The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Classification of patients with osteoarthritis through clusters of comorbidities using 633 330 individuals from Spain.

OBJECTIVES: To explore clustering of comorbidities among patients with a new diagnosis of OA and estimate the 10-year mortality risk for each identified cluster. METHODS: This is a population-based cohort study of individuals with first incident diagnosis of OA of the hip, knee, ankle/foot, wrist/hand or 'unspecified' site between 2006 and 2020, using SIDIAP (a primary care database representative of Catalonia, Spain). At the time of OA diagnosis, conditions associated with OA in the literature that were found in ≥1% of the individuals (n = 35) were fitted into two cluster algorithms, k-means and latent class analysis. Models were assessed using a range of internal and external evaluation procedures. Mortality risk of the obtained clusters was assessed by survival analysis using Cox proportional hazards. RESULTS: We identified 633 330 patients with a diagnosis of OA. Our proposed best solution used latent class analysis to identify four clusters: 'low-morbidity' (relatively low number of comorbidities), 'back/neck pain plus mental health', 'metabolic syndrome' and 'multimorbidity' (higher prevalence of all studied comorbidities). Compared with the 'low-morbidity' cluster, the 'multimorbidity' cluster had the highest risk of 10-year mortality (adjusted hazard ratio [HR]: 2.19 [95% CI: 2.15, 2.23]), followed by the 'metabolic syndrome' cluster (adjusted HR: 1.24 [95% CI: 1.22, 1.27]) and the 'back/neck pain plus mental health' cluster (adjusted HR: 1.12 [95% CI: 1.09, 1.15]). CONCLUSION: Patients with a new diagnosis of OA can be clustered into groups based on their comorbidity profile, with significant differences in 10-year mortality risk. Further research is required to understand the interplay between OA and particular comorbidity groups, and the clinical significance of such results.

Drug utilization analysis of osteoporosis medications in seven European electronic health databases.

We studied the characteristics of patients prescribed osteoporosis medication and patterns of use in European databases. Patients were mostly female, older, had hypertension. There was suboptimal persistence particularly for oral medications. Our findings would be useful to healthcare providers to focus their resources on improving persistence to specific osteoporosis treatments. PURPOSE: To characterise the patients prescribed osteoporosis therapy and describe the drug utilization patterns. METHODS: We investigated the treatment patterns of bisphosphonates, denosumab, teriparatide, and selective estrogen receptor modulators (SERMs) in seven European databases in the United Kingdom, Italy, the Netherlands, Denmark, Spain, and Germany. In this cohort study, we included adults aged ≥ 18 years, with ≥ 1 year of registration in the respective databases, who were new users of the osteoporosis medications. The study period was between 01 January 2018 to 31 January 2022. RESULTS: Overall, patients were most commonly initiated on alendronate. Persistence decreased over time across all medications and databases, ranging from 52-73% at 6 months to 29-53% at 12 months for alendronate. For other oral bisphosphonates, the proportion of persistent users was 50-66% at 6 months and decreased to 30-44% at 12 months. For SERMs, the proportion of persistent users at 6 months was 40-73% and decreased to 25-59% at 12 months. For parenteral treatment groups, the proportions of persistence with denosumab were 50-85% (6 month), 30-63% (12 month) and with teriparatide 40-75% (6 month) decreasing to 21-54% (12 month). Switching occurred most frequently in the alendronate group (2.8-5.8%) and in the teriparatide group (7.1-14%). Switching typically occurred in the first 6 months and decreased over time. Patients in the alendronate group most often switched to other oral or intravenous bisphosphonates and denosumab. CONCLUSION: Our results show suboptimal persistence to medications that varied across different databases and treatment switching was relatively rare.

Risk of adverse events following the initiation of antihypertensives in older people with complex health needs: a self-controlled case series in the United Kingdom.

