Hypertension and diabetes, but not leptin and adiponectin, mediate the relationship between body fat and chronic kidney disease.

PURPOSE: Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and adiponectin mediated these associations. METHODS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, 6671 participants (45-65 y) were included. We defined CKD as eGFR <60 ml/min/1.73 m2 and/or moderately increased albuminuria. The percentage of mediation was calculated using general structural equation modeling, adjusted for potential confounding factors age, sex, smoking, ethnicity, physical activity and Dutch healthy diet index. RESULTS: At baseline mean (SD) age was 56 (6), BMI 26.3 (4.4), 44% men, and 4% had CKD. Higher BMI and TBF were associated with 1.08 (95%CI 1.05; 1.11) and 1.05-fold (95%CI 1.02; 1.08) increased odds of CKD, respectively. As adiponectin was not associated with any of the outcomes, it was not studied further as a mediating factor. The association between BMI and CKD was 8.5% (95%CI 0.5; 16.5) mediated by diabetes and 22.3% (95%CI 7.5; 37.2) by hypertension. In addition, the association between TBF and CKD was 9.6% (95%CI -0.4; 19.6) mediated by diabetes and 22.4% (95%CI 4.2; 40.6) by hypertension. We could not confirm mediation by leptin in the association between BMI and CKD (35.6% [95%CI -18.8; 90.3]), nor between TBF and CKD (59.7% [95%CI -7.1; 126.6]). CONCLUSION: Our results suggest that the relations between BMI, TBF and CKD are in part mediated by diabetes and hypertension.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Surgical denervation as a treatment strategy for pain in hand osteoarthritis: a systematic literature review.

OBJECTIVE: Surgical denervation has been proposed as a treatment for pain in hand osteoarthritis (OA). This review aimed to summarise the available evidence and to propose a research agenda. METHODS: A systematic literature search was performed up to September 2022. Two investigators independently identified studies that reported on denervation for OA of the proximal interphalangeal, distal interphalangeal, metacarpophalangeal or carpometacarpal joints. Quality of studies was assessed and study characteristics, patient characteristics, details of the surgical technique and outcomes of the surgery were extracted. RESULTS: Of 169 references, 17 articles reporting on 384 denervations in 351 patients were selected. Sixteen case series reported positive outcomes with respect to pain, function and patient satisfaction. One non-randomised clinical trial reported no difference in outcome when comparing denervation of the first carpometacarpal (CMC I) joint to trapeziectomy. Adverse events were frequent, with sensory abnormalities occurring the most, followed by the need for revision surgery. All studies had significant risk of bias. CONCLUSION: Surgical denervation for pain in hand OA shows some promise, but the available evidence does not allow any conclusions of efficacy and higher-quality research is needed. Techniques should be harmonised and more data regarding how denervation compares to current usual care, other denervation methods or placebo in terms of outcomes and adverse events are needed.

Health Outcomes and Cost-effectiveness of Monoclonal SARS-CoV-2 Antibodies as Pre-exposure Prophylaxis.

Importance: Pre-exposure prophylaxis with neutralizing SARS-CoV-2 monoclonal antibodies (mAbs PrEP) prevents infection and reduces hospitalizations and the duration thereof for COVID-19 and death among high-risk individuals. However, reduced effectiveness due to a changing SARS-CoV-2 viral landscape and high drug prices remain substantial implementation barriers. Objective: To assess the cost-effectiveness of mAbs PrEP as COVID-19 PrEP. Design, Setting, and Participants: For this economic evaluation, a decision analytic model was developed and parameterized with health care outcome and utilization data from individuals with high risk for COVID-19. The SARS-CoV-2 infection probability, mAbs PrEP effectiveness, and drug pricing were varied. All costs were collected from a third-party payer perspective. Data were analyzed from September 2021 to December 2022. Main Outcomes and Measures: Health care outcomes including new SARS-CoV-2 infections, hospitalization, and deaths. The cost per death averted and cost-effectiveness ratios using a threshold for prevention interventions of $22 000 or less per quality-adjusted life year (QALY) gained. Results: The clinical cohort consisted of 636 individuals with COVID-19 (mean [SD] age 63 [18] years; 341 [54%] male). Most individuals were at high risk for severe COVID-19, including 137 (21%) with a body mass index of 30 or higher, 60 (9.4%) with hematological malignant neoplasm, 108 (17%) post-transplantation, and 152 (23.9%) who used immunosuppressive medication before COVID-19. Within the context of a high (18%) SARS-CoV-2 infection probability and low (25%) effectiveness the model calculated a short-term reduction of 42% ward admissions, 31% intensive care unit (ICU) admissions, and 34% deaths. Cost-saving scenarios were obtained with drug prices of $275 and 75% or higher effectiveness. With a 100% effectiveness mAbs PrEP can reduce ward admissions by 70%, ICU admissions by 97%, and deaths by 92%. Drug prices, however, need to reduce to $550 for cost-effectiveness ratios less than $22 000 per QALY gained per death averted and to $2200 for ratios between $22 000 and $88 000. Conclusions and Relevance: In this study, use of mAbs PrEP for preventing SARS-CoV-2 infections was cost-saving at the beginning of an epidemic wave (high infection probability) with 75% or higher effectiveness and drug price of $275. These results are timely and relevant for decision-makers involved in mAbs PrEP implementation. When newer mAbs PrEP combinations become available, guidance on implementation should be formulated ensuring a fast rollout. Nevertheless, advocacy for mAbs PrEP use and critical discussion on drug prices are necessary to ensuring cost-effectiveness for different epidemic settings.

What Changes Have Occurred in Opioid Prescriptions and the Prescribers of Opioids Before TKA and THA? A Large National Registry Study.

BACKGROUND: Opioid use before TKA or THA is linked to a higher risk of revision surgery and less functional improvement. In Western countries, the frequency of preoperative opioid use has varied, and robust information on temporal changes in opioid prescriptions over time (in the months before surgery as well as annual changes) and among prescribers is necessary to pinpoint opportunities to improve on low-value care patterns, and when they are recognized, to target physician populations for intervention strategies. QUESTIONS/PURPOSES: (1) What proportion of patients undergoing arthroplasties receive an opioid prescription in the year before TKA or THA, and what were the preoperative opioid prescription rates over time between 2013 and 2018? (2) Does the preoperative prescription rate vary between 12 and 10 months and between 3 and 1 months in the year before TKA or THA, and did it change between 2013 and 2018? (3) Which medical professionals were the main prescribers of preoperative opioids 1 year before TKA or THA? METHODS: This was a large-database study drawn from longitudinally maintained national registry sources in the Netherlands. The Dutch Foundation for Pharmaceutical Statistics was linked to the Dutch Arthroplasty Register from 2013 to 2018. TKAs and THAs performed because of osteoarthritis in patients older than 18 years, which were also uniquely linked by age, gender, patient postcode, and low-molecular weight heparin use, were eligible. Between 2013 and 2018, 146,052 TKAs were performed: 96% (139,998) of the TKAs were performed for osteoarthritis in patients older than 18 years; of them, 56% (78,282) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, which was necessary to follow patients over time, leaving 28% (40,989) of the initial TKAs as our study population. Between 2013 and 2018, 174,116 THAs were performed: 86% (150,574) were performed for osteoarthritis in patients older than 18 years, one arthroplasty was excluded because of an outlier opioid dose, and a further 57% (85,724 of 150,574) were excluded because of our linkage criteria. Some of the linked arthroplasties could not be linked to a community pharmacy, leaving 28% (42,689 of 150,574) of THAs, which were performed between 2013 and 2018. For both TKA and THA, the mean age before surgery was 68 years, and roughly 60% of the population were women. We calculated the proportion of patients undergoing arthroplasties who had at least one opioid prescription in the year before arthroplasty and compared data from 2013 to 2018. Opioid prescription rates are given as defined daily dosages and morphine milligram equivalents (MMEs) per arthroplasty. Opioid prescriptions were assessed by preoperative quarter and by operation year. Possible changes over time in opioid exposure were investigated using linear regression, adjusted for age and gender, in which the month of operation since January 2013 was used as the determinant and MME as the outcome. This was done for all opioids combined and per opioid type. Possible changes in opioid prescription rates in the year before arthroplasty were assessed by comparing the time period of 1 to 3 months before surgery with the other quarters. Additionally, preoperative prescriptions per operation year were assessed per prescriber category: general practitioners, orthopaedic surgeons, rheumatologists, and others. All analyses were stratified by TKA or THA. RESULTS: The proportion of patients undergoing arthroplasties who had an opioid prescription before TKA increased from 25% (1079 of 4298) in 2013 to 28% (2097 of 7460) in 2018 (difference 3% [95% CI 1.35% to 4.65%]; p < 0.001), and before THA increased from 25% (1111 to 4451) to 30% (2323 to 7625) (difference 5% [95% CI 3.8% to 7.2%]; p < 0.001). The mean preoperative opioid prescription rate increased over time between 2013 and 2018 for both TKA and THA. For TKA, an adjusted monthly increase of 3.96 MME was observed (95% CI 1.8 to 6.1 MME; p < 0.001). For THA, the monthly increase was 3.8 MME (95% CI 1.5 to 6.0; p = 0.001. For both TKA and THA, there was a monthly increase in the preoperative oxycodone rate (3.8 MME [95% CI 2.5 to 5.1]; p < 0.001 and 3.6 [95% CI 2.6 to 4.7]; p < 0.001, respectively). For TKA, but not for THA, there was a monthly decrease in tramadol prescriptions (-0.6 MME [95% CI -1.0 to -0.2]; p = 0.006). Regarding the opioids prescribed in the year before surgery, there was a mean increase of 48 MME (95% CI 39.3 to 56.7 MME; p < 0.001) for TKA between 10 and 12 months and the last 3 months before surgery. For THA, this increase was 121 MME (95% CI 110 to 131 MME; p < 0.001). Regarding possible differences between 2013 and 2018, we only found differences in the period 10 to 12 months before TKA (mean difference 61 MME [95% CI 19.2 to 103.3]; p = 0.004) and the period 7 to 9 months before TKA (mean difference 66 MME [95% CI 22.0 to 110.9]; p = 0.003). For THA, there was an increase in the MMEs prescribed between 2013 and 2018 for all four quarters, with mean differences ranging from 43.9 to 55.4 MME (p < