composite neonatal outcome indicator (E-NAOI). Binomial regression models estimated risk differences (with 95% confidence intervals (CIs)) between the IOL group and the expectant management group, adjusting for ethnicity, socioeconomic background, maternal age, parity, year of birth, and birthweight centile. Interaction tests examined risk differences according to ethnicity, socioeconomic background, and parity. Of the 1 567 004 women with singleton pregnancies, 501 072 women with low-risk pregnancies and with sufficient data quality were included in the analysis. Approximately 3.3% of births in the IOL group (1 555/47 352) and 3.6% in the expectant management group (16 525/453 720) had an adverse perinatal outcome. After adjustment, a lower risk of adverse perinatal outcomes was found in the IOL group (risk difference -0.28%; 95% CI -0.43%, -0.12%; p = 0.001). This risk difference varied according to socioeconomic background from 0.38% (-0.08%, 0.83%) in the least deprived to -0.48% (-0.76%, -0.20%) in the most deprived national quintile (p-value for interaction = 0.01) and by parity with risk difference of -0.54% (-0.80%, -0.27%) in nulliparous women and -0.15% (-0.35%, 0.04%) in multiparous women (p-value for interaction = 0.02). There was no statistically significant evidence that risk differences varied according to ethnicity (p = 0.19). Key limitations included absence of additional confounding factors such as smoking, BMI, and the indication for induction in the HES datasets, which may mean some higher risk pregnancies were included. CONCLUSIONS: IOL with birth at 39 weeks was associated with a small reduction in the risk of adverse perinatal outcomes, with 360 inductions in low-risk pregnancies needed to avoid 1 adverse outcome. The risk reduction was mainly present in women from more socioeconomically deprived areas and in nulliparous women. There was no significant risk difference found by ethnicity. Increased uptake of IOL at 39 weeks, especially in women from more socioeconomically deprived areas, may help reduce inequalities in adverse perinatal outcomes.
Subject(s)
Cesarean Section , Stillbirth , Infant, Newborn , Pregnancy , Female , Humans , Parity , Cohort Studies , Ethnicity , State Medicine , Placenta , Labor, Induced/adverse effects , England/epidemiology , Socioeconomic FactorsABSTRACT
Sentinel lymph node biopsy (SLNB) is the standard of care for staging the clinically node-negative axilla in early breast cancer. Evidence guiding current practice describes dual localization technique using Patent blue dye and radioisotope (99mTc). Adverse effects of blue dye include 1:1000 risk of anaphylaxis, skin staining and loss of plane visibility, which may increase operative time and reduce resectional accuracy. The risk to a patient posed by anaphylaxis may be greater when operating in a unit without on-site ITU support - a situation more common with recent restructuring during the COVID-19 pandemic. Aim is to quantify the benefit of blue dye above radioisotope alone in identifying nodal disease. This is a retrospective analysis of prospectively collected sentinel node data including all consecutive sentinel node biopsies in a single center during the period 2016-2019.In terms of results, 760 sentinel nodes were taken in 435 patients. 59 nodes (7.8%) were detected by blue dye alone; 120 (15.8%) 'hot' only, 581 (76.5%) hot and blue. 4 of the blue only nodes contained macrometastases but 3 of these patients had further hot nodes excised that also contained macrometastases. 1 out of 435 patients (0.2%) had macro metastatic disease identified as a result of blue dye alone which would have been missed had it not been used. In conclusion, the use of blue dye carries risk and offers little benefit in terms of staging in SLNB and its use may be unnecessary in the hands of the skilled surgeon. This study supports the omission of blue dye, which may be advisable if operating in units without ITU support. If larger studies support these figures, it may become as outdated.
