Publications
scientifiques

BACKGROUND: As a global public health issue, childhood maltreatment is associated with significant morbidity and mortality. We aimed to investigate the association between childhood maltreatment and immune-mediated inflammatory disorders (IMIDs). METHODS: We conducted a retrospective matched open cohort study using a UK primary care database between January 1, 1995 and January 31, 2021. Clinical codes were used to identify patients exposed to childhood maltreatment who were matched by general practice (GP), age, and sex to up to four unexposed patients. Cox regression analysis was used to evaluate the risk of developing IMIDs (inflammatory bowel disease, coeliac disease, rheumatoid arthritis, psoriasis, multiple sclerosis, systemic lupus erythematosus) during follow-up in the exposed versus unexposed groups. RESULTS: 256,130 exposed patients were matched to 712,478 unexposed patients. Those exposed to childhood maltreatment were 1) at an increased risk of developing Rheumatoid arthritis (aHR 1·39; 95 % CI 1·12-1·74) and Psoriasis (aHR 1·16; 95 % CI 1·10-1·23), 2) not statistically significantly at risk of developing inflammatory bowel disease (aHR 0·87; 95 % CI 0·75-1·00), multiple sclerosis (aHR 1·07; 95 % CI 0·77-1·49) and systemic lupus erythematosus (aHR 1·28; 95 % CI 0·89-1·85) and 3) at a reduced risk of coeliac disease (aHR 0·74; 95 % CI 0·62-0·88) compared to the unexposed group. INTERPRETATIONS: Childhood maltreatment is estimated to affect one in three children globally; therefore, an increased risk of developing rheumatoid arthritis and psoriasis represents a substantial contribution to the burden of IMIDs. Implementation of broad public health approaches to prevent and detect childhood maltreatment and its negative downstream consequences, such as, IMID development, is essential.

IMPORTANCE: Clinicians often approach urate-lowering therapy (ULT) cautiously in patients with gout and impaired kidney function because they are concerned about the risk of progression to severe or end-stage kidney disease. However, evidence from randomized clinical trials of this association remains inconclusive. OBJECTIVE: To evaluate the association between achieving target serum urate level with ULT and progression of chronic kidney disease (CKD) to severe or end-stage in patients with gout and impaired kidney function. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study using the target trial emulation approach using data from a general practice database (IQVIA Medical Research Database) for 2000 to 2023. Eligible patients were 40 to 89 years old and had gout and CKD stage 3. Data analyses were performed from November 2023 to September 2024. EXPOSURES: Lowering serum urate level to target level (<6 mg/dL) using ULT. MAIN OUTCOMES AND MEASURES: Severe or end-stage kidney disease, determined by an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 on at least 2 occasions more than 90 days apart within 1 year, or at least 1 Read code (per the Refined Etiology, Anatomical Site, and Diagnosis classification) for CKD stages 4 or 5, hemodialysis, peritoneal dialysis, or kidney transplant. The prespecified noninferiority margin of the hazard ratio (HR) was set at 1.2, comparing those who achieved the target serum urate level with those who did not. RESULTS: Among the 14 792 participants (mean [SD] age, 73.1 [9.5] years; 9215 men [62.3%] and 5577 women [37.7%]) with gout and with CKD stage 3, the 5-year risk of severe or end-stage kidney disease was 10.32% for those who achieved the target serum urate level and 12.73% for those who did not. Compared with those not achieving the target level, the adjusted 5-year risk difference and HR of severe or end-stage kidney disease for patients achieving the target serum urate level was -2.41% (95% CI, -4.61% to -0.21%) and 0.89 (95% CI, 0.80 to 0.98), respectively. CONCLUSIONS AND RELEVANCE: The findings of this cohort study indicate that in patients with gout and CKD stage 3, lowering serum urate level to less than 6 mg/dL vs 6 mg/dL or greater using ULT was not associated with an increased risk of severe or end-stage kidney disease. These findings support optimizing ULT to achieve target serum urate levels when treating patients with gout and impaired kidney function.

In a population-based cohort study of menopausal women with common mental health diagnoses, SSRIs/SNRIs were associated with a 32% increased risk of osteoporotic fractures. The risk of osteoporotic fractures was particularly increased for longer periods of treatment with SSRIs/SNRIs (> 5 years) and in younger menopausal women (< 50 years old). PURPOSE: To investigate the association between selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and the risk of osteoporotic fractures (OF) in menopausal women with common mental health diagnoses (CMHD). METHODS: We conducted the study with two designs (cohort and self-controlled case series [SCCS]), using the IQVIA Medical Research Database (IMRD) UK. The source population comprised women aged ≥ 50 years and women with a record indicating menopause (< 50 years). All women had a recorded CMHD. For the cohort analysis, the risk of OFs was estimated by comparing women prescribed SSRIs/SNRIs (exposed) to those not exposed. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CIs). For the SCCS, women acted as their own controls; periods of exposure to SSRIs/SNRIs were compared to periods of non-exposure using conditional Poisson regression to estimate incidence rate ratios (IRR) with 95% CIs. RESULTS: We identified 292,848 women, of whom 35,222 experienced OFs within a median follow-up of 6.01 years. We found strong evidence of an association between SSRIs/SNRIs and the risk of OFs (adjusted HR = 1.32, 95% CI:1.29-1.35). Compared to periods of no exposure, SSRIs/SNRIs increased the risk of OFs during the first 30 days (IRR = 1.38, 95% CI:1.26-1.51), during the first 90 days (IRR = 1.58, 95% CI: 1.48-1.69), and the remaining exposure (IRR = 1.42, 95% CI:1.37-1.48). CONCLUSIONS: In a population of menopausal women with CMHDs, the prescribing of SSRIs/SNRIs antidepressants was associated with a higher risk of OFs. Careful assessment of osteoporosis risk needs to be considered when treating menopausal women with SSRIs/SNRIs antidepressants.

BACKGROUND: Severe mental illness (SMI) has been associated with reduced bone density and increased risk of fractures, although some studies have shown inconsistent results. AIM: To examine the association between SMI and recorded diagnosis of osteoporosis and fragility fracture in people aged ≥50 years. DESIGN AND SETTING: Population-based cohort study set in UK primary care. METHOD: Anonymised primary care data (IQVIA Medical Research Database) were used. Patients with a diagnosis of SMI aged 50-99 years (2000-2018) were matched to individuals without SMI. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Analyses were stratified by sex and age, accounting for social deprivation, year, smoking, alcohol, and body mass index. RESULTS: In total, 444 480 people were included (SMI = 50 006; unexposed = 394 474). In men, diagnosis of SMI increased the likelihood of an osteoporosis diagnosis, with differences mainly observed among the youngest (aged 50-54 years: HR 2.12, 95% CI = 1.61 to 2.79) and the oldest (aged 85-99 years: HR 2.15, 95% CI = 1.05 to 4.37), and SMI increased the risk of fragility fractures across all ages. In women, SMI increased the risk of an osteoporosis diagnosis only in those aged 50-54 years (HR 1.16, 95% CI = 1.01 to 1.34), but increased the risk of fragility fractures across all ages. There were more than twice as many men with SMI with fragility fracture records than with an osteoporosis diagnosis: fragility fracture:osteoporosis = 2.10, compared with fragility fracture:osteoporosis = 1.89 in men without SMI. The fragility fracture:osteoporosis ratio was 1.56 in women with SMI versus 1.11 in women without SMI. CONCLUSION: SMI is associated with an increased likelihood of fragility fractures and osteoporosis underdiagnosis. Interventions should be considered to mitigate the increased risk of fractures in people with SMI.

BACKGROUND: Nasopharyngitis is a common viral infection that has led to an overuse of prescription drugs, in particular antibiotics, which are not indicated for this condition. AIM: The purpose of this study was to describe drug prescriptions for patients with a diagnosis of acute rhinopharyngitis in general practices in France. DESIGN & SETTING: Retrospective study of 1 067 403 prescriptions for a diagnosis of nasopharyngitis issued by 2637 physicians to 754 476 patients living in metropolitan France. METHOD: The data were sourced from the prescription software, Cegedim, for the period 1 January 2018 to 31 December 2021 and analysed according to patients' and physicians' ages. RESULTS: A total of 2 591 584 medications were prescribed by GPs, with a median of three medications per patient. A total of 171 540 courses of antibiotics were prescribed (16% prescription rates), with amoxicillin being the most frequently prescribed (102 089 prescriptions; 59.5% of antibiotic prescriptions). Amoxicillin prescription increased in extreme age groups (18.2% of visits in those aged 9 years and under, and 10.0% of visits in those aged over 80 years, while patients aged 20-29-years were prescribed amoxicillin in just 2.9% of visits), and more prescriptions are issued by older doctors (GPs older than 70 years prescribed antibiotics in 26.4% of visits versus 3.2% of visits by GPs aged under 29 years). CONCLUSION: Nasopharyngitis is frequently a cause of therapeutic over-prescriptions including antibiotics, with an antibiotic prescription rate of 16%. Additional research is required to enhance our understanding of factors linked to drug prescriptions.

BACKGROUND: Dyslipidemia remains the major cause of atherosclerotic cardiovascular disease (ASCVD). Lipid management in patients with increased cardiovascular (CV) risk needs improvement across Europe, and data gaps are noticeable at the country level. HYPOTHESIS: We described the current treatment landscape in Belgium, hypothesizing that lipid management in patients with ASCVD remains inadequate and aiming to understand the reasons. METHODS: Using data from an anonymized primary care database in Belgium derived from 494 750 individuals, we identified those with any CV risk factor between November 2019 and October 2022 and described the clinical features of patients with ASCVD. The main outcomes were the proportion of patients (i) receiving lipid-lowering therapies (LLTs), (ii) per low-density lipoprotein cholesterol (LDL-C) threshold, stratified per LLT, (iii) reaching the 2021 ESC recommended LDL-C goals, and (iv) LDL-C reduction per type of LLT was also determined. RESULTS: Among 40 888 patients with very high CV risk, 24 859 had established ASCVD. Most patients with ASCVD were either receiving monotherapy (59.6%) or had no documented LLT (25.1%). Further, 64.2% of those with no documented LLT exhibited LDL-C levels ≥ 100 mg/dL. Among common treatment options, one of the greatest improvements in LDL-C levels was achieved with combination therapy of statin and ezetimibe, reducing LDL-C levels by 41.5% (p < 0.0001). Yet, in this group, 24.8% of patients had still LDL-C levels ≥ 100 mg/dL and only 20.7% were at goal. CONCLUSION: Our study emphasizes the importance of developing strategies to help patients achieve their LDL-C goals, with a focus on supporting the implementation of combination LLT in routine clinical practice.

BACKGROUND: Memantine, which is an FDA-proven drug for the treatment of dementia, exerts its function by blocking the function of NMDA (N-methyl-D-aspartate) receptor, a calcium-permeable ion channel that reduces cytotoxic calcium overload. Chondrocyte senescence is a crucial cellular event that contributes to articular cartilage degeneration during osteoarthritis (OA) development. To date, the effects of memantine and its downstream NMDA receptor on chondrocyte senescence and OA have been rarely reported. METHODS: The protein levels of NMDA receptor and its agonistic ligand, glutamate, were compared between normal and OA chondrocytes. The quantity of intracellular calcium ions and the level of mitochondrial damage were evaluated using specific fluorescent probes and transmission electron microscopy (TEM), respectively. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-Gal) staining and p16 analysis. The function of NMDA receptor in chondrocyte senescence and OA was tested via agonists activation and gene knockdown experiments. The therapeutic effects of memantine on OA were examined both and . Additionally, to verify the findings from animal samples, a propensity score-matched cohort study was conducted using data from a United Kingdom primary care database (i.e., IQVIA Medical Research Database [IMRD]) to compare the risk of OA-related joint replacement involved in memantine initiators versus active comparators (i.e., acetylcholinesterase [AchE] initiators) in patients with dementia. RESULTS: The protein expression of NMDA receptor and the secretion of glutamate were both significantly increased in OA chondrocytes. NMDA receptor activation was found to stimulate chondrocyte calcium overload, which further led to mitochondrial fragmentation and chondrocyte senescence. Blocking the NMDA receptor with memantine and N-methyl-D-aspartate receptor subunit 1(NR1, the gene encoding NMDA receptor) knockdown resulted in reduced calcium influx, mitochondrial fragmentation, as well as cellular senescence in OA chondrocytes. Intra-articular injection of memantine in OA mice also exhibited protective effects against cartilage degeneration. Moreover, in the 1:5 propensity score-matched cohort study consisting of 6218 patients (n = 1435 in the memantine cohort; n = 4783 in the AchE cohort), the memantine initiator was associated with a lower risk of OA-related joint replacement than AchE initiators (Hazard ratio = 0.56, 95 % confidence interval: 0.34 to 0.99). CONCLUSION: NMDA receptor plays an important role in inflammatory-induced cytotoxic calcium overload in chondrocytes, while memantine can effectively block the NMDA receptor to reduce chondrocyte senescence and retard the development of OA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: As a clinically licensed drug used for the treatment of dementia, memantine has shown promising therapeutic effects on OA. Mechanistically, it functions by blocking NMDA receptor from mediating chondrocyte senescence. The protective effects of memantine against OA were verified not only by and experiments but also via a propensity score-matched human cohort study. These findings presented robust evidence for repurposing memantine for the treatment of OA.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

