Vascular Access Outcomes in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading hereditary cause of end-stage kidney disease (ESKD), often utilising hemodialysis as a form of kidney replacement therapy. Patients with ADPKD may also present with extrarenal manifestations, including arterial aneurysms. The gold standard for hemodialysis access is an arteriovenous vascular access (VA), such fistulas (AVFs) or grafts (AVGs). However, limitations, such as low VA flow and inadequate AVF outward remodelling, impact VA utilization. This study aimed to explore whether ADPKD impacts patency rates of AVFs/AVGs in comparison to other underlying ESKD causes. METHODS: We conducted a retrospective cohort study using data from the Swedish Renal Registry from 2011 to 2020, with follow-up until 2022. We included 496 ADPKD patients and 4321 propensity-score matched controls. VA patency rates of ADPKD patients were compared to those of non-ADPKD patients using Kaplan-Meier survival curves and the Mantel-Cox log-rank test. Interventions to maintain or restore patency were also analysed. RESULTS: Patients with ADPKD constituted 8.0% of all patients, with a higher proportion in the pre-ESKD phase during VA creation (51.6% vs. 40.6%). No significant differences were observed in primary, post-cannulation primary, secondary, or functional patency between ADPKD and non-ADPKD patients. However, more VAs were ligated in ADPKD patients (10.5% vs. 7.7%, p=0.03), and they underwent more first interventions to re-establish flow (49.4% vs. 41.9%, p=0.02). CONCLUSIONS: These findings suggest that AVF/AVG patency remains comparable in ESKD patients with or without ADPKD, and vascular access monitoring and treatment strategies for ADPKD patients should align with those for individuals with other ESKD causes.

The prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma.

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment. METHODS: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm. RESULTS: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma. CONCLUSIONS: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.

Are there lost opportunities in chronic kidney disease? A region-wide cohort study.

OBJECTIVES: Identify the windows of opportunity for the diagnosis of chronic kidney disease (CKD) and the prevention of its adverse outcomes and quantify the potential population gains of such prevention. DESIGN AND SETTING: Observational, population-wide study of residents in the Stockholm and Skåne regions of Sweden between 1 January 2015 and 31 December 2020. PARTICIPANTS: All patients who did not yet have a diagnosis of CKD in healthcare but had CKD according to laboratory measurements of CKD biomarkers available in electronic health records. OUTCOME MEASURES: We assessed the proportions of the patient population that received a subsequent diagnosis of CKD in healthcare, that used guideline-directed pharmacological therapy (statins, renin-angiotensin aldosterone system inhibitors (RAASi) and/or sodium-glucose cotransporter-2 inhibitors (SGLT2i)) and that experienced adverse outcomes (all-cause mortality, cardiovascular mortality or major adverse cardiovascular events (MACE)). The potential to prevent adverse outcomes in CKD was assessed using simulations of guideline-directed pharmacological therapy in untreated subsets of the study population. RESULTS: We identified 99 382 patients with undiagnosed CKD during the study period. Only 33% of those received a subsequent diagnosis of CKD in healthcare after 5 years. The proportion that used statins or RAASi was of similar size to the proportion that didn't, regardless of how advanced their CKD was. The use of SGLT2i was negligible. In simulations of optimal treatment, 22% of the 21 870 deaths, 27% of the 14 310 cardiovascular deaths and 39% of the 22 224 MACE could have been avoided if every patient who did not use an indicated medication for their laboratory-confirmed CKD was treated with guideline-directed pharmacological therapy for CKD. CONCLUSIONS: While we noted underdiagnosis and undertreatment of CKD in this large contemporary population, we also identified a substantial realisable potential to improve CKD outcomes and reduce its burden by treating patients early with guideline-directed pharmacological therapy.

Heart failure outcomes by left ventricular ejection fraction in a contemporary region-wide patient cohort.

AIMS: This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF. METHODS AND RESULTS: Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population-based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90 days of their first HF diagnosis, and patients with prevalent HF within 5 years prior to the index date. The 13 375 patients with prevalent HF (39.2% women, mean age 73.9 years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3 years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system. CONCLUSIONS: This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes.

A retrospective nationwide analysis of evolocumab use in Sweden and its effect on low-density lipoprotein cholesterol levels.

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment. Methods: Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively. Results: Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively. Conclusions: The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.

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.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D.

PURPOSE: To evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism. METHODS: mRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine). RESULTS: DRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis. CONCLUSION: The results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.

Trends in renal function in Northern Sweden 1986-2014: data from the seven cross-sectional surveys within the Northern Sweden MONICA study.

OBJECTIVE: The prevalence of chronic kidney disease (CKD) is increasing globally, and CKD is closely related to cardiovascular disease (CVD). CKD and CVD share several risk factors (RF), such as diabetes, hypertension, obesity and smoking, and the prevalence of these RF has changed during the last decades, and we aimed to study the effect on renal function over time. DESIGN: Repeated cross-sectional population-based studies. SETTING: The two Northern counties (Norr- and Västerbotten) in Sweden. PARTICIPANTS: Within the MONitoring Trends and Determinants of CArdiovascular Disease (MONICA) study, seven surveys were performed between 1986 and 2014, including participants aged 25-64 years (n=10 185). INTERVENTIONS: None. MEASURES: Information on anthropometry, blood pressure and cardiovascular risk factors was collected. Creatinine and cystatin C were analysed in stored blood samples and the estimated glomerular filtration rate (eGFR) calculated using the creatinine-based Lund-Malmö revised and Chronic Kidney Disease Epidemiology Collaboration (eGFRcrea) equations as well as the cystatin C-based Caucasian, Asian, Paediatric and Adult cohort (CAPA) equation (eGFRcysC). Renal function over time was analysed using univariable and multivariable linear regression models. RESULTS: Renal function, both eGFRcrea and eGFRcysC, decreased over time (both p<0.001) and differed between counties and sexes. In a multivariable analysis, study year remained inversely associated with both eGFRcrea and eGFRcysC (both p<0.001) after adjustment for classical cardiovascular RF. CONCLUSION: Renal function has deteriorated in Northern Sweden between 1986 and 2014.

Health care registers can be instrumental for endpoint capture in clinical diabetes trials: example of microvascular complications in Swedish patients with type 2 diabetes.

AIMS: SMARTEST is a register-based randomized clinical trial (RRCT) that compares dapagliflozin to metformin in early-stage type 2 diabetes. The primary outcome includes progression of microvascular complications based on data from the Swedish National Diabetes Register (NDR). In this sub-study, the aim was to validate microvascular complication variables in the NDR against electronic health records (EHRs). METHODS: Data were extracted from EHRs of 276 SMARTEST participants with a median observation period of 3 years in the Uppsala, Örebro and Sörmland counties and compared with NDR data. Agreement was determined for all corresponding data entries as well as for progression of microvascular complications after randomization. RESULTS: The agreement for all corresponding data entries was 98.9% (Intraclass Correlation Coefficient 0.999) for creatinine and eGFR, 95.1% for albuminuria, 91.6% for foot-at-risk and 98.2% for retinopathy status (Kappa 0.67-0.91). The agreement for progression of microvascular complications was 98.0% for CKD stage, 98.9% for albuminuria grade, 96.3% for foot-at-risk grade and 99.6% for retinopathy grade progression (Gwet's AC1 0.96-1.00). CONCLUSION: Microvascular complication variables in the NDR show good agreement with EHR data. The use of a well-established national health care registry, exemplified by the NDR, for endpoint collection in RRCTs such as SMARTEST is supported by this study.

The use of models and modelling in design projects in three different technology classrooms.

In this study, we aim to investigate activities using models in a design project in three technology classrooms. Activities that use models are important for students' development of knowledge and skills connected to the design process. Nevertheless, few empirical studies have thus far examined how models and modelling are used in a classroom environment when students and teachers are involved in a design project. In order to meet our aim, we video-recorded eight lessons from three different technology classrooms (students aged 13-15), where the students were involved in different problem-solving activities using models and modelling. The three projects had different specifications, and the students' degrees of freedom thereby varied. The video recordings were analysed using a qualitative content analysis. The analysis resulted in seven activities being identified where the teachers and students talked about models and modelling in order to solve the problem. The results also revealed three different dimensions of models: material, structure and function. These dimensions are present in almost all activities that use models. In a project with a high degree of freedom, all three dimensions of models are present. On the contrary, in a project with a lower freedom, only one of the dimensions is present, resulting in a lower degree of complexity for the students. The study emphasizes that the presumptions and openness of a design project in technology education can provide different possibilities for students learning in relation to models and modelling.

A third dose SARS­CoV­2 BNT162b2 mRNA vaccine results in improved immune response in hemodialysis patients.

Background: The hemodialysis (HD) population has been a vulnerable group during the coronavirus disease 2019 (COVID-19) pandemic. Advanced chronic kidney disease with uremia is associated with weaker immune response to infections and an attenuated response to vaccines. The aim of this study was to study the humoral and cellular response to the second and third doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS­CoV­2) BNT162b2 mRNA vaccine in HD patients and to follow the response over time. Methods: The patients received their first two vaccine doses from 28 December 2020 within a 4-week interval and the third dose in September 2021 and were followed-up for humoral and cellular immune response at 1) 7-15 weeks and 2) 6-8 months after dose two (no t-cell reactivity measured), and 3) 3 weeks and 4) 3 months after dose three. Fifty patients were initially enrolled, and 40 patients were followed during the entire study. Levels of COVID-19 (SARS-CoV-2) IgG antibody against the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using Enzyme-Linked ImmunoSpot (ELISPOT) technology were evaluated. Results: IgG antibodies to anti-S were detected in 35 (88%) of the 40 patients 7-15 weeks after vaccine dose two, 31 (78%) were positive, and 4 (10%) borderline. The median anti-S titer was 606 Abbott Units/milliliter (AU/mL) (interquartile range [IQR] 134-1,712). Three months after the third dose, anti-S was detected in 38 (95%) of 40 patients (P < 0.01 compared to after dose two), and the median anti-S titer was 9,910 AU/mL (IQR 2,325-26,975). Cellular reactivity was detected in 22 (55%), 34 (85%), and 28 (71%) of the 40 patients, and the median T-cell response was 9.5 (IQR 3.5-80), 51.5 (14.8-132), and 19.5 (8.8-54.2) units, respectively, for 6-8 months after dose two, 3 weeks, and 3 months after dose three. Conclusions: Our data show that a third dose of SARS­CoV­2 BNT162b2 mRNA vaccine gives a robust and improved immunological response in HD patients, but a few patients did not develop any anti-S response during the entire study, indicating the importance to monitor the vaccine response since those who do not respond could now be given monoclonal antibodies if they contract a COVID-19 infection or in the future antivirals.

Effects of lipid-lowering treatment intensity and adherence on cardiovascular outcomes in patients with a recent myocardial infarction: a Swedish register-based study.

Background: Oral lipid-lowering treatment (LLT) is the standard of care for patients with cardiovascular disease (CVD). However, insufficient treatment intensity and poor adherence can lead to suboptimal treatment benefit, rendering patients at increased risk of CVD. Aims: The objective of this study was to evaluate trends in LLT intensity and adherence in Sweden over time, and their association with major adverse cardiovascular events (MACE) after recent myocardial infarction (MI), and also to assess the impact of transition from secondary to primary care on intensity and adherence. Methods and results: This retrospective observational cohort study used data from Swedish nationwide patient registers and included patients on LLT after an MI in the years 2010-2016 (n = 50,298; mean age, 68 years; 69% men). LLT intensity was evaluated over time (overall, for 2010-2013 and for 2014-2016) as the proportion of patients prescribed low-, moderate-, and high-intensity LLT. Adherence was assessed as the proportion of days covered. A combined measure of intensity and adherence was also considered. Differences in treatment patterns and MACE were assessed. Initiation of high-intensity LLT increased over the two time periods studied (2010-2013, 32%; 2014-2016, 91%). Adherence varied by LLT intensity and was highest in patients receiving high-intensity LLT (>80%), especially during the first time period. Little change in treatment intensity or the combined measure of intensity and adherence was observed after transition to primary care. There was a significant association between the combined measure of intensity and adherence and MACE reduction (hazard ratio [95% confidence interval] per 10% increase in the combined measure: 0.84 [0.82-0.86]; P < 0.01). Conclusion: The proportion of post-MI patients with high LLT intensity and adherence has increased in recent years, with little change after transfer from specialist to primary care. The combination of LLT intensity and adherence is important for preventing future cardiovascular events.

High Infiltration of CD68+/CD163- Macrophages Is an Adverse Prognostic Factor after Neoadjuvant Chemotherapy in Esophageal and Gastric Adenocarcinoma.

Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68+/CD163-, CD68+/CD163+, and MARCO+ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68+/CD163+ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68+/CD163+ TAMs was increased in PT post-NAC, while the density of MARCO+ TAMs was decreased. CD68+/CD163- TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68+/CD163- TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.

Clinical features and treatment response to differentiate idiopathic peritonitis from non-strangulating intestinal infarction of the pelvic flexure associated with Strongylus vulgaris infection in the horse.

BACKGROUND: Peritonitis in horses secondary to non-strangulating infarction (NSII) has a guarded prognosis, even after intestinal resection. In contrast, horses with idiopathic peritonitis respond well to medical treatment. Affected horses in both cases often show signs of both colic and systemic inflammation, but early diagnosis is crucial for optimal treatment and an accurate prognosis. One cause of NSII is thrombus formation secondary to Strongylus vulgaris larval migration. There has been a documented increase in S. vulgaris prevalence in Sweden since the implementation of selective anthelmintic treatment in 2007, which subsequently could result in a rise in NSII cases. In a retrospective clinical study, medical records from cases diagnosed with NSII of the pelvic flexure or idiopathic peritonitis from three equine referral hospitals in Sweden during 2017-2020 were reviewed. Information including demographic data, relevant medical history, and clinical- and laboratory parameters were obtained from patient records. To facilitate the differentiation between cases of idiopathic peritonitis and cases with confirmed NSII of the pelvic flexure, the aim of the study was to compare clinical and laboratory parameters, clinical progression and initial response to antimicrobial treatment. A secondary aim was to compare survival-rates. RESULTS: Horses with NSII (n = 20) were significantly more likely to present during the winter months with a poorer response to medical treatment within 48 h. Cases of idiopathic peritonitis (n = 107) had a 100% survival rate with medical treatment, although one case required surgical correction of a colon displacement. In comparison, all confirmed NSII cases were non-responsive to antimicrobial treatment, with a survival rate to discharge of 50% after colon resection. Specific rectal findings and peripheral blood neutropenia were strongly associated with NSII. CONCLUSIONS: In Sweden, idiopathic peritonitis cases still predominate over S. vulgaris associated NSII cases and have an excellent survival rate with antimicrobial treatment. However, horses presenting with septic peritonitis during the winter months with a palpable rectal mass and displaying fever and colic signs beyond 48 h of medical treatment are likely to suffer from NSII of the pelvic flexure and should be considered for abdominal surgery.

Real-World Effectiveness of Anti-Resorptive Treatment in Patients With Incident Fragility Fractures-The STORM Cohort-A Swedish Retrospective Observational Study.

Results from real-world evidence (RWE) from the largest healthcare region in Sweden show low uptake of antiresorptive (AR) treatment, but beneficial effect in those receiving treatment, especially for the composite outcome of hip fracture or death. For RWE studies, Sweden is unique, with virtually complete coverage of electronic medical records (EMRs) and both regional and national registries, in a universal publicly funded healthcare system. To our knowledge, there is no previous RWE study evaluating the efficacy of AR treatment compared to no AR treatment after fragility fracture, including data on parenteral treatments administered in hospital settings. The Stockholm Real World Management (STORM) study cohort was established in the healthcare region of Stockholm to retrospectively assess the effectiveness of AR treatment after first fragility fracture using the regional EMR system for both hospital and primary care. Between 2012 and 2018, we identified 69,577 fragility fracture episodes among 59,078 patients, men and women, 50 years and older. Of those, 21,141 patients met inclusion and exclusion criteria (eligible cohort). From these, the final matched study cohort comprised 9840 fragility fractures (cases receiving AR treatment [n = 1640] and controls not receiving AR treatment [n = 8200]). Propensity scores were estimated using logistic regression models with AR treatment as outcome and confounders as independent variables followed by analysis using Cox proportional hazard models. Real world evidence from Sweden's largest healthcare region, comprising a quarter of the Swedish population, show that only 10% of patients receive AR treatment within 1 year after a fragility fracture. Factors associated with not receiving treatment include having a diagnosis of cardiovascular disease. In those treated, AR have positive effects particularly on the composite of fracture and death (any fracture/death and hip fracture/death) in individuals matched for all major confounders. © 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).

Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women.

CONTEXT: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood. OBJECTIVE: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes. METHODS: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits. RESULTS: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage. CONCLUSION: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.

Cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab in patients with a history of myocardial infarction in Sweden.

AIMS: To assess the cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to standard-of-care lipid-lowering treatment [maximum tolerated dose (MTD) of statin and ezetimibe] in Swedish patients with a history of myocardial infarction (MI). METHODS AND RESULTS: Cost-effectiveness was evaluated using a Markov model based on Swedish observational data on cardiovascular event rates and efficacy from the FOURIER trial. Three risk profiles were considered: recent MI in the previous year; history of MI with a risk factor; and history of MI with a second event within 2 years. For each population, three minimum baseline low-density lipoprotein cholesterol (LDL-C) levels were considered: 2.5 mmol/L (≈100 mg/dL), based on the current reimbursement recommendation in Sweden; 1.8 mmol/L (≈70 mg/dL), based on 2016 ESC/EAS guidelines; and 1.4 mmol/L (≈55 mg/dL), or 1.0 mmol/L (≈40 mg/dL) for MI with a second event, based on 2019 ESC/EAS guidelines. Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab was associated with increased quality-adjusted life-years and costs vs. standard-of-care therapy. Incremental cost-effectiveness ratios (ICERs) were below SEK700 000 (∼€66 500), the generally accepted willingness-to-pay threshold in Sweden, for minimum LDL-C levels of 2.3 (recent MI), 1.7 (MI with a risk factor), and 1.7 mmol/L (MI with a second event). Sensitivity analyses demonstrated that base-case results were robust to changes in model parameters. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to MTD of statin and ezetimibe may be considered cost-effective at its list price for minimum LDL-C levels of 1.7-2.3 mmol/L, depending on risk profile, with ICERs below the accepted willingness-to-pay threshold in Sweden.

Estimation of kidney function in patients with primary neuromuscular diseases: is serum cystatin C a better marker of kidney function than creatinine?

BACKGROUND: Using serum creatinine leads to an overestimation of kidney function in patients with primary neuromuscular disorders, and reduced kidney function may remain undetected. Cystatin C (CysC) could provide a better estimation. AIM: To evaluate the precision, accuracy, and bias of two creatinine-, one cystatin C-based and one combined equation to estimate glomerular filtration rate (eGFR) in patients with primary neuromuscular disease. PATIENTS AND METHODS: Of the 418 patients initially identified at the out-patient clinic, data on kidney function was obtained for 145 adult patients (age 46 ± 14 years, BMI 26 ± 6 kg/m2) with primary neuromuscular disease. Kidney function was measured by iohexol clearance, and blood samples for serum creatinine and CysC were drawn simultaneously. Bias was defined as the mean difference between eGFR and measured iohexol clearance, and accuracy as the proportion of eGFRs within ± 10% (P10) of measured clearance. RESULTS: Kidney function (iohexol clearance) was 81 ± 19 (38-134) ml/min/1.73m2. All equations overestimated kidney function by 22-60 ml/min/1.73m2. eGFR CysC had the lowest bias overall 22 (95% CI 20-26) ml/min/1.73m2 also at all levels of kidney function we evaluated (at 30-59 ml/min/1.73m2 bias was 27 (95% CI 21-35), at 60-89 it was 25 (95% CI 20-28) and at ≥ 90 it was 12 (95% CI 7-22)). eGFR CysC also had the best accuracy in patients with reduced kidney function (P10 was 5.9% at 30-59 ml/min/1.73m2). CONCLUSIONS: Cystatin C-based estimations of kidney function performed better than creatinine-based ones in patients with primary neuromuscular disease, but most importantly, all evaluated equations overestimated kidney function, especially in patients with reduced kidney function. Therefore, kidney function should be measured by gold-standard methods when precision and accuracy are needed.

CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage?

CDKN2C/p18 (Cyclin-Dependent Kinase Inhibitor 2C) is a cell growth regulator that controls cell cycle progression and has previously been associated with increased risk for type II diabetes (T2D) and reduced peripheral adipose tissue (AT) storage capacity. This study explored the role of CDKN2C in AT lipid and glucose metabolism in T2D. Expression of CDKN2C and other genes was analyzed by transcriptomics, or real-time PCR in subcutaneous AT (SAT) samples obtained from T2D and control subjects matched for sex, age and BMI and also in paired SAT and omental AT (OAT) samples. Functional studies included adipocyte glucose uptake and lipolysis rates. CRISPR/Cas9 CDKN2C gene knockdown was performed in human preadipocytes to assess adipogenesis. CDKN2C mRNA expression in SAT and OAT was reduced in T2D and obese subjects compared to controls. CDKN2C expression in SAT was inversely correlated with measures of hyperglycemia, insulin resistance and visceral adiposity and positively correlated with expression of genes in several metabolic pathways, including insulin signaling and fatty acid and carbohydrate metabolism. CDKN2C protein was mainly expressed in adipocytes compared to stromal vascular cells, and its gene and protein expression was up-regulated during adipocyte differentiation. Knockdown of CDKN2C did not affect the percentage of differentiating cells compared to wild type cultures. However, CDKN2C knockdown cultures had significantly lower expression of differentiation markers CEBPA, ADIPOQ and FASN and transiently reduced lipid accumulation per adipocyte during differentiation. Our findings suggest that adipose CDKN2C expression might be reduced as a consequence of insulin resistance and obesity, and this can further contribute to impairment of SAT lipid storage.