Subject(s)
Anaphylaxis , Breast Neoplasms , COVID-19 , Humans , Female , Sentinel Lymph Node Biopsy , Axilla , Pandemics , Retrospective StudiesABSTRACT
BACKGROUND: There is currently mixed evidence on the influence of long-term conditions and deprivation on mortality. We aimed to explore whether number of long-term conditions contribute to socioeconomic inequalities in mortality, whether the influence of number of conditions on mortality is consistent across socioeconomic groups and whether these associations vary by working age (18-64 years) and older adults (65 + years). We provide a cross-jurisdiction comparison between England and Ontario, by replicating the analysis using comparable representative datasets. METHODS: Participants were randomly selected from Clinical Practice Research Datalink in England and health administrative data in Ontario. They were followed from 1 January 2015 to 31 December 2019 or death or deregistration. Number of conditions was counted at baseline. Deprivation was measured according to the participant's area of residence. Cox regression models were used to estimate hazards of mortality by number of conditions, deprivation and their interaction, with adjustment for age and sex and stratified between working age and older adults in England (N = 599,487) and Ontario (N = 594,546). FINDINGS: There is a deprivation gradient in mortality between those living in the most deprived areas compared to the least deprived areas in England and Ontario. Number of conditions at baseline was associated with increasing mortality. The association was stronger in working age compared with older adults respectively in England (HR = 1.60, 95% CI 1.56,1.64 and HR = 1.26, 95% CI 1.25,1.27) and Ontario (HR = 1.69, 95% CI 1.66,1.72 and HR = 1.39, 95% CI 1.38,1.40). Number of conditions moderated the socioeconomic gradient in mortality: a shallower gradient was seen for persons with more long-term conditions. CONCLUSIONS: Number of conditions contributes to higher mortality rate and socioeconomic inequalities in mortality in England and Ontario. Current health care systems are fragmented and do not compensate for socioeconomic disadvantages, contributing to poor outcomes particularly for those managing multiple long-term conditions. Further work should identify how health systems can better support patients and clinicians who are working to prevent the development and improve the management of multiple long-term conditions, especially for individuals living in socioeconomically deprived areas.
Subject(s)
Socioeconomic Factors , Humans , Aged , Adolescent , Young Adult , Adult , Middle Aged , Ontario , EnglandABSTRACT
BACKGROUND: Hip fracture is a leading cause of disability and mortality among older people. During the COVID-19 pandemic, orthopaedic care pathways in the National Health Service in England were restructured to manage pressures on hospital capacity. We examined the indirect consequences of the pandemic for hospital mortality among older patients with hip fracture, admitted from care homes or the community. METHODS: Retrospective analysis of linked care home and hospital inpatient data for patients with hip fracture aged 65 years and over admitted to hospitals in England during the first year of the pandemic (1 March 2020 to 28 February 2021) or during the previous year. We performed survival analysis, adjusting for case mix and COVID-19 infection, and considered live discharge as a competing risk. We present cause-specific hazard ratios (HRCS) for the effect of admission year on hospital mortality risk. RESULTS: During the first year of the pandemic, there were 55 648 hip fracture admissions: a 5.2% decrease on the previous year. 9.5% of patients had confirmed or suspected COVID-19. Hospital stays were substantially shorter (p<0.05), and there was a higher daily chance of discharge (HRCS 1.40, 95% CI 1.38 to 1.41). Overall hip fracture inpatient mortality increased (7.2% in 2020/2021 vs 6.4% in 2019/2020), but patients without concomitant COVID-19 infection had lower mortality rates compared with the year before (5.3%). Admission during the pandemic was associated with a 11% increase in the daily risk of hospital death for patients with hip fracture (HRCS 1.11, 95% CI 1.05 to 1.16). CONCLUSIONS: Although COVID-19 infections led to increases in hospital mortality, overall hospital mortality risk for older patients with hip fracture remained largely stable during the first year of the pandemic.
Subject(s)
COVID-19 , Hip Fractures , Humans , Aged , COVID-19/complications , Hospital Mortality , Pandemics , Retrospective Studies , State Medicine , Hip Fractures/epidemiology , Hip Fractures/complications , Survival AnalysisABSTRACT
OBJECTIVE: To describe the rates of and risk factors associated with iatrogenic and spontaneous preterm birth and the variation in rates between hospitals. DESIGN: Cohort study using electronic health records. SETTING: English National Health Service. POPULATION: Singleton births between 1 April 2015 and 31 March 2017. METHODS: Multivariable Poisson regression models were used to estimate adjusted risk ratios (adjRR) to measure association with maternal demographic and clinical risk factors. MAIN OUTCOME MEASURES: Preterm births (<37 weeks of gestation) were defined as iatrogenic or spontaneous according to mode of onset of labour. RESULTS: Of the births, 6.1% were preterm and of these, 52.8% were iatrogenic. The proportion of preterm births that were iatrogenic increased after 32 weeks. Both sub-groups were associated with previous preterm birth, extremes of maternal age, socio-economic deprivation and smoking. Iatrogenic preterm birth was associated with higher body mass index (BMI) (BMI >40 kg/m2 adjRR 1.59, 95% CI 1.50-1.69) and previous caesarean (adjRR 1.88, 95% CI 1.83-1.95). Spontaneous preterm birth was less common in women with a higher BMI (BMI >40 kg/m2 adjRR 0.77, 95% CI 0.70-0.84) and in women with a previous caesarean (adjRR 0.87, 95% CI 0.83-0.90). More variation between NHS hospital trusts was observed in rates of iatrogenic, compared with spontaneous, preterm births. CONCLUSIONS: Just over half of all preterm births resulted from iatrogenic intervention. Iatrogenic births have overlapping but different patterns of maternal demographic and clinical risk factors to spontaneous preterm births. Iatrogenic and spontaneous sub-groups should therefore be measured and monitored separately, as well as in aggregate, to facilitate different prevention strategies. This is feasible using routinely acquired hospital data.
Subject(s)
Premature Birth , Pregnancy , Infant, Newborn , Female , Humans , Premature Birth/epidemiology , Premature Birth/etiology , Gestational Age , Cohort Studies , State Medicine , Risk Factors , Iatrogenic Disease/epidemiologyABSTRACT
The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.
Subject(s)
Retinal Dystrophies , Humans , Mutation , Pedigree , Retinal Dystrophies/diagnosis , Retinal Dystrophies/genetics , Whole Genome Sequencing , Patient Care Team , DNA Mutational Analysis/methods , Eye Proteins/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/geneticsABSTRACT
INTRODUCTION: To assess the prevalence of fatigue and its association with disease activity and patient-reported outcomes among patients with ulcerative colitis (UC) or Crohn's disease (CD). METHODS: Data from a cross-sectional survey conducted with gastroenterologists and their consulting adult patients with UC or CD were analyzed. Data were collected via gastroenterologist-completed patient record forms and patient-self completion forms. Patient demographics, clinical characteristics, disease activity and medication use were reported by the gastroenterologist, while current symptoms (fatigue, rectal urgency, abdominal pain, sleep disturbance), work productivity and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) were reported by the patient. Logistic regression models were used to identify measures associated with fatigue and expressed as odds ratio (OR) with 95% confidence interval. p < 0.05 was considered statistically significant. RESULTS: A total of 1057 patients with UC and 1228 patients with CD were included in this analysis. Fatigue was reported in 22.6% of UC and 26.0% of patients with CD. Higher proportion of patients with UC and fatigue had moderate/severe disease activity (p = 0.0001), had a higher Mayo score (5.0 vs. 4.0, p < 0.0001) and were unemployed (5.6% vs. 3.9%, p = 0.0149) compared to those without fatigue. In patients with CD reporting fatigue, a higher proportion were female (55.9% vs. 48.2%, p = 0.0193), were unemployed (5.8% vs. 4.9%, p = 0.0069), had moderate/severe disease (p < 0.0001) and had a higher mean Crohn's Disease Activity Index score (145.0 vs. 96.2, p < 0.0001) than patients without fatigue. Patients with UC and fatigue had higher mean level of pain (p < 0.0001) and sleep disturbance (p < 0.0001), whereas patients with CD and fatigue had lower SIBDQ scores (p < 0.0001) and greater work impairment (p = 0.0015) than patients without fatigue. Abdominal pain (OR: 2.01, p = 0.001) and use of immunomodulators (OR: 1.69, p = 0.006) increased the odds of having fatigue in patients with UC. In patients with CD, abdominal pain (OR: 2.29, p < 0.001) and use of biologics or biosimilars (OR: 2.02, p = 0.003) increased the odds of having fatigue. CONCLUSION: Fatigue is a common symptom among patients with UC or CD that is associated with higher levels of disease activity and decreased work productivity and is driven by various factors. A multidisciplinary approach may be needed to manage fatigue.
Subject(s)
Biosimilar Pharmaceuticals , Colitis, Ulcerative , Crohn Disease , Gastroenterologists , Inflammatory Bowel Diseases , Sleep Wake Disorders , Adult , Humans , Female , Male , Crohn Disease/complications , Crohn Disease/epidemiology , Crohn Disease/diagnosis , Colitis, Ulcerative/complications , Colitis, Ulcerative/epidemiology , Cross-Sectional Studies , Inflammatory Bowel Diseases/complications , Abdominal Pain/epidemiology , Abdominal Pain/etiology , Surveys and Questionnaires , Fatigue/epidemiology , Fatigue/etiologyABSTRACT
A failure of central immune tolerance driven by autoantigen specific T regulatory (Treg) cells is a major cause of many autoimmune diseases. Restoration of proper autoantigen Treg specific response holds promise as a highly effective, long-term therapy for a wide variety of autoimmune diseases. Generating autoantigen specific Tregs remains a challenge due to the non-specific nature of most tolerizing agents and the complexities of generating Tregs in vivo. Here we show a new push/pull method for inducing antigen-specific Treg tolerance via induction of tolerogenic dendritic cells (tolDCs). We identified a combination of three tolerogenic drugs, dexamethasone, simvastatin and SC-514, which when used in combination with toll-like-receptor (TLR) agonists induces an active tolDC phenotype. When the tolerogenic combination was packaged into a liposome with a model antigen such as ovalbumin (OVA), these tolDCs induce differentiation of OVA specific Tregs both ex vivo and in vivo. We examined the tolerizing potential of the combination in an experimental autoimmune encephalomyelitis (EAE) disease model. Given the antigen specificity of this technique, this paper presents an attractive preclinical autoimmune therapy.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Adjuvants, Immunologic , Animals , Autoantigens , Dendritic Cells , Immune Tolerance , Immunologic Factors , Mice , Mice, Inbred C57BL , T-Lymphocytes, RegulatoryABSTRACT
BACKGROUND: Multiple conditions are more prevalent in some minoritised ethnic groups and are associated with higher mortality rate but studies examining differential mortality once conditions are established is US-based. Our study tested whether the association between multiple conditions and mortality varies across ethnic groups in England. METHODS AND FINDINGS: A random sample of primary care patients from Clinical Practice Research Datalink (CPRD) was followed from 1st January 2015 until 31st December 2019. Ethnicity, usually self-ascribed, was obtained from primary care records if present or from hospital records. Long-term conditions were counted from a list of 32 that have previously been associated with greater primary care, hospital admissions, or mortality risk. Cox regression models were used to estimate mortality by count of conditions, ethnicity and their interaction, with adjustment for age and sex for 532,059 patients with complete data. During five years of follow-up, 5.9% of patients died. Each additional condition at baseline was associated with increased mortality. The direction of the interaction of number of conditions with ethnicity showed a statistically higher mortality rate associated with long-term conditions in Pakistani, Black African, Black Caribbean and Other Black ethnic groups. In ethnicity-stratified models, the mortality rate per additional condition at age 50 was 1.33 (95% CI 1.31,1.35) for White ethnicity, 1.43 (95% CI 1.26,1.61) for Black Caribbean ethnicity and 1.78 (95% CI 1.41,2.24) for Other Black ethnicity. CONCLUSIONS: The higher mortality rate associated with having multiple conditions is greater in minoritised compared with White ethnic groups. Research is now needed to identify factors that contribute to these inequalities. Within the health care setting, there may be opportunities to target clinical and self-management support for people with multiple conditions from minoritised ethnic groups.
Subject(s)
Black People , Ethnicity , Asian People , England/epidemiology , Hospitalization , Humans , Middle AgedABSTRACT
OBJECTIVE: To establish a methodological approach to compare two high-need, high-cost (HNHC) patient personas internationally. DATA SOURCES: Linked individual-level administrative data from the inpatient and outpatient sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) across 11 countries: Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States. STUDY DESIGN: We outline a methodological approach to identify HNHC patient types for international comparisons that reflect complex, priority populations defined by the National Academy of Medicine. We define two patient profiles using accessible patient-level datasets linked across different domains of care-hospital care, primary care, outpatient specialty care, post-acute rehabilitative care, long-term care, home-health care, and outpatient drugs. The personas include a frail older adult with a hip fracture with subsequent hip replacement and an older person with complex multimorbidity, including heart failure and diabetes. We demonstrate their comparability by examining the characteristics and clinical diagnoses captured across countries. DATA COLLECTION/EXTRACTION METHODS: Data collected by ICCONIC partners. PRINCIPAL FINDINGS: Across 11 countries, the identification of HNHC patient personas was feasible to examine variations in healthcare utilization, spending, and patient outcomes. The ability of countries to examine linked, individual-level data varied, with the Netherlands, Canada, and Germany able to comprehensively examine care across all seven domains, whereas other countries such as England, Switzerland, and New Zealand were more limited. All countries were able to identify a hip fracture persona and a heart failure persona. Patient characteristics were reassuringly similar across countries. CONCLUSION: Although there are cross-country differences in the availability and structure of data sources, countries had the ability to effectively identify comparable HNHC personas for international study. This work serves as the methodological paper for six accompanying papers examining differences in spending, utilization, and outcomes for these personas across countries.
Subject(s)
Costs and Cost Analysis/economics , Delivery of Health Care/economics , Health Services Needs and Demand , Patient Acceptance of Health Care/statistics & numerical data , Research Design , Aged , Australia , Developed Countries/statistics & numerical data , Diabetes Mellitus/therapy , Europe , Health Services Needs and Demand/economics , Health Services Needs and Demand/statistics & numerical data , Heart Failure/therapy , Humans , North AmericaABSTRACT
OBJECTIVE: To identify and explore differences in spending and utilization of key health services at the end of life among hip fracture patients across seven developed countries. DATA SOURCES: Individual-level claims data from the inpatient and outpatient health care sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC). STUDY DESIGN: We retrospectively analyzed utilization and spending from acute hospital care, emergency department, outpatient primary care and specialty physician visits, and outpatient drugs. Patterns of spending and utilization were compared in the last 30, 90, and 180 days across Australia, Canada, England, Germany, New Zealand, Spain, and the United States. We employed linear regression models to measure age- and sex-specific effects within and across countries. In addition, we analyzed hospital-centricity, that is, the days spent in hospital and site of death. DATA COLLECTION/EXTRACTION METHODS: We identified patients who sustained a hip fracture in 2016 and died within 12 months from date of admission. PRINCIPAL FINDINGS: Resource use, costs, and the proportion of deaths in hospital showed large variability being high in England and Spain, while low in New Zealand. Days in hospital significantly decreased with increasing age in Canada, Germany, Spain, and the United States. Hospital spending near date of death was significantly lower for women in Canada, Germany, and the United States. The age gradient and the sex effect were less pronounced in utilization and spending of emergency care, outpatient care, and drugs. CONCLUSIONS: Across seven countries, we find important variations in end-of-life care for patients who sustained a hip fracture, with some differences explained by sex and age. Our work sheds important insights that may help ongoing health policy discussions on equity, efficiency, and reimbursement in health care systems.
Subject(s)
Cross-Cultural Comparison , Health Care Costs/statistics & numerical data , Hip Fractures , Patient Acceptance of Health Care/statistics & numerical data , Terminal Care/economics , Aged , Aged, 80 and over , Australia , Developed Countries , Europe , Female , Hip Fractures/economics , Hip Fractures/surgery , Hospitalization/economics , Hospitalization/statistics & numerical data , Humans , Insurance Claim Review/statistics & numerical data , Longitudinal Studies , Male , North America , Retrospective Studies , Sex FactorsABSTRACT
OBJECTIVE: The objectives of this study are to compare the relative use of different postacute care settings in different countries and to compare three important outcomes as follows: total expenditure, total days of care in different care settings, and overall longevity over a 1-year period following a hip fracture. DATA SOURCES: We used administrative data from hospitals, institutional and home-based long-term care (LTC), physician visits, and medications compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) from five countries as follows: Canada, France, Germany, the Netherlands, and Sweden. DATA EXTRACTION METHODS: Data were extracted from existing administrative data systems in each participating country. STUDY DESIGN: This is a retrospective cohort study of all individuals admitted to acute care for hip fracture. Descriptive comparisons were used to examine aggregate institutional and home-based postacute care. Care trajectories were created to track sequential care settings after acute-care discharge through institutional and community-based care in three countries where detailed information allowed. Comparisons in patient characteristics, utilization, and costs were made across these trajectories and countries. PRINCIPAL FINDINGS: Across five countries with complete LTC data, we found notable variations with Germany having the highest days of home-based services with relatively low costs, while Sweden incurred the highest overall expenditures. Comparisons of trajectories found that France had the highest use of inpatient rehabilitation. Germany was most likely to discharge hip fracture patients to home. Over 365 days, France averaged the highest number of days in institution with 104, Canada followed at 94, and Germany had just 87 days of institutional care on average. CONCLUSION: In this comparison of LTC services following a hip fracture, we found international differences in total use of institutional and noninstitutional care, longevity, and total expenditures. There exist opportunities to organize postacute care differently to maximize independence and mitigate costs.