BACKGROUND: Routinely collected electronic healthcare records (EHRs) document many details of a person's health, including demographics, preventive services, symptoms, tests, disease diagnoses and prescriptions. Although not collected for research purposes, these data provide a wealth of information which can be incorporated into epidemiological investigations, and records can be analysed to understand a range of important health questions. We aimed to understand the use of routinely collected health data in epidemiological studies relating to three of the most common chronic respiratory conditions, namely: asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). We also characterised studies using EHR data to investigate respiratory diseases more generally, relative to cardiovascular disease and COVID-19, to understand trends in the use of these data. METHODS: We conducted a search of the Scopus database, to identify original research articles (irrespective of date) which used data from one of the following most frequently used UK EHR databases: Clinical Practice Research Datalink (including General Practice Research Database (CPRD's predecessor)), The Health Improvement Network and QResearch, defined through the presence of keywords. These databases were selected as they had been previously included in the works of Vezyridis and Timmons. FINDINGS: A total of 716 manuscripts were included in the analysis of the three chronic respiratory conditions. The majority investigated either asthma or COPD, whilst only 28 manuscripts investigated ILD. The number of publications has increased for respiratory conditions over the past 10 years (888% increase from 2000 to 2022) but not as much as for cardiovascular diseases (1105%). These data have been used to investigate comorbidities, off-target effects of medication, as well as assessing disease incidence and prevalence. Most papers published across all three domains were in journals with an impact factor less than 10.

AIMS: This study aimed to assess the proportions of type 2 diabetes (T2D) subjects meeting cardiovascular outcome trials (CVOTs) criteria for sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and estimate SGLT2i utilization, along with associated demographic and clinical characteristics, in a primary care setting. METHODS: T2D patients in Italy were selected between January 1, 2021, and December 31, 2022, from The Health Improvement Network (THIN ) database. Representativeness was determined by dividing patients meeting key inclusion criteria for four CVOTs (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) to the total T2D population. Demographic and clinical characteristics of eligible T2D subjects and SGLT2i users were compared, and logistic regression models assessed the likelihood of receiving SGLT2i. RESULTS: Out of 17,102 T2D patients, 8,828 met eligibility criteria for at least one CVOT. DECLARE-TIMI 58 exhibited the highest representativeness (51.1%), compared to CANVAS (21.1%), EMPA-REG OUTCOME (5.5%), and VERTIS-CV (4.9%) trials. Eligible CVOTs patients were older (74.6 vs. 68.3 years), with a longer disease duration (10.2 vs. 9.7 years), and higher established cardiovascular disease (CVD) prevalence (36.0 vs. 27.3%) compared to SGLT2i users. Less than 10% of eligible T2D patients received SGLT2i. Males (OR: 1.43; 95%CI: 1.24-1.66) were more likely to be prescribed SGLT2i than other antidiabetic drugs, while the elderly (80 + vs. 40-64 years, OR: 0.17; 95% CI: 0.14-0.22) were less likely. Eligible T2D patients with CVD reported an increased likelihood of receiving SGLT2is compared to other antidiabetics. CONCLUSION: This study highlights significant variability in the proportion of T2D subjects meeting SGLT2i CVOT inclusion criteria, with DECLARE-TIMI-58 being the most represented. Low SGLT2i prescription rates in the Italian primary care setting, along with substantial demographic and clinical differences between SGLT-2i users and T2D eligible patients, emphasize the need for targeted interventions to optimize the use of these medications in primary care settings.

BACKGROUND: Clinical practice guidelines for patients with chronic kidney disease (CKD) recommend regular monitoring and management of kidney function and CKD risk factors. However, the majority of patients with stage 3 CKD lack a diagnosis code, and data on the implementation of these recommendations in the real world are limited. AIM: To assess the implementation of guideline-directed monitoring and management practices in the real world in patients with stage 3 CKD without a recorded diagnosis code. METHODS: REVEAL-CKD (NCT04847531) is a multinational, observational study of patients with stage 3 CKD. Eligible patients had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD recorded >90 and ≤730 days apart, lacked an International Classification of Diseases 9/10 diagnosis code corresponding to CKD any time before and up to 6 months after the second eGFR measurement. Testing of key measures of care quality were assessed. RESULTS: The study included 435,971 patients from 9 countries. In all countries, the prevalence of urinary albumin-creatinine ratio and albuminuria testing was low. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and statin prescriptions were highly variable, and sodium-glucose cotransporter-2 inhibitor prescriptions remained below 21%. Blood pressure measurements were recorded in 20.2%-89.9% of patients. CONCLUSIONS: Overall, a large proportion of patients with evidence of stage 3 CKD did not receive recommended, guideline-directed monitoring and management. The variability in standard of care among countries demonstrates a clear opportunity to improve monitoring and management of these patients, most likely improving long-term outcomes.

BACKGROUND: Adverse drug reactions (ADRs) represent a significant barrier to achieve optimal treatment outcomes. Cardiovascular drugs, including antihypertensive drugs, lipid-lowering drugs, and antithrombotic drugs, are among the most prescribed medications in the primary care setting. OBJECTIVES: To estimate the prevalence of cardiovascular drug-related ADRs consultations in United Kingdom (UK) primary care and identify risk factors of these ADRs. METHODS: This was a cross-sectional study of cardiovascular drug users between 2000-2019 using UK IQVIA Medical Research Data. ADRs consultations were identified using database screening method employing standardised designated codes. The overall and annual age-standardised prevalence was estimated using direct standardisation method using 2019 mid-year UK population. Risk factors of ADRs consultations were estimated using logistic regression model stratified by therapeutic areas. RESULTS: The standardised prevalence of consultations related to cardiovascular drugs ADRs was 10.60 (95% CI. 10.46, 10.75) per 1000 patients. Patients aged 70-79 years had the highest occurrence of ADRs consultations. The most frequently drug classes implicated in the ADRs consultations were statins (n = 9,993 events, 27.09%), beta-blockers (n = 8,538 events, 23.15%), ACEIs/ARBs (n = 8,345 events, 22.62%), and aspirin (n = 6,482 events, 17.57%). Risk factors of ADRs consultations were previous history of cardiovascular diseases, e.g., myocardial infarction and stroke; advanced age, comorbidities; diabetes and dyslipidaemia; and polypharmacy. CONCLUSIONS: The burden of cardiovascular drug-related ADRs consultations in primary care was considerable. Statins, beta-blockers, ACEIs/ARBs, and aspirin were the most frequently implicated drug classes. Closer clinical monitoring should be performed for patients affected by the ADRs to mitigate the risk of suboptimal treatment outcomes.

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine). Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44-0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures.

We studied the association between non-osteoporotic fractures and future major osteoporotic fractures, using UK health records. Non-osteoporotic fractures were found to increase the risk of major osteoporotic fractures, although to a lesser extent than osteoporotic fractures. This highlights the importance of considering all previous fractures in assessing future fracture risk. PURPOSE: Previous studies demonstrated that osteoporotic fractures-minor and major-increase the risk for future major osteoporotic fractures; we test whether non-osteoporotic fractures are also associated with such increased risk. METHODS: The study is a retrospective cohort study using UK primary care electronic health records. Exposure groups were defined according to fracture location prior to the year 2011 (index date): major, minor, and non-osteoporotic. The outcome of incident major osteoporotic fractures following the index date was compared between the exposure groups and the general population. RESULTS: The general study population included 1,951,388 patients. The exposure groups included 39,931 patients with a prior major osteoporotic fracture, 19,397 with a prior minor osteoporotic fracture, and 50,115 patients with a prior non-osteoporotic fracture. The standardized Incidence Rate Ratio for future major osteoporotic fractures was 2.73 (95% confidence interval: 2.64-2.82), 2.43 (2.32-2.54), and 1.83 (1.74-1.92), respectively. CONCLUSION: Non-osteoporotic fractures are significantly associated with increased risk for future major osteoporotic fractures relative to the general population, yet to a lesser extent compared to major and minor osteoporotic fractures.

BACKGROUND: To our knowledge, only one study has examined the association between glucose variability (GV) and mortality in the elderly population with diabetes. GV was assessed by HbA1c, and a J-shaped curve was observed in the relationship between HbA1c thresholds and mortality. No study of GV was conducted during the COVID-19 pandemic and its lockdown. This study aims to evaluate whether GV is an independent predictor of all-cause mortality in patients aged 75 years or older with and without COVID-19 who were followed during the first year of the COVID-19 pandemic and its lockdown measures. METHODS: This was a retrospective cohort study of 407,492 patients from the AGED-MADRID dataset aged 83.5 (SD 5.8) years; 63.2% were women, and 29.3% had diabetes. GV was measured by the coefficient of variation of fasting plasma glucose (CV-FPG) over 6 years of follow-up (2015-2020). The outcome measure was all-cause mortality in 2020. Four models of logistic regression were performed, from simple (age, sex) to fully adjusted, to assess the effect of CV-FPG on all-cause mortality. RESULTS: During follow-up, 34,925 patients died (14,999 women and 19,926 men), with an all-cause mortality rate of 822.3 per 10,000 person-years (95% confidence interval (CI), 813.7 to 822.3) (739 per 10,000; 95% CI 728.7 to 739.0 in women and 967.1 per 10,000; 95% CI 951.7 to 967.2 in men). The highest quartile of CV-FPG was significantly more common in the deceased group (40.1% vs. 23.6%; p < 0.001). In the fully adjusted model including dementia (Alzheimer's disease) and basal FPG, the odds ratio for mortality ranged from 1.88 to 2.06 in patients with T2DM and from 2.30 to 2.61 in patients with normoglycaemia, according to different sensitivity analyses. CONCLUSIONS: GV has clear implications for clinical practice, as its assessment as a risk prediction tool should be included in the routine follow-up of the elderly and in a comprehensive geriatric assessment. Electronic health records can incorporate tools that allow its calculation, and with this information, clinicians will have a broader view of the medium- and long-term prognosis of their patients.

BACKGROUND: A history of anxiety is more common in people with Parkinson's disease (PD). The prospective risk of PD in those newly presenting with anxiety and factors that increase the risk of PD in patients with anxiety have not been investigated. AIM: To investigate the incidence of PD in people with anxiety aged ≥50 years and clinical features associated with later diagnosis of PD in people with anxiety. DESIGN AND SETTING: A retrospective cohort study using UK primary care data between 2008 and 2018, assessing patients with new-onset anxiety aged ≥50 years. METHOD: Weibull survival regression models were fitted and hazard ratios (HRs) for modelling time-to-PD was estimated in those with and without anxiety, and when determining the risk of developing PD in those with anxiety. Results were adjusted for sociodemographic and lifestyle factors, and relevant physical and mental health conditions. RESULTS: The risk of PD increased two-fold compared with the non-anxiety group after adjustment for age, sex, social deprivation, lifestyle factors, severe mental illness, head trauma, and dementia (HR 2.1, 95% confidence interval = 1.9 to 2.4). In those with anxiety, the presence of depression, hypotension, tremor, rigidity, balance impairment, constipation, sleep disturbance, fatigue, and cognitive impairment were associated with an increased risk of developing PD. CONCLUSION: The risk of developing PD was at least doubled in people with anxiety compared with those without. The clinical features of those who developed PD can help identify patients presenting with anxiety who are in the prodromal phase of PD.

The prevention of thromboembolism in atrial fibrillation (AF) is typically restricted to patients with specific risk factors and ignores outcomes such as vascular dementia. This population-based cohort study used electronic healthcare records from 5,199,994 primary care patients (UK; 2005-2020). A total of 290,525 (5.6%) had a diagnosis of AF and were aged 40-75 years, of which 36,340 had no history of stroke, a low perceived risk of stroke based on clinical risk factors and no oral anticoagulant prescription. Matching was performed for age, sex and region to 117,298 controls without AF. During 5 years median follow-up (831,005 person-years), incident stroke occurred in 3.8% with AF versus 1.5% control (adjusted hazard ratio (HR) 2.06, 95% confidence interval (CI) 1.91-2.21; P < 0.001), arterial thromboembolism 0.3% versus 0.1% (HR 2.39, 95% CI 1.83-3.11; P < 0.001), and all-cause mortality 8.9% versus 5.0% (HR 1.44, 95% CI 1.38-1.50; P < 0.001). AF was associated with all-cause dementia (HR 1.17, 95% CI 1.04-1.32; P = 0.010), driven by vascular dementia (HR 1.68, 95% CI 1.33-2.12; P < 0.001) rather than Alzheimer's disease (HR 0.85, 95% CI 0.70-1.03; P = 0.09). Death and thromboembolic outcomes, including vascular dementia, are substantially increased in patients with AF despite a lack of conventional stroke risk factors.

Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.