BACKGROUND: We assessed the risk of adverse events-severe acute kidney injury (AKI), falls and fractures-associated with use of antihypertensives in older patients with complex health needs (CHN). SETTING: UK primary care linked to inpatient and mortality records. METHODS: The source population comprised patients aged >65, with ≥1 year of registration and unexposed to antihypertensives in the year before study start. We identified three cohorts of patients with CHN, namely, unplanned hospitalisations, frailty (electronic frailty index deficit count ≥3) and polypharmacy (prescription of ≥10 medicines). Patients in any of these cohorts were included in the CHN cohort. We conducted self-controlled case series for each cohort and outcome (AKI, falls, fractures). Incidence rate ratios (IRRs) were estimated by dividing event rates (i) during overall antihypertensive exposed patient-time over unexposed patient-time; and (ii) in the first 30 days after treatment initiation over unexposed patient-time. RESULTS: Among 42,483 patients in the CHN cohort, 7,240, 5,164 and 450 individuals had falls, fractures or AKI, respectively. We observed an increased risk for AKI associated with exposure to antihypertensives across all cohorts (CHN: IRR 2.36 [95% CI: 1.68-3.31]). In the 30 days post-antihypertensive treatment initiation, a 35-50% increased risk for falls was found across all cohorts and increased fracture risk in the frailty cohort (IRR 1.38 [1.03-1.84]). No increased risk for falls/fractures was associated with continuation of antihypertensive treatment or overall use. CONCLUSION: Treatment with antihypertensives in older patients was associated with increased risk of AKI and transiently elevated risk of falls in the 30 days after starting antihypertensive therapy.

Characterising complex health needs and the use of preventive therapies in the older population: a population-based cohort analysis of UK primary care and hospital linked data.

BACKGROUND: While several definitions exist for multimorbidity, frailty or polypharmacy, it is yet unclear to what extent single healthcare markers capture the complexity of health-related needs in older people in the community. We aimed to identify and characterise older people with complex health needs based on healthcare resource use (unplanned hospitalisations or polypharmacy) or frailty using large population-based linked records. METHODS: In this cohort study, data was extracted from UK primary care records (CPRD GOLD), with linked Hospital Episode Statistics inpatient data. People aged > 65 on 1st January 2010, registered in CPRD for ≥ 1 year were included. We identified complex health needs as the top quintile of unplanned hospitalisations, number of prescribed medicines, and electronic frailty index. We characterised all three cohorts, and quantified point-prevalence and incidence rates of preventive medicines use. RESULTS: Overall, 90,597, 110,225 and 116,076 individuals were included in the hospitalisation, frailty, and polypharmacy cohorts respectively; 28,259 (5.9%) were in all three cohorts, while 277,332 (58.3%) were not in any (background population). Frailty and polypharmacy cohorts had the highest bi-directional overlap. Most comorbidities such as diabetes and chronic kidney disease were more common in the frailty and polypharmacy cohorts compared to the hospitalisation cohort. Generally, prevalence of preventive medicines use was highest in the polypharmacy cohort compared to the other two cohorts: For instance, one-year point-prevalence of statins was 64.2% in the polypharmacy cohort vs. 60.5% in the frailty cohort. CONCLUSIONS: Three distinct groups of older people with complex health needs were identified. Compared to the hospitalisation cohort, frailty and polypharmacy cohorts had more comorbidities and higher preventive therapies use. Research is needed into the benefit-risk of different definitions of complex health needs and use of preventive therapies in the older population.

Estimating the population health burden of musculoskeletal conditions using primary care electronic health records.

OBJECTIVES: Better indicators from affordable, sustainable data sources are needed to monitor population burden of musculoskeletal conditions. We propose five indicators of musculoskeletal health and assessed if routinely available primary care electronic health records (EHR) can estimate population levels in musculoskeletal consulters. METHODS: We collected validated patient-reported measures of pain experience, function and health status through a local survey of adults (≥35 years) presenting to English general practices over 12 months for low back pain, shoulder pain, osteoarthritis and other regional musculoskeletal disorders. Using EHR data we derived and validated models for estimating population levels of five self-reported indicators: prevalence of high impact chronic pain, overall musculoskeletal health (based on Musculoskeletal Health Questionnaire), quality of life (based on EuroQoL health utility measure), and prevalence of moderate-to-severe low back pain and moderate-to-severe shoulder pain. We applied models to a national EHR database (Clinical Practice Research Datalink) to obtain national estimates of each indicator for three successive years. RESULTS: The optimal models included recorded demographics, deprivation, consultation frequency, analgesic and antidepressant prescriptions, and multimorbidity. Applying models to national EHR, we estimated that 31.9% of adults (≥35 years) presenting with non-inflammatory musculoskeletal disorders in England in 2016/17 experienced high impact chronic pain. Estimated population health levels were worse in women, older aged and those in the most deprived neighbourhoods, and changed little over 3 years. CONCLUSION: National and subnational estimates for a range of subjective indicators of non-inflammatory musculoskeletal health conditions can be obtained using information from routine electronic health records.

What influences patients' opinion of remission and low disease activity in psoriatic arthritis? Principal component analysis of an international study.

OBJECTIVE: In PsA, the treatment objective is remission or low disease activity (LDA), but patients' perception of remission is poorly studied. This analysis aimed to identify factors associated with patient-defined remission. METHODS: This analysis uses ReFlaP data, an international PsA study, with remission defined as 'At this time, is your psoriatic arthritis in remission, if this means: you feel your disease is as good as gone?'. Variables associated with, first, patient-defined remission and, second, LDA were identified using multivariable logistic regression and principal component analysis (PCA) to explore correlated variables. RESULTS: Of 424 patients (50.2% male, mean age 52 years) with established disease, 94 (22.2%) reported themselves as being in remission and 191 (45.0%) as LDA alone. In multivariable analysis pain, psoriasis, impact of disease, physician opinion of symptoms from joint damage and Groll comorbidity index were independent predictors of remission. For LDA, results were similar. Using PCA, variance explained was 74% by five components for men and 80% by six components for women. The key component from PCA for remission was, for both sex, disease impact (Psoriatic Arthritis Impact of Disease, pain and HAQ) explaining 22.2-27.5% of variance. Other factors included musculoskeletal disease activity, chronicity/joint damage, psoriasis, enthesitis and CRP. For LDA, similar factors were identified but the variance explained was lower (64-68%). CONCLUSION: Many factors impact on patients' opinion of remission, dominated by disease impact. Disease activity in multiple domains, chronicity/age, comorbidities and symptoms due to other conditions contribute to a robust model highlighting that patient-defined remission is multifaceted. TRIALS REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov, NCT03119805.

Pulmonary embolus in patients with COVID-19: an Australian perspective.

Pulmonary embolus (PE) is a known complication of coronavirus disease 2019 (COVID-19). The diagnosis of PE in our hospitalised patients with COVID-19 correlated with more severe disease and occurred despite the use of routine thromboprophylaxis. Higher D-dimers were seen on admission in patients who developed PE and rose at PE diagnosis, suggesting a role for D-dimer in risk stratification.

Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34SCKO ) mice show severe hypomyelination in peripheral nerves. Vps34-/- Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34-/- Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34-/- Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic through endosomes. In Vps34SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34SCKO mice.

Multicenter Clinical Evaluation of BacT/Alert Virtuo Blood Culture System.

BacT/Alert Virtuo is an advanced, automated blood culture system incorporating improved automation and an enhanced detection algorithm to shorten time to detection. A multicenter study of the investigational Virtuo system (bioMérieux, Inc., Durham, NC) compared to BacT/Alert 3D (BTA3D) for detection of bacteremia/fungemia in four bottle types, SA and FA Plus (aerobic) and SN and FN Plus (anaerobic), was performed in a clinical setting with patient samples in a matched system design clinical trial. Blood was added to paired aerobic or anaerobic bottles, with the volume in each bottle in each pair required to be ≤10 ml and with the volumes required to be within 30% of each other. Of 5,709 bottle sets (52.5% aerobic pairs and 47.5% anaerobic pairs), 430 (7.5%) were positive for bacterial or fungal growth, with 342 (6.0%) clinically significant and 83 (1.5%) contaminated. A total of 3,539 sets (62.0%) were volume compliant, with 203 sets (5.7%) clinically significant. The positivity rates for volume-compliant bottle pairs determined by the two systems were comparable, with 68.7% of clinically significant isolates detected by both instruments, 15.7% by Virtuo only, and 15.7% by BTA3D only. Virtuo detected microbial growth nearly 2 h sooner overall than BTA3D (mean, 15.9 h versus 17.7 h). Shorter time to detection by Virtuo was related to organism group, with the time to detection being significantly shorter for enteric Gram-negative bacilli and enterococci (means, 3.6 h and 2.3 h shorter, respectively). This large clinical study demonstrated that the Virtuo blood culture system produced results comparable to those seen with the long-established BTA3D system, with significantly shorter time to detection.

Longitudinal trajectories of frailty are associated with short-term mortality in older people: a joint latent class models analysis using 2 UK primary care databases.

OBJECTIVES: Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of deterioration. The objective of this study was to evaluate the application of joint latent class model in identifying trajectories of frailty progression over time and their group-specific risk of death in older people. STUDY DESIGN AND SETTING: The primary care records of UK patients, aged over 65 as of January 1, 2010, included in the Clinical Practice Research Datalink: GOLD and AURUM databases, were analyzed and linked to mortality data. The electronic frailty index (eFI) scores were calculated at baseline and annually in subsequent years (2010-2013). Joint latent class model was used to divide the population into clusters with different trajectories and associated mortality hazard ratios. The model was built in GOLD and validated in AURUM. RESULTS: Five trajectory clusters were identified and characterized based on baseline and speed of progression: low-slow, low-moderate, low-rapid, high-slow, and high-rapid. The high-rapid cluster had the highest average starting eFI score; 7.9, while the low-rapid cluster had the steepest rate of eFI progression; 1.7. Taking the low-slow cluster as reference, low-rapid and high-rapid had the highest hazard ratios: 3.73 (95% CI 3.71, 3.76) and 3.63 (3.57-3.69), respectively. Good validation was found in the AURUM population. CONCLUSION: Our research found that there are vulnerable subgroups of the older population who are currently frail or have rapid frailty progression. Such groups may be targeted for greater healthcare monitoring.

Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior.

The nucleus accumbens (Acb) contains subpopulations of neurons defined by their receptor content and potential involvement in sensorimotor gating and other behaviors that are dysfunctional in schizophrenia. In Acb neurons, the NMDA NR1 (NR1) subunit is coexpressed not only with the dopamine D1 receptor (D1R), but also with the µ-opioid receptor (µ-OR), which mediates certain behaviors that are adversely impacted by schizophrenia. The NMDA-NR1 subunit has been suggested to play a role in the D1R trafficking and behavioral dysfunctions resulting from systemic administration of apomorphine, a D1R and dopamine D2 receptor agonist that impacts prepulse inhibition to auditory-evoked startle (AS). Together, this evidence suggests that the NMDA receptor may regulate D1R trafficking in Acb neurons, including those expressing µ-OR, in animals exposed to auditory startle and apomorphine. We tested this hypothesis by combining spatial-temporal gene deletion technology, dual labeling immunocytochemistry, and behavioral analysis. Deleting NR1 in Acb neurons prevented the increase in the dendritic density of plasma membrane D1Rs in single D1R and dual (D1R and µ-OR) labeled dendrites in the Acb in response to apomorphine and AS. Deleting NR1 also attenuated the decrease in AS induced by apomorphine. In the absence of apomorphine and startle, deletion of Acb NR1 diminished social interaction, without affecting novel object recognition, or open field activity. These results suggest that NR1 expression in the Acb is essential for apomorphine-induced D1R surface trafficking, as well as auditory startle and social behaviors that are impaired in multiple psychiatric disorders.

Weight Gain in People with HIV: The Role of Demographics, Antiretroviral Therapy, and Lifestyle Factors on Weight.

We explored factors associated with weight gain among people with HIV (PWH) on antiretroviral therapy (ART) at The Ohio State University Wexner Medical Center (OSUWMC). This was a retrospective cohort study of adult PWH on ART for ≥3 months. Patients with CD4+ T cell count <200 cells/mm3, viral load >200 copies/mL, history of malignancy, or pregnancy were excluded. Eight hundred seventy patients met criteria. The primary outcome was percent weight change over the follow-up period (Δ = relative effects). The secondary outcome was the odds of ≥5 kg weight gain over the study period. The effects of concurrent medications, medical comorbidities, ART combinations, and lifestyle behaviors on these outcomes were modeled using mixed effects regression analyses. Over a mean follow-up of 1.86 years, the study population gained a mean percent weight of 2.12% ± 0.21% (p < .001) with the odds of ≥5 kg weight gain of 0.293 (p < .001). Males gained an average of 1.88% ± 0.22% over follow up, while females gained an average of 3.37% ± 0.51% over follow up (p = .008 for the difference). In regression models, combination therapy with tenofovir alafenamide (TAF) and integrase strand transfer inhibitor (INSTI) containing regimens was associated with an increase in weight over the study period (Δ = 2.14% ± 0.45%, p < .001 and Δ = 1.09% ± 0.39%, p = .005, respectively). Increasing age was significantly associated with a decrease in percent weight change over the study period (Δ = -0.68% ± 0.18% per year, p < .001). Self-reported improvement in diet was associated with a decrease in weight change (Δ = -1.99% ± 0.47%, p ≤ .001) and reduced odds of ≥5 kg weight gain (odds ratio = 0.70, 95% confidence interval = 0.50-0.97, p = .03). Factors associated with weight gain include therapy with TAF and INSTI. Diet may play an influential role in attenuating weight gain in PWH.

Oral Bisphosphonates Are Associated With Increased Risk of Severe Acute Kidney Injury in Elderly Patients With Complex Health Needs: A Self-Controlled Case Series in the United Kingdom.

Although oral bisphosphonates (BP) are commonly used, there is conflicting evidence for their safety in the elderly. Safety concerns might trump BP use in older patients with complex health needs. Our study evaluated the safety of BP, focusing on severe acute kidney injury (AKI), gastrointestinal ulcer (GI ulcer), osteonecrosis of the jaw (ONJ), and femur fractures. We used UK primary care data (Clinical Practice Research Datalink [CPRD GOLD]), linked to hospital (Hospital Episode Statistics [HES] inpatient) and ONS mortality data. We included all patients aged >65 with complex health needs and no BP use in the year before study start (January 1, 2010). Complex health needs were defined in three cohorts: an electronic frailty index score ≥3 (frailty cohort), one or more unplanned hospitalization/s (hospitalization cohort); and prescription of ≥10 different medicines in 2009 (polypharmacy cohort). Incidence rates were calculated for all outcomes. Subsequently, all individuals who experienced AKI or GI ulcer anytime during follow-up were included for Self-Controlled Case Series (SCCS) analyses. Incidence rate ratios (IRRs) were estimated separately for AKI and GI ulcer, comparing event rates between BP-exposed and unexposed time windows. No SCCS were conducted for ONJ and femur fractures. We identified 94,364 individuals in the frailty cohort, as well as 78,184 and 95,621 persons in the hospitalization and polypharmacy cohorts. Of those, 3023, 1950, and 2992 individuals experienced AKI and 1403, 1019, and 1453 had GI ulcer/s during follow-up, respectively. Age-adjusted SCCS models found evidence of increased risk of AKI associated with BP use (frailty cohort: IRR 1.65; 95% confidence interval [CI], 1.25-2.19), but no association with GI ulcers (frailty cohort: IRR 1.24; 95% CI, 0.86-1.78). Similar results were obtained for the hospitalization and polypharmacy cohorts. Our study found a 50% to 65% increased risk of AKI associated with BP use in elderly patients with complex health needs. Future studies should further investigate the risk-benefit of BP use in these patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Comorbidities in osteoarthritis (ComOA): a combined cross-sectional, case-control and cohort study using large electronic health records in four European countries.

INTRODUCTION: Osteoarthritis (OA) is one of the leading chronic conditions in the older population. People with OA are more likely to have one or more other chronic conditions than those without. However, the temporal associations, clusters of the comorbidities, role of analgesics and the causality and variation between populations are yet to be investigated. This paper describes the protocol of a multinational study in four European countries (UK, Netherlands, Sweden and Spain) exploring comorbidities in people with OA. METHODS AND ANALYSIS: This multinational study will investigate (1) the temporal associations of 61 identified comorbidities with OA, (2) the clusters and trajectories of comorbidities in people with OA, (3) the role of analgesics on incidence of comorbidities in people with OA, (4) the potential biomarkers and causality between OA and the comorbidities, and (5) variations between countries.A combined case-control and cohort study will be conducted to find the temporal association of OA with the comorbidities using the national or regional health databases. Latent class analysis will be performed to identify the clusters at baseline and joint latent class analysis will be used to examine trajectories during the follow-up. A cohort study will be undertaken to evaluate the role of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and paracetamol on the incidence of comorbidities. Mendelian randomisation will be performed to investigate the potential biomarkers for causality between OA and the comorbidities using the UK Biobank and the Rotterdam Study databases. Finally, a meta-analyses will be used to examine the variations and pool the results from different countries. ETHICS AND DISSEMINATION: Research ethics was obtained according to each database requirement. Results will be disseminated through the FOREUM website, scientific meetings, publications and in partnership with patient organisations.

Acetylcholine α7 nicotinic and dopamine D2 receptors are targeted to many of the same postsynaptic dendrites and astrocytes in the rodent prefrontal cortex.

The alpha-7 nicotinic acetylcholine receptor (α7nAChR) and the dopamine D(2) receptor (D(2) R) are both implicated in attentional processes and cognition, mediated in part through the prefrontal cortex (PFC). We examined the dual electron microscopic immunolabeling of α7nAChR and either D(2) R or the vesicular acetylcholine transporter (VAChT) in rodent PFC to assess convergent functional activation sites. Immunoreactivity (ir) for α7nAChR and/or D(2) R was seen in the same as well as separate neuronal and glial profiles. At least half of the dually labeled profiles were somata and dendrites, while most labeled axon terminals expressed only D(2) R-ir. The D(2) R-labeled terminals were without synaptic specializations or formed inhibitory or excitatory-type synapses with somatodendritic profiles, some of which expressed the α7nAChR and/or D(2) R. Astrocytic glial processes comprised the majority of nonsomatodendritic α7nAChR or α7nAChR and D(2) R-labeled profiles. Glial processes containing α7nAChR-ir were frequently located near VAChT-labeled terminals and also showed perisynaptic and perivascular associations. We conclude that in rodent PFC α7nACh and D(2) R activation can dually modulate (1) postsynaptic dendritic responses within the same or separate but synaptically linked neurons in which the D(2) R has the predominately presynaptic distribution, and (2) astrocytic signaling that may be crucial for synaptic transmission and functional hyperemia.

Health Resource and Cost Savings Achieved in a Multidisciplinary Lung Cancer Clinic.

Background: Lung cancer (LC) care is resource and cost intensive. We launched a Multidisciplinary LC Clinic (MDC), where patients with a new LC diagnosis received concurrent oncology consultation, resulting in improved time to LC assessment and treatment. Here, we evaluate the impact of MDC on health resource utilization, patient and caregiver costs, and secondary patient benefits. Methods: We retrospectively analyzed patients in a rapid assessment clinic with a new LC diagnosis pre-MDC (September 2016-February 2017) and post-MDC implementation (February 2017-December 2018). Data are reported as means; unpaired t-tests and ANOVA were used to assess for significance. We also conducted a cost analysis. Resource utilization, out-of-pocket costs, procedure-related costs, and indirect costs were evaluated from the societal perspective and presented in 2019 Canadian dollars (CAD); multi-way worst/best case and threshold sensitivity analyses were conducted. Results: We reviewed 428 patients (78 traditional model, 350 MDC). Patients in the MDC model required significantly fewer oncology visits from LC diagnosis to first LC treatment (1.62 vs. 2.68, p < 0.001), which was significant for patients with stage 1, 3, and 4 disease. Compared with the traditional model, there was no change in mean biopsies/patient (1.32 traditional vs. 1.17 MDC, p = 0.18) or staging investigations/patient (2.24 traditional vs. 2.02 MDC, p = 0.20). Post-MDC, there was an increase in invasive mediastinal staging for patients with stage 2/3 LC (15.0% vs. 60.0%, p < 0.001). Over 22 months, MDC resulted in savings of CAD 48,389 including CAD 24,167 CAD in direct patient out-of-pocket expenses. For the threshold analyses, MDC was estimated to cost CAD 25,708 per quality-adjusted life year (QALY), considered to be below current willingness to pay thresholds (at CAD 80,000 per QALY). MDC also facilitated oncology assessment for 29 non-LC patients. Conclusions: An MDC led to a reduction in patient visits and direct patient and caregiver costs.

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink.

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m2 between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34-5.75) and 3.78 (95% CI, 1.42-10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08-2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.

BACKGROUND: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects. OBJECTIVES: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time. DESIGN: This was a new-user cohort study design with propensity score matching. SETTING AND DATA SOURCES: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4. PARTICIPANTS: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4. INTERVENTIONS/EXPOSURE: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure. MAIN OUTCOME MEASURES: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change. RESULTS: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users. LIMITATIONS: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively. CONCLUSIONS: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness. FUTURE WORK: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data. STUDY REGISTRATION: This study is registered as EUPAS10029. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.

RATIONALE AND AIMS: Bisphosphonates are used to prevent fractures in people with fragile bones. People with chronic kidney disease have a high risk of fracturing, but the safety and effectiveness of bisphosphonates in severe chronic kidney disease is unclear. The aim of this study was to assess the benefits (e.g. bone strength improvement and fracture prevention) and the risks of unwanted effects associated with bisphosphonates for people with moderate to severe chronic kidney disease. METHODS: Anonymised primary and secondary care electronic medical records data from the UK NHS were used, as well as a Danish equivalent that included bone density scans. Anyone in these databases with a measure of reduced kidney function that suggested moderate to severe chronic kidney disease was eligible, which was > 220,000 people from the UK. Over 20,000 of them used bisphosphonates. Bisphosphonate users were matched to non-users with similar age, sex and other characteristics. RESULTS: Bisphosphonate users had a 12% higher risk of their chronic kidney disease getting worse than non-users. Their risks of other side effects, such as acute kidney injuries and gastrointestinal problems, did not change. Bisphosphonate users had a 25% higher risk of fractures than non-users in the UK database, probably because the matching methods did not create similar-enough groups of users and non-users. However, it was found that bisphosphonate improved bone density in the Danish database. Bone density is a proxy for bone strength, so better bone density should mean fewer fractures. CONCLUSIONS: These results suggest that bisphosphonate therapy may make moderate to severe chronic kidney disease worse. More studies are needed on how bisphosphonates affect milder chronic kidney disease. Bisphosphonates were associated with better bone strength, but it could not be demonstrated that they reduced fracture risk. More data are required, probably from a placebo-controlled trial, to determine whether or not bisphosphonates prevent fractures in people with moderate to severe chronic kidney disease and whether or not this is worth the risk of their chronic kidney disease worsening.