Clinical Outcomes in Patients with CKD and Rapid or Non-rapid eGFR Decline: A Report from the DISCOVER CKD Retrospective Cohort.

INTRODUCTION: This analysis examined the baseline characteristics and clinical outcomes of patients with chronic kidney disease (CKD) and rapid or non-rapid estimated glomerular filtration rate (eGFR) decline, using retrospective data from DISCOVER CKD (ClinicalTrials.gov, NCT04034992). METHODS: Data (2008-2020) were extracted from UK Clinical Practice Research Datalink, US TriNetX, US Limited Claims and Electronic Health Record Dataset, and Japan Medical Data Vision. Patients with CKD (two consecutive eGFR measures < 75 mL/min/1.73 m2 recorded 90-730 days apart) were included. Rapid eGFR decline was defined as an annual decline of > 4 mL/min/1.73 m2 at 2 years post-index; non-rapid eGFR decline was defined as an annual decline of ≤ 4 mL/min/1.73 m2. Clinical outcomes assessed included all-cause mortality, kidney outcomes (composite risk of kidney failure [progression to CKD stage 5] or > 50% eGFR decline, and kidney failure alone), cardiovascular events-including major adverse cardiovascular events (MACE; non-fatal myocardial infarction/stroke and cardiovascular death)-and all-cause hospitalization. RESULTS: Across databases, rapid eGFR decline occurred in 13.7% of 804,237 eligible patients. Mean annual eGFR decline ranged between - 6.21 and - 6.86 mL/min/1.73 m2 in patients with rapid eGFR decline versus between - 0.11 and - 0.77 mL/min/1.73 m2 in patients with non-rapid eGFR decline. Rapid eGFR decline was associated with increased comorbidity burden and medication prescriptions. Across databases, the composite risk of kidney failure or > 50% decline in eGFR was significantly greater in patients with rapid versus non-rapid eGFR decline (P < 0.01); all-cause mortality, kidney failure alone, MACE, and all-cause hospitalization each significantly increased in two databases (P < 0.01-0.05). CONCLUSION: Understanding patient factors associated with rapid eGFR decline in patients with CKD may help identify individuals who would benefit from proactive management to minimize the risk of adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04034992.

Mesoporous Metal Sponges Produced by Explosive Decomposition.

The formation of mesoporous gold sponges by explosive decomposition of 'knallgold' (also known as 'fulminating' gold) is studied. Proof-of-principle experiments are conducted and then the phenomena are further investigated using 'toy physics' molecular dynamics simulations. The simulations invoked various ratios of a volatile Lennard-Jones element G and a noble metal element N. In both experiment and simulation the morphology of the resulting sponge is found to depend on the stoichiometry of the starting material. As the mole fraction of G (χG) is increased from 0.5 to close to 1.0 in the simulations, the morphology of the sponges changes from closed to open, with a corresponding increase in the average mean curvature from 0 to +0.12 inverse Lennard-Jones length (L) units. The average Gaussian curvature of the simulated sponges is always negative, with the minimum value of 0.05 L-2 being found for χG ≈0.65. In broad agreement with experiment, sponge formation in the simulations is bounded by stoichiometry; no sponges form if χG is <0.52, for χG between 0.52 and 0.70 the sponge is characterized by vermicular cavities whereas classic bicontinuous fibrous sponges form for 0.70< χG < 0.85 and, finally, discrete particles result if χG >0.85.

Maintained renin-angiotensin-aldosterone system inhibitor therapy with sodium zirconium cyclosilicate following a hyperkalaemia episode: a multicountry cohort study.

Background: This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods: Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results: The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92-3.41; P < .0001). Conclusions: In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment.

ChatGPT-Based Learning: Generative Artificial Intelligence in Medical Education.

Large language models like ChatGPT are a type of machine learning model that can offer a positive paradigm shift in case-based/problem-based learning (CBL/PBL). ChatGPT may be able to augment the existing paradigm to work in conjunction with the clinical-teacher in PBL/CBL case generation. It can develop realistic patient cases that could be revised by clinical teachers to ensure accuracy and relevance. Further, it can be directed to include specific case content in order to facilitate the constructive alignment of the case with the broader learning objectives of the curriculum. There is also the possibility of improving engagement by 'gamifying' CBL/PBL. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01934-5.

Reduction in Long COVID Symptoms and Symptom Severity in Vaccinated Compared to Unvaccinated Adults.

Background: The impact of vaccination prior to infection on postacute sequelae of coronavirus disease 2019 (COVID-19, PASC), also known as long COVID, remains unclear. Here we assess the protective effect of vaccination on long COVID in a community-based setting. Methods: The Immunity Associated with SARS-CoV-2 (IASO) study is an ongoing prospective cohort of working adults that began in October 2020. Participants are actively followed for severe acute respiratory syndrome coronavirus 2 infection. We compared the prevalence of symptoms and symptom severity in vaccinated compared to unvaccinated cases. Our primary definition of long COVID was the presence of symptoms at 90 days postinfection; 30 days postinfection was also examined. Results: Overall, by 90 days postinfection, 13% of cases had long COVID, with 27% of unvaccinated cases and 8% of vaccinated cases reporting long COVID (relative risk [RR], 0.31 [95% confidence interval {CI}, .22-.42]). Vaccination was also associated with significantly lower average severity scores at all timepoints (eg, relative severity at 90 days postinfection: -2.70 [95% CI, -1.68 to -3.73]). In the pre-Omicron era, 28% of unvaccinated cases and 18% of vaccinated cases reported long COVID (P = .07), and vaccinated cases reported less severe symptoms including less difficulty breathing (P = .01; 90-day RR, 0.07). Conclusions: Vaccinated cases had lower prevalence of long COVID and reduced symptom severity.

Hyperkalaemia-related reduction of RAASi treatment associates with more subsequent inpatient care.

BACKGROUND: Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and number of hospitalized days in patients with CKD and/or HF in Sweden and Japan. METHODS: Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASi who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity-score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD-, and HF-related hospitalized days per patient-year during 6 months before versus after index, and the number of days alive and out of hospital (DAOH) during 6 months post-index were described. RESULTS: Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization (95% confidence intervals) increased by 18.2 (17.0-19.2) days per person-year in Sweden and 17.9 (17.4-18.5) days per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 (8.6-10.4) and 8.5 (8.0-9.0) days per person-year, respectively, among patients with maintained RAASi treatment. Mean (standard deviation) DAOH were 121.5 (75.0) in Sweden and 141.7 (54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (51.3) and 157.5 (31.6) days, respectively, among patients with maintained RAASi treatment. CONCLUSION: Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained.

TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.

Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.

Computation via Neuron-like Spiking in Percolating Networks of Nanoparticles.

The biological brain is a highly efficient computational system in which information processing is performed via electrical spikes. Neuromorphic computing systems that work on similar principles could support the development of the next generation of artificial intelligence and, in particular, enable low-power edge computing. Percolating networks of nanoparticles (PNNs) have previously been shown to exhibit critical spiking behavior, with promise for highly efficient natural computation. Here we employ a rate coding scheme to show that PNNs can perform Boolean operations and image classification. Near perfect accuracy is achieved in both tasks by manipulating the spiking activity using certain control voltages. We demonstrate that the key to successful computation is that nanoscale tunnel gaps within the percolating networks transform input data through a powerful modulus-like nonlinearity. These results provide a basis for implementation of further computational schemes that exploit the brain-like criticality of these networks.

A community of practice to address system-based issues and promote clinical leadership among trainee medical officers in a large public health service: an evaluation of a trainee-led forum.

Clinical leadership is necessary to improve the performance of large public hospitals. Trainee medical officers (TMOs) are important stakeholders in organisation-wide initiatives that affect the medical workforce and support clinician engagement. This case study describes the development of a representative body known as the 'TMO Forum' within the Central Adelaide Local Health Network as a mechanism to promote engagement between medical trainees and the hospital executive to facilitate escalation and discussion of system-based issues. Over the past 8 years, this group has evolved into a community of practice with steady and sustained growth since inception. Trainees have fostered relationships with the executive, and have engaged in leadership and quality improvement initiatives. Here we explore the evolution, value and barriers to success of the TMO Forum. Our discussion is supplemented with findings from anonymous online evaluation surveys of both the TMO and executive stakeholder groups. We propose that initiatives such as the described may offer reciprocal benefits to both constituent groups regarding communication, and that the development of a dedicated community of practice will enhance engagement of TMOs in health service improvement initiatives and advocacy. However, there are obstacles to overcome in order to attract a greater number of trainees and maximise the benefits from this initiative.

Prioritising cardiovascular disease risk assessment to high risk individuals based on primary care records.

OBJECTIVE: To provide quantitative evidence for systematically prioritising individuals for full formal cardiovascular disease (CVD) risk assessment using primary care records with a novel tool (eHEART) with age- and sex- specific risk thresholds. METHODS AND ANALYSIS: eHEART was derived using landmark Cox models for incident CVD with repeated measures of conventional CVD risk predictors in 1,642,498 individuals from the Clinical Practice Research Datalink. Using 119,137 individuals from UK Biobank, we modelled the implications of initiating guideline-recommended statin therapy using eHEART with age- and sex-specific prioritisation thresholds corresponding to 5% false negative rates to prioritise adults aged 40-69 years in a population in England for invitation to a formal CVD risk assessment. RESULTS: Formal CVD risk assessment on all adults would identify 76% and 49% of future CVD events amongst men and women respectively, and 93 (95% CI: 90, 95) men and 279 (95% CI: 259, 297) women would need to be screened (NNS) to prevent one CVD event. In contrast, if eHEART was first used to prioritise individuals for formal CVD risk assessment, we would identify 73% and 47% of future events amongst men and women respectively, and a NNS of 75 (95% CI: 72, 77) men and 162 (95% CI: 150, 172) women. Replacing the age- and sex-specific prioritisation thresholds with a 10% threshold identify around 10% less events. CONCLUSIONS: The use of prioritisation tools with age- and sex-specific thresholds could lead to more efficient CVD assessment programmes with only small reductions in effectiveness at preventing new CVD events.

Chemically induced reprogramming to reverse cellular aging.

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

Using Polygenic Risk Scores for Prioritizing Individuals at Greatest Need of a Cardiovascular Disease Risk Assessment.

Background The aim of this study was to provide quantitative evidence of the use of polygenic risk scores for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment. Methods and Results A total of 108 685 participants aged 40 to 69 years, with measured biomarkers, linked primary care records, and genetic data in UK Biobank were used for model derivation and population health modeling. Prioritization tools using age, polygenic risk scores for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. We modeled the implications of initiating guideline-recommended statin therapy after prioritizing individuals for invitation to a formal CVD risk assessment. If primary care records were used to prioritize individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false-negative rates, then the numbers of men and women needed to be screened to prevent 1 CVD event are 149 and 280, respectively. In contrast, adding polygenic risk scores to both prioritization and formal assessments, and selecting thresholds to capture the same number of events, resulted in a number needed to screen of 116 for men and 180 for women. Conclusions Using both polygenic risk scores and primary care records to prioritize individuals at highest risk of a CVD event for a formal CVD risk assessment can efficiently prioritize those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of risk assessments in primary care while still preventing the same number of CVD events.

Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study.

OBJECTIVES: REVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD). DESIGN: Multinational, observational study. SETTING: Data from six country-specific electronic medical records and/or insurance claims databases from five countries (France, Germany, Italy, Japan and the USA [two databases]). PARTICIPANTS: Eligible participants (≥18 years old) had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements (calculated from serum creatinine values, sex and age) taken from 2015 onwards that were indicative of stage 3 CKD (≥30 and <60 mL/min/1.73 m2). Undiagnosed cases lacked an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before, and up to 6 months after, the second qualifying eGFR measurement (study index). MAIN OUTCOME MEASURES: The primary outcome was point prevalence of undiagnosed stage 3 CKD. Time to diagnosis was assessed using the Kaplan-Meier approach. Factors associated with lacking a CKD diagnosis and risk of diagnostic delay were assessed using logistic regression adjusted for baseline covariates. RESULTS: The prevalence of undiagnosed stage 3 CKD was 95.5% (19 120/20 012 patients) in France, 84.3% (22 557/26 767) in Germany, 77.0% (50 547/65 676) in Italy, 92.1% (83 693/90 902) in Japan, 61.6% (13 845/22 470) in the US Explorys Linked Claims and Electronic Medical Records Data database and 64.3% (161 254/250 879) in the US TriNetX database. The prevalence of undiagnosed CKD increased with age. Factors associated with undiagnosed CKD were female sex (vs male, range of odds ratios across countries: 1.29-1.77), stage 3a CKD (vs 3b, 1.81-3.66), no medical history (vs a history) of diabetes (1.26-2.77) or hypertension (1.35-1.78). CONCLUSIONS: There are substantial opportunities to improve stage 3 CKD diagnosis, particularly in female patients and older patients. The low diagnosis rates in patients with comorbidities that put them at risk of disease progression and complications require attention. TRIAL REGISTRATION: NCT04847531.

Surgical treatment of ankle instability in children with os subfibulare.

INTRODUCTION: Ankle instability in children due to soft tissue injury usually resolves after non-operative treatment. However, some children and adolescents with chronic instability require surgical treatment. A rarer cause of developing ankle instability is injury to the ligament complex in the presence of os subfibulare, an accessory bone inferior to the lateral malleolus. The aim of this study was to assess the results of operative management of chronic ankle instability in children with os subfibulare. MATERIALS AND METHODS: 16 children with os subfibulare and chronic ankle instability who failed non-operative treatment were enrolled prospectively into the study. One child was lost to follow-up and excluded from analysis. The mean age at the time of the surgery was 14 years and 2 months (range 9.5-17 years). The mean follow-up time was 43.2 months (range 28-48 months). Surgical treatment in all cases involved removal of os subfibulare and a modified Broström-Gould lateral complex reconstruction with anchors. Ankle status was assessed before and after surgery with The 100 mm Visual Analogue Scale and Foot and Ankle Outcome Score questionnaire. RESULTS: The mean Foot and Ankle Outcome Score improved from 66.8 to 92.3 (p < 0.001). Pain level improved from 67.1 preoperatively to 12.7 (p < 0.001). All children reported improvement in their ankle stability. There was one case of scar hypersensitivity that improved during observation and one superficial wound infection that resolved with oral antibiotics. One child reported intermittent pain without symptoms of instability following another injury. CONCLUSIONS: Ankle joint sprain with associated injury to os subfibulare complex can lead to chronic instability in children. If conservative management fails, then surgical treatment with modified Broström-Gould technique and excision of accessory bone is a safe and reliable method.

Medication Deprescribing Among Patients With Type 2 Diabetes: A Qualitative Case Series of Lifestyle Medicine Practitioner Protocols.

This study is a qualitative case series of lifestyle medicine practitioners' protocols for medication de-escalation in the context of reduced need for glucose-lowering medications due to lifestyle modifications. Increasing numbers of lifestyle medicine practitioners report achieving reductions in medications among patients with type 2 diabetes, and in some cases remission, but limited data exist on the clinical decision-making process used to determine when and how medications are deprescribed. Practitioners interviewed here provide accounts of their deprescribing protocols. This information can serve as pilot data for other practitioners seeking examples of how deprescribing in the context of lifestyle medicine treatment is conducted.

Rates of adverse clinical events in patients with chronic kidney disease: analysis of electronic health records from the UK clinical practice research datalink linked to hospital data.

BACKGROUND: Further understanding of adverse clinical event rates in patients with chronic kidney disease (CKD) is required for improved quality of care. This study described baseline characteristics, adverse clinical event rates, and mortality risk in patients with CKD, accounting for CKD stage and dialysis status. METHODS: This retrospective, noninterventional cohort study included data from adults (aged ≥ 18 years) with two consecutive estimated glomerular filtration rates of < 60 ml/min/1.73 m2, recorded ≥ 3 months apart, from the UK Clinical Practice Research Datalink of electronic health records obtained between January 1, 2004, and December 31, 2017. Select adverse clinical events, associated with CKD and difficult to quantify in randomized trials, were assessed; defined by Read codes and International Classification of Diseases, Tenth Revision codes. Clinical event rates were assessed by dialysis status (dialysis-dependent [DD], incident dialysis-dependent [IDD], or non-dialysis-dependent [NDD]), dialysis modality (hemodialysis [HD] or peritoneal dialysis [PD]), baseline NDD-CKD stage (3a-5), and observation period. RESULTS: Overall, 310,953 patients with CKD were included. Comorbidities were more common in patients receiving dialysis than in NDD-CKD, and increased with advancing CKD stage. Rates of adverse clinical events, particularly hyperkalemia and infection/sepsis, also increased with advancing CKD stage and were higher in patients on HD versus PD. Mortality risk during follow-up (1-5-year range) was lowest in patients with stage 3a NDD-CKD (2.0-18.5%) and highest in patients with IDD-CKD (26.3-58.4%). CONCLUSIONS: These findings highlight the need to monitor patients with CKD for comorbidities and complications, as well as signs or symptoms of clinical adverse events.

Health Care Resource Utilization and Related Costs of Patients With CKD From the United States: A Report From the DISCOVER CKD Retrospective Cohort.

Introduction: It is well established that chronic kidney disease (CKD) results in a significant burden on patients' health and health care providers. However, detailed estimates of the health care resource utilization (HCRU) of CKD are limited, particularly those which consider severity, comorbidities, and payer type. This study aimed to bridge this evidence gap by reporting contemporary HCRU and costs in patients with CKD across the US health care providers. Methods: Cost and HCRU estimates of CKD and reduced kidney function without CKD (estimated glomerular filtration rate [eGFR]: 60-75 and urine albumin-to-creatinine ratio [UACR]: <30) were derived for US patients included in the DISCOVER CKD cohort study, using linked inpatient and outpatient data from the limited claims-EMR data set (LCED) and TriNetX database. Patients with a history of transplant or undergoing dialysis were not included. HCRU and costs were stratified by CKD severity using UACR and eGFR. Results: Overall health care costs ranged from $26,889 (A1) to $42,139 (A3), and from $28,627 (G2) to $42,902 (G5) per patient per year (PPPY), demonstrating a considerable early disease burden which continued to increase with declining kidney function. The PPPY costs of later stage CKD were particularly notable for patients with concomitant heart failure ($50,191 [A3]) and those covered by commercial payers ($55,735 [A3]). Conclusions: Health care costs and resource use associated with CKD and reduced kidney function pose a substantial burden across health care systems and payers, increasing in line with CKD progression. Early CKD screening, particularly of UACR, paired with proactive disease management may provide both an improvement to patient outcomes and a significant HCRU and cost saving to health care providers.

Background rate estimations for thrombosis with thrombocytopaenia: challenges in evaluating rare safety signals following vaccination in real time during a pandemic.

OBJECTIVES: During COVID-19 vaccination programmes, new safety signals have emerged for vaccines, including extremely rare cases of thrombosis with thrombocytopaenia syndrome (TTS). Background event rates before and during the pandemic are essential for contextualisation of such infrequent events. In the literature, most studies do not report an overall TTS event rate. Rather, background rates are mainly reported for subtypes of thrombotic/thromboembolic diagnoses included in the TTS clinical definition mostly by anatomical location, with reported rates for TTS subtypes varying widely. The objective of this study was to report prepandemic TTS background event rates in the general population. METHODS: Prepandemic background TTS rates were generated via secondary data analysis using a cohort design in the IBM Truven MarketScan (now Merative MarketScan) US health insurance claims database, from 1 January 2019 to 31 December 2019. Two algorithms were applied: thrombocytopaenia occurring±7 days (algorithm 1) or occurring 1 day prior to ≤14 days after the thrombotic/thromboembolic event (algorithm 2). RESULTS: The study population derived from the MarketScan database analysis included approximately 9.8 million adults (aged ≥18 years; mean age 45 years, 52% females). Using this study population, prepandemic background TTS incidence was estimated as 9.8-11.1 per 100 000 person-years. Event rates were higher in males and increased with age. Similar patterns were observed with both algorithms. CONCLUSIONS: This study presents an estimate of aggregate prepandemic background TTS event rates including by type of thrombosis/thromboembolism and age group. The background event rates are dependent on the precision of capturing underlying TTS events in variable data sources, and the ability of electronic health records or insurance claims databases to reflect the TTS clinical definition. Differences between reported event rates demonstrate that estimating background event rates for rare, unprecedented safety events is methodologically challenging.

Coexistence between similar invaders: The case of two cosmopolitan exotic insects.

Biological invasions are usually examined in the context of their impacts on native species. However, few studies have examined the dynamics between invaders when multiple exotic species successfully coexist in a novel environment. Yet, long-term coexistence of now established exotic species has been observed in North American lady beetle communities. Exotic lady beetles Harmonia axyridis and Coccinella septempunctata were introduced for biological control in agricultural systems and have since become dominant species within these communities. In this study, we investigated coexistence via spatial and temporal niche partitioning among H. axyridis and C. septempunctata using a 31-year data set from southwestern Michigan, USA. We found evidence of long-term coexistence through a combination of small-scale environmental, habitat, and seasonal mechanisms. Across years, H. axyridis and C. septempunctata experienced patterns of cyclical dominance likely related to yearly variation in temperature and precipitation. Within years, populations of C. septempunctata peaked early in the growing season at 550 degree days, while H. axyridis populations grew in the season until 1250 degree days and continued to have high activity after this point. C. septempunctata was generally most abundant in herbaceous crops, whereas H. axyridis did not display strong habitat preferences. These findings suggest that within this region H. axyridis has broader habitat and abiotic environmental preferences, whereas C. septempunctata thrives under more specific ecological conditions. These ecological differences have contributed to the continued coexistence of these two invaders. Understanding the mechanisms that allow for the coexistence of dominant exotic species contributes to native biodiversity conservation management of invaded ecosystems.