Use of non-surgical treatments on the journey to knee replacement in patients with knee osteoarthritis: a 10-year population-based case-control study

AimTo investigate temporal trends in primary care visits, physiotherapy visits, dispensed non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in knee osteoarthritis (OA) patients who have and have not undergone knee replacement.MethodsWe analysed 5665 OA patients from the Skåne Healthcare Register, Sweden, who underwent knee replacement between 2015 and 2019. Controls were OA patients without knee replacement, matched 1:1 by sex, age, time and healthcare level of initial OA diagnosis, and assigned a pseudo-index date corresponding to their case's knee replacement date. Annual prevalence and prevalence ratio of primary care and physiotherapy visits, dispensed NSAIDs and opioids (all for any cause) in the 10 years before knee replacement were estimated using Poisson regression.ResultsThe annual prevalence of all-cause primary care visits, physiotherapy visits and opioid use was similar between cases and controls until 3 years before the index date when it started to increase among the cases. The year before the index date, the prevalence ratio (cases vs controls) for physiotherapy use was 1.8 (95% CI 1.7, 1.8), while for opioid use 1.6 (1.5, 1.7). NSAID use was consistently higher among cases, even 10 years before the index date when the prevalence ratio versus controls was 1.3 (1.2, 1.3), increasing to 1.8 (1.7, 1.9) in the year preceding the index date.ConclusionsManagement of OA patients who have and have not undergone knee replacement appears largely similar except for higher use of NSAIDs in knee replacement cases. Symptomatic treatments start to increase a few years before the surgery in knee replacement cases

Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2

Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involving impaired recruitment of mural cells. Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with reduced pericyte vessel coverage and enhanced macrophage infiltration, and this transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels. Our study suggests that GRK2 downregulation is a relevant event in the tumoral angiogenic switch.Our laboratory is funded by grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación Ramón Areces, The Cardiovascular Network (RECAVA) of Ministerio Sanidad y Consumo-Instituto Carlos III (RD06-0014/0037 and RD12/0042/0012), and Comunidad de Madrid (S-2010/BMD- 2332) to F. Mayor Jr. and Instituto Carlos III (PI11/00859), Fundación Ramón Areces, and Fundación Rodríguez Pascual to P. Penela. Marta Mendiola is supported by a postdoctoral research contract from Fondo de Investigación Sanitaria (“Sara Borrell” Programme), Instituto de Salud Carlos III

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Nationwide prevalence of primary dystonia, progressive ataxia and hereditary spastic paraplegia

Objective: To determine the nationwide prevalence of primary dystonia, ataxia and hereditary spastic paraplegia (HSP) in Sweden. Methods: We extracted data on all patients who were registered in The National Patient Register (NPR) in Sweden (population 9.64 million) at least twice during five consecutive years with a diagnosis of primary dystonia, ataxia or HSP. We excluded patients with an additional diagnosis possibly indicating secondary causes, and determined the proportion of wrongly diagnosed patients at our own tertiary center by patient examination or chart review. We analyzed patients’ age and disorder subtypes, geographical distribution of patients within Sweden and the country of birth of all patients. Results: Nationwide, we identified 4239 patients (31.6% male) with a diagnosis of primary dystonia. Of 347 patients with dystonia at our center, 20.2% may have had a different final diagnosis. Extrapolation of this uncertainty rate to the national population resulted in a prevalence for primary dystonia of 35.1/100,000. There were 672 patients (49.6% male) with ataxia in NPR, and the diagnostic uncertainty rate among 81 patients in our center was 13.6% (prevalence 6.0/100,000). HSP was diagnosed in 235 patients nationwide (52.3% male, prevalence 2.4/100,000). Patients were distributed relatively evenly throughout the country. The proportions of patients with these diagnoses who were born outside of Sweden were lower (8.0–12.7%) than the proportion of all Swedish residents born abroad (15.9%). Conclusions: In this large, nationwide study, the prevalence of dystonia was high compared to previous studies, which partly may be explained by the high coverage of NPR

Identifying Non-Steroidal Anti-Inflammatory Drug (NSAID) Users Among People with Osteoarthritis Through Administrative and Clinician-Reported Data - A Validation Study of 116,162 Patients

PURPOSE: (i) To report the prevalence of participants to a first-line intervention for OA in Sweden using over-the-counter (OTC) and/or prescribed NSAIDs; (ii) To estimate the accuracy of dispensed prescriptions of NSAIDs recorded in a Swedish health-care register to capture the use of NSAID considering clinician-report as reference standard.METHODS: Register-based study. We used data from OA individuals who participated in the Swedish first-line intervention recorded in the Swedish Osteoarthritis Register (SOAR). SOAR includes clinician-reported use of NSAIDs in the three months preceding the intervention. We used the Prescribed Drug Register to retrieve data on NSAID prescriptions dispensed in the same period. We estimated the prevalence of OTC users (individuals with clinicians-reported use of NSAID but no prescription dispensed), prescription users (individuals with clinicians-reported use of NSAID and a prescription dispensed) and non-users (neither of the previous). We calculated sensitivity, specificity, positive predictive value, and negative predictive value of dispensed prescriptions of NSAIDs vs clinician-report.RESULTS: We included 116,162 individuals (mean age [Standard Deviation]: 66 [9.6] years, 79% women, 77% knee OA). Overall, 24.7% (95% Confidence Intervals [CI] 24.5%; 25.0%) used OTC NSAIDs only, 18.2% (18.0%; 18.5%) used prescribed NSAIDs, 6.6% (6-4%; 6.7%) reported not using NSAIDs while having an NSAID prescription dispensed. Of the 49,913 individuals with clinician-reported use of NSAIDs, 21,190 had a prescription dispensed (sensitivity: 42.5% [95% CI 42.0%, 42.9%]; positive predictive value: 73.5% [73.0%, 74.0%]). Of the 66,249 individuals reporting not using NSAIDs, 58,617 did not have a prescription dispensed (specificity: 88.5% [88.2%, 88.7%]; negative predictive value: 67.1% [66.8%, 67.4%]).CONCLUSION: Overall, 24.7% of participants in a first-line intervention for OA used OTC NSAIDs only while 18.2% used prescribed NSAIDs. Dispensed prescriptions of NSAIDs have high specificity but low sensitivity and can correctly identify about 70% of both the non-users and users in this population

The Road to Total Knee Replacement - Utilisation of Knee Surgeries up to 10 Years Before TKR in England and Sweden.

Objectives To compare the prevalence and timing of knee surgery (including meniscal, ligamentous, synovial and osteotomy) in the ten years prior to primary total knee replacement (TKR) between England and Sweden. Methods This was a population-based, case-control study within England and southern Sweden using electronic healthcare databases. Cases underwent primary TKR between 2015 and 2019. Risk-set sampling identified general population controls matched 1:1 by age, sex and practice/municipality. The annual prevalence and prevalence ratio (PR) of having at least one recorded surgery in each of the 10 years preceding TKR was estimated using Poisson regressions. Results We included 6,308 and 47,010 TKR cases in Sweden and England, respectively. Meniscal surgeries were the most frequent procedure prior to TKR in both countries - prevalence was higher in England across all time points. The prevalence of meniscal surgery increased in both countries in the years approaching TKR, reaching 33.2 (95% confidence interval 31.6-34.9) per 1,000 persons in England, and 9.83 (7.66, 12.61) in Sweden. In England, we observed a decrease from 2014 to 2018 in the utilisation of this procedure in the four years preceding a TKR. The prevalence of all analysed surgeries was consistently lower in controls. Conclusions There are comparable trends in the use of knee surgery in the years preceding TKR across England and Sweden. Of note, meniscal surgeries remain common, even within the year prior to TKR, highlighting that these patients may experience low-value care. Careful consideration of knee surgery in those with late-stage disease is required

Dairy Intake and Parkinson's Disease : A Mendelian Randomization Study

BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury