ABSTRACT
OBJECTIVE: To describe the collection methods for perilymph fluid biopsy during cochlear implantation, detect levels of amyloid ß 42 and 40 (Aß42 and Aß40), and total tau (tTau) analytes with a high-precision assay, to compare these levels with patient age and Montreal Cognitive Assessment (MoCA) scores, and explore potential mechanisms and relationships with otic pathology. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. METHODS: Perilymph was collected from 25 patients using polyimide tubing to avoid amyloid adherence to glass, and analyzed with a single-molecule array advanced digital enzyme-linked immunosorbent assay platform for Aß40, Aß42, and tTau. Cognition was assessed by MoCA. RESULTS: Perilymph volumes ranged from â¼1 to 13 µL, with analyte concentrations spanning 2.67 to 1088.26 pg/mL. All samples had detectable levels of tTau, Aß40, and Aß42, with a significant positive correlation between Aß42 and Aß40 levels. Levels of Aß42, Aß40, and tTau were positively correlated with age, while MoCA scores were inversely correlated with age. tTau and Aß42/Aß40-ratios were significantly correlated with MoCA scores. CONCLUSION: Alzheimer's disease-associated peptides Aß42, Aß40, and tau analytes are detectable in human perilymph at levels approximately 10-fold lower than those found in cerebrospinal fluid (CSF). These species increase with age and correlate with cognitive impairment indicators, suggesting their potential utility as biomarkers for cognitive impairment in patients undergoing cochlear implantation. Future research should investigate the origin of these analytes in the perilymph and their potential links to inner ear pathologies and hearing loss, as well as their relationships to CSF and plasma levels in individuals.
ABSTRACT
There is increasing interest in the use of cure modelling to inform health technology assessment (HTA) due to the development of new treatments that appear to offer the potential for cure in some patients. However, cure models are often not included in evidence dossiers submitted to HTA agencies, and they are relatively rarely relied upon to inform decision-making. This is likely due to a lack of understanding of how cure models work, what they assume, and how reliable they are. In this tutorial we explain why and when cure models may be useful for HTA, describe the key characteristics of mixture and non-mixture cure models, and demonstrate their use in a range of scenarios, providing Stata code. We highlight key issues that must be taken into account by analysts when fitting these models and by reviewers and decision-makers when interpreting their predictions. In particular, we note that flexible parametric non-mixture cure models have not been used in HTA, but they offer advantages that make them well suited to an HTA context when a cure assumption is valid but follow-up is limited.
Subject(s)
Health Expenditures , Neoplasms , Humans , Neoplasms/mortality , Neoplasms/economics , Health Care CostsABSTRACT
AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3WT and Gria3KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3KO mice in ambient sound compared to Gria3WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. Swollen afferent terminals were observed by 5-weeks only in Gria3KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.
ABSTRACT
Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
Subject(s)
Cochlea , Animals , Mice , Guinea Pigs , Humans , Rats , Swine , Hair Cells, Auditory , Microscopy, Fluorescence , Machine LearningABSTRACT
OBJECTIVES: Parametric models are used to estimate the lifetime benefit of an intervention beyond the range of trial follow-up. Recent recommendations have suggested more flexible survival approaches and the use of external data when extrapolating. Both of these can be realized by using flexible parametric relative survival modeling. The overall aim of this article is to introduce and contrast various approaches for applying constraints on the long-term disease-related (excess) mortality including cure models and evaluate the consequent implications for extrapolation. METHODS: We describe flexible parametric relative survival modeling approaches. We then introduce various options for constraining the long-term excess mortality and compare the performance of each method in simulated data. These methods include fitting a standard flexible parametric relative survival model, enforcing statistical cure, and forcing the long-term excess mortality to converge to a constant. We simulate various scenarios, including where statistical cure is reasonable and where the long-term excess mortality persists. RESULTS: The compared approaches showed similar survival fits within the follow-up period. However, when extrapolating the all-cause survival beyond trial follow-up, there is variation depending on the assumption made about the long-term excess mortality. Altering the time point from which the excess mortality is constrained enables further flexibility. CONCLUSIONS: The various constraints can lead to applying explicit assumptions when extrapolating, which could lead to more plausible survival extrapolations. The inclusion of general population mortality directly into the model-building process, which is possible for all considered approaches, should be adopted more widely in survival extrapolation in health technology assessment.
Subject(s)
Survival Analysis , HumansABSTRACT
Multi-state survival models are used to represent the natural history of a disease, forming the basis of a health technology assessment comparing a novel treatment to current practice. Constructing such models for rare diseases is problematic, since evidence sources are typically much sparser and more heterogeneous. This simulation study investigated different one-stage and two-stage approaches to meta-analyzing individual patient data (IPD) in a multi-state survival setting when the number and size of studies being meta-analyzed are small. The objective was to assess methods of different complexity to see when they are accurate, when they are inaccurate and when they struggle to converge due to the sparsity of data. Biologically plausible multi-state IPD were simulated from study- and transition-specific hazard functions. One-stage frailty and two-stage stratified models were estimated, and compared to a base case model that did not account for study heterogeneity. Convergence and the bias/coverage of population-level transition probabilities to, and lengths of stay in, each state were used to assess model performance. A real-world application to Duchenne Muscular Dystrophy, a neuromuscular rare disease, was conducted, and a software demonstration is provided. Models not accounting for study heterogeneity were consistently out-performed by two-stage models. Frailty models struggled to converge, particularly in scenarios of low heterogeneity, and predictions from models that did converge were also subject to bias. Stratified models may be better suited to meta-analyzing disparate sources of IPD in rare disease natural history/economic modeling, as they converge more consistently and produce less biased predictions of lengths of stay.
Subject(s)
Frailty , Models, Statistical , Humans , Rare Diseases/epidemiology , Computer Simulation , SoftwareABSTRACT
OBJECTIVES: A long-term, constant, protective treatment effect is a strong assumption when extrapolating survival beyond clinical trial follow-up; hence, sensitivity to treatment effect waning is commonly assessed for economic evaluations. Forcing a hazard ratio (HR) to 1 does not necessarily estimate loss of individual-level treatment effect accurately because of HR selection bias. A simulation study was designed to explore the behavior of marginal HRs under a waning conditional (individual-level) treatment effect and demonstrate bias in forcing a marginal HR to 1 when the estimand is "survival difference with individual-level waning". METHODS: Data were simulated under 4 parameter combinations (varying prognostic strength of heterogeneity and treatment effect). Time-varying marginal HRs were estimated in scenarios where the true conditional HR attenuated to 1. Restricted mean survival time differences, estimated having constrained the marginal HR to 1, were compared with true values to assess bias induced by marginal constraints. RESULTS: Under loss of conditional treatment effect, the marginal HR took a value >1 because of covariate imbalances. Constraining this value to 1 lead to restricted mean survival time difference bias of up to 0.8 years (57% increase). Inflation of effect size estimates also increased with the magnitude of initial protective treatment effect. CONCLUSIONS: Important differences exist between survival extrapolations assuming marginal versus conditional treatment effect waning. When a marginal HR is constrained to 1 to assess efficacy under individual-level treatment effect waning, the survival benefits associated with the new treatment will be overestimated, and incremental cost-effectiveness ratios will be underestimated.
Subject(s)
Proportional Hazards Models , Humans , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, muscle-degenerative disease predominantly affecting males. Natural history models capture the full disease pathway under current care and combine with estimates of new interventions' effects to assess cost-effectiveness by health technology decision-makers. These models require mortality estimates throughout a patient's lifetime, but rare disease datasets typically contain relatively few patients with short follow-ups. Alternative (published) sources of mortality data may therefore be required. METHODS: The Clinical Practice Research Datalink (CPRD) was evaluated as a source of mortality and natural history data for future economic evaluations of health technologies for DMD and rare diseases in general in the UK population. This retrospective longitudinal cohort study provides flexible parametric estimates of mortality rates and survival probabilities in the current UK DMD population through primary/secondary records in the CPRD since 1990. It also investigates clinically significant milestones such as corticosteroid use, spinal surgery, and cardiomyopathy in these patients. RESULTS: A total of 1121 male patients were included in the study, observed from 0.7 to 48.9 years. Median life expectancy was 25.64 years (95% confidence interval 24.73, 26.47), consistent with previous global estimates. This has improved to 26.47 (25.16, 27.89) years in patients born after 1990. The median ages at corticosteroid initiation, spinal surgery, ventilation, and cardiomyopathy diagnosis were 6.06 years (5.77, 6.29), 14.79 years (14.29, 15.09), 16.97 years (16.50, 18.31), and 15.26 years (14.22, 16.70), respectively. CONCLUSIONS: Estimates of mortality in UK-based DMD patients are age-specific in a uniquely large and nationally representative sample from the CPRD.
Subject(s)
Cardiomyopathies , Muscular Dystrophy, Duchenne , Humans , Male , Muscular Dystrophy, Duchenne/epidemiology , Muscular Dystrophy, Duchenne/therapy , Retrospective Studies , Longitudinal Studies , Adrenal Cortex Hormones , Cardiomyopathies/complications , United Kingdom/epidemiologyABSTRACT
Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
ABSTRACT
BACKGROUND: Life expectancy is a simple measure of assessing health differences between two or more populations but current life expectancy calculations are not reliable for small populations. A potential solution to this is to borrow strength from larger populations from the same source, but this has not formally been investigated. METHODS: Using data on 451,222 individuals from the Clinical Practice Research Datalink on the presence/absence of intellectual disability and type 2 diabetes mellitus, we compared stratified and combined flexible parametric models, and Chiang's methods, for calculating life expectancy. Confidence intervals were calculated using the Delta method, Chiang's adjusted life table approach and bootstrapping. RESULTS: The flexible parametric models allowed calculation of life expectancy by exact age and beyond traditional life expectancy age thresholds. The combined model that fit age interaction effects as a spline term provided less bias and greater statistical precision for small covariate subgroups by borrowing strength from the larger subgroups. However, careful consideration of the distribution of events in the smallest group was needed. CONCLUSIONS: Life expectancy is a simple measure to compare health differences between populations. The use of combined flexible parametric methods to calculate life expectancy in small samples has shown promising results by allowing life expectancy to be modelled by exact age, greater statistical precision, less bias and prediction of different covariate patterns without stratification. We recommend further investigation of their application for both policymakers and researchers.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Life Expectancy , Life TablesABSTRACT
We have previously proposed temporal recalibration to account for trends in survival over time to improve the calibration of predictions from prognostic models for new patients. This involves first estimating the predictor effects using data from all individuals (full dataset) and then re-estimating the baseline using a subset of the most recent data whilst constraining the predictor effects to remain the same. In this article, we demonstrate how temporal recalibration can be applied in competing risk settings by recalibrating each cause-specific (or subdistribution) hazard model separately. We illustrate this using an example of colon cancer survival with data from the Surveillance Epidemiology and End Results (SEER) program. Data from patients diagnosed in 1995-2004 were used to fit two models for deaths due to colon cancer and other causes respectively. We discuss considerations that need to be made in order to apply temporal recalibration such as the choice of data used in the recalibration step. We also demonstrate how to assess the calibration of these models in new data for patients diagnosed subsequently in 2005. Comparison was made to a standard analysis (when improvements over time are not taken into account) and a period analysis which is similar to temporal recalibration but differs in the data used to estimate the predictor effects. The 10-year calibration plots demonstrated that using the standard approach over-estimated the risk of death due to colon cancer and the total risk of death and that calibration was improved using temporal recalibration or period analysis.
Subject(s)
Colonic Neoplasms , Humans , Calibration , Prognosis , Proportional Hazards Models , Colonic Neoplasms/diagnosisABSTRACT
BACKGROUND: In population-based cancer studies it is common to try to isolate the impact of cancer by estimating net survival. Net survival is defined as the probability of surviving cancer in the absence of any other-causes of death. Net survival can be estimated either in the cause-specific or relative survival framework. Cause-specific survival considers deaths from the cancer as the event of interest. Relative survival incorporates general population expected mortality rates to represent the other-cause mortality rate. Estimation approaches in both frameworks are impacted by the systematic removal of patients from the risk-set, commonly referred to as informative censoring in the cause-specific framework. In the relative survival framework, the Pohar Perme estimator combats the effect of this systematic removal of patients through weighting. When the two frameworks have been compared, informative censoring is rarely accounted for in the cause-specific framework. METHODS: We investigate the use of weighted cause-specific Kaplan-Meier estimates to overcome the impact of informative censoring and compared approaches to defining weights. Individuals remaining in the risk-set are upweighted using their predicted other-cause survival obtained through various model-based approaches. We also compare weights derived from expected mortality rates. We applied the approaches to US cancer registry data and conducted a simulation study. RESULTS: Using weighted cause-specific estimates provides a better estimate of marginal net survival. The unweighted Kaplan-Meier estimates have a similar bias to the Ederer II method for relative survival. Weighted Kaplan-Meier estimates are unbiased and similar to the Pohar Perme estimator. There was little variation between the several weighting approaches. CONCLUSION: In comparisons of cause-specific and relative survival, it is important to compare "like-with-like", therefore, a weighted approach should be considered for both frameworks. If researchers are interested in obtaining net measures in a cause-specific framework, then weighting is needed to account for informative censoring.
Subject(s)
Neoplasms , Humans , Survival Analysis , Computer Simulation , Kaplan-Meier Estimate , ProbabilityABSTRACT
BACKGROUND: Different parametric survival models can lead to widely discordant extrapolations and decision uncertainty in cost-effectiveness analyses. The use of excess hazard (EH) methods, which incorporate general population mortality data, has the potential to reduce model uncertainty. This review highlights key practical considerations of EH methods for estimating long-term survival. METHODS: Demonstration of methods used a case study of 686 patients from the German Breast Cancer Study Group, followed for a maximum of 7.3 y and divided into low (1/2) and high (3) grade cancers. Seven standard parametric survival models were fit to each group separately. The same 7 distributions were then used in an EH framework, which incorporated general population mortality rates, and fitted both with and without a cure parameter. Survival extrapolations, restricted mean survival time (RMST), and difference in RMST between high and low grades were compared up to 30 years along with Akaike information criterion goodness-of-fit and cure fraction estimates. The sensitivity of the EH models to lifetable misspecification was investigated. RESULTS: In our case study, variability in survival extrapolations was extensive across the standard models, with 30-y RMST ranging from 7.5 to 14.3 y. Incorporation of general population mortality rates using EH cure methods substantially reduced model uncertainty, whereas EH models without cure had less of an effect. Long-term treatment effects approached the null for most models but at varying rates. Lifetable misspecification had minimal effect on RMST differences. CONCLUSIONS: EH methods may be useful for survival extrapolation, and in cancer, EHs may decrease over time and be easier to extrapolate than all-cause hazards. EH cure models may be helpful when cure is plausible and likely to result in less extrapolation variability. HIGHLIGHTS: In health economic modeling, to help anchor long-term survival extrapolation, it has been recommended that survival models incorporate background mortality rates using excess hazard (EH) methods.We present a thorough description of EH methods with and without the assumption of cure and demonstrate user-friendly software to aid researchers wishing to use these methods.EH models are applied to a case study, and we demonstrate that EHs are easier to extrapolate and that the use of the EH cure model, when cure is plausible, can reduce extrapolation variability.EH methods are relatively robust to lifetable misspecification.
Subject(s)
Breast Neoplasms , Humans , Female , Survival Analysis , Proportional Hazards Models , Breast Neoplasms/therapy , Survival RateABSTRACT
BACKGROUND: Routine reporting of cancer patient survival is important, both to monitor the effectiveness of health care and to inform about prognosis following a cancer diagnosis. A range of different survival measures exist, each serving different purposes and targeting different audiences. It is important that routine publications expand on current practice and provide estimates on a wider range of survival measures. We examine the feasibility of automated production of such statistics. METHODS: We used data on 23 cancer sites obtained from the Cancer Registry of Norway (CRN). We propose an automated way of estimating flexible parametric relative survival models and calculating estimates of net survival, crude probabilities, and loss in life expectancy across many cancer sites and subgroups of patients. RESULTS: For 21 of 23 cancer sites, we were able to estimate survival models without assuming proportional hazards. Reliable estimates of all desired measures were obtained for all cancer sites. DISCUSSION: It may be challenging to implement new survival measures in routine publications as it can require the application of modeling techniques. We propose a way of automating the production of such statistics and show that we can obtain reliable estimates across a range of measures and subgroups of patients.
Subject(s)
Neoplasms , Humans , Survival Analysis , Feasibility Studies , Neoplasms/therapy , Probability , AlgorithmsABSTRACT
BACKGROUND: An increasing proportion of patients with cancer experience acute myocardial infarction (AMI). We investigated differences in quality of AMI care and survival between patients with and without previous cancer diagnoses. METHODS: A retrospective cohort study using Virtual Cardio-Oncology Research Initiative data. Patients aged 40+ years hospitalized in England with AMI between January 2010 and March 2018 were assessed, ascertaining previous cancers diagnosed within 15 years. Multivariable regression was used to assess effects of cancer diagnosis, time, stage, and site on international quality indicators and mortality. RESULTS: Of 512 388 patients with AMI (mean age, 69.3 years; 33.5% women), 42 187 (8.2%) had previous cancers. Patients with cancer had significantly lower use of ACE (angiotensin-converting enzyme) inhibitors/angiotensin receptor blockers (mean percentage point decrease [mppd], 2.6% [95% CI, 1.8-3.4]) and lower overall composite care (mppd, 1.2% [95% CI, 0.9-1.6]). Poorer quality indicator attainment was observed in patients with cancer diagnosed in the last year (mppd, 1.4% [95% CI, 1.8-1.0]), with later stage disease (mppd, 2.5% [95% CI, 3.3-1.4]), and with lung cancer (mppd, 2.2% [95% CI, 3.0-1.3]). Twelve-month all-cause survival was 90.5% in noncancer controls and 86.3% in adjusted counterfactual controls. Differences in post-AMI survival were driven by cancer-related deaths. Modeling improving quality indicator attainment to noncancer patient levels showed modest 12-month survival benefits (lung cancer, 0.6%; other cancers, 0.3%). CONCLUSIONS: Measures of quality of AMI care are poorer in patients with cancer, with lower use of secondary prevention medications. Findings are primarily driven by differences in age and comorbidities between cancer and noncancer populations and attenuated after adjustment. The largest impact was observed in recent cancer diagnoses (<1 year) and lung cancer. Further investigation will determine whether differences reflect appropriate management according to cancer prognosis or whether opportunities to improve AMI outcomes in patients with cancer exist.
Subject(s)
Lung Neoplasms , Myocardial Infarction , Humans , Female , Aged , Male , Retrospective Studies , Cohort Studies , Myocardial Infarction/therapy , Myocardial Infarction/drug therapy , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , England/epidemiology , Lung Neoplasms/therapy , Lung Neoplasms/drug therapyABSTRACT
AIMS: Currently, little evidence exists on survival and quality of care in cancer patients presenting with acute heart failure (HF). The aim of the study is to investigate the presentation and outcomes of hospital admission with acute HF in a national cohort of patients with prior cancer. METHODS AND RESULTS: This retrospective, population-based cohort study identified 221 953 patients admitted to a hospital in England for HF during 2012-2018 (12 867 with a breast, prostate, colorectal, or lung cancer diagnosis in the previous 10 years). We examined the impact of cancer on (i) HF presentation and in-hospital mortality, (ii) place of care, (iii) HF medication prescribing, and (iv) post-discharge survival, using propensity score weighting and model-based adjustment. Heart failure presentation was similar between cancer and non-cancer patients. A lower percentage of patients with prior cancer were cared for in a cardiology ward [-2.4% age point difference (ppd) (95% CI -3.3, -1.6)] or were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists (ACEi/ARB) for heart failure with reduced ejection fraction [-2.1 ppd (-3.3, -0.9)] than non-cancer patients. Survival after HF discharge was poor with median survival of 1.6 years in prior cancer and 2.6 years in non-cancer patients. Mortality in prior cancer patients was driven primarily by non-cancer causes (68% of post-discharge deaths). CONCLUSION: Survival in prior cancer patients presenting with acute HF was poor, with a significant proportion due to non-cancer causes of death. Despite this, cardiologists were less likely to manage cancer patients with HF. Cancer patients who develop HF were less likely to be prescribed guideline-based HF medications compared with non-cancer patients. This was particularly driven by patients with a poorer cancer prognosis.
Subject(s)
Heart Failure , Neoplasms , Male , Humans , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Patient Discharge , Longitudinal Studies , Retrospective Studies , Aftercare , Cohort Studies , Heart Failure/complications , Heart Failure/diagnosis , Heart Failure/epidemiology , Stroke Volume , Neoplasms/complications , Neoplasms/epidemiologyABSTRACT
Cochlear sound encoding depends on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), but reliance on specific pore-forming subunits is unknown. With 5-week-old male C57BL/6J Gria3-knockout mice (i.e., subunit GluA3KO) we determined cochlear function, synapse ultrastructure, and AMPAR molecular anatomy at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons. GluA3KO and wild-type (GluA3WT) mice reared in ambient sound pressure level (SPL) of 55-75 dB had similar auditory brainstem response (ABR) thresholds, wave-1 amplitudes, and latencies. Postsynaptic densities (PSDs), presynaptic ribbons, and synaptic vesicle sizes were all larger on the modiolar side of the IHCs from GluA3WT, but not GluA3KO, demonstrating GluA3 is required for modiolar-pillar synapse differentiation. Presynaptic ribbons juxtaposed with postsynaptic GluA2/4 subunits were similar in quantity, however, lone ribbons were more frequent in GluA3KO and GluA2-lacking synapses were observed only in GluA3KO. GluA2 and GluA4 immunofluorescence volumes were smaller on the pillar side than the modiolar side in GluA3KO, despite increased pillar-side PSD size. Overall, the fluorescent puncta volumes of GluA2 and GluA4 were smaller in GluA3KO than GluA3WT. However, GluA3KO contained less GluA2 and greater GluA4 immunofluorescence intensity relative to GluA3WT (threefold greater mean GluA4:GluA2 ratio). Thus, GluA3 is essential in development, as germline disruption of Gria3 caused anatomical synapse pathology before cochlear output became symptomatic by ABR. We propose the hearing loss in older male GluA3KO mice results from progressive synaptopathy evident in 5-week-old mice as decreased abundance of GluA2 subunits and an increase in GluA2-lacking, GluA4-monomeric Ca2+-permeable AMPARs.
Subject(s)
Cochlea , Synapses , Animals , Male , Mice , Mice, Inbred C57BL , Neurons , Synapses/physiology , Synaptic Vesicles , Receptors, AMPA/metabolism , Receptors, Glutamate/metabolismABSTRACT
The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival.
Subject(s)
Ovarian Neoplasms , Humans , Female , Aged , Carcinoma, Ovarian Epithelial/epidemiology , Incidence , Ovarian Neoplasms/pathology , United Kingdom/epidemiology , Norway/epidemiology , RegistriesABSTRACT
BACKGROUND: In the United Kingdom, 15-min appointments with the general practitioner (GP) are recommended for people with complex health conditions, including intellectual disabilities and health needs, but we do not know whether this happens. AIMS: We compared number and length of primary care consultations (GP, nurse, other allied health, other) for people with and without intellectual disabilities and health needs. METHODS: Linked primary care data from the Clinical Practice Research Datalink (CPRD) in England were used to investigate face-to-face and telephone primary care consultations in 2017-2019. Health needs investigated were: epilepsy; incontinence; severe visual/hearing impairments; severe mobility difficulties; cerebral palsy; and percutaneous endoscopic gastrostomy feeding. Age and gender-standardized consultation rates per year (Poisson), duration of consultations, and the proportion of "long consultations" (≥15 min) were reported. RESULTS: People with intellectual disabilities (n = 7,794) had 1.9 times as many GP consultations per year as those without (n = 176,807; consultation rate ratio = 1.87 [95% confidence interval 1.86-1.89]). Consultation rates with nurses and allied healthcare professionals were also twice as high. Mean GP consultation time was 9-10 min regardless of intellectual disability/health need status. Long GP consultations were less common in people with intellectual disabilities (18.2% [17.8-18.7] vs. 20.9% [20.8-21.0]). Long consultations with practice nurses were more common in people with health needs, particularly severe visual loss. CONCLUSIONS: People with intellectual disabilities and/or health needs tend to have more, rather than longer, GP consultations compared with the rest of the population. We recommend further investigation into the role of practice nurses to support people with intellectual disabilities and health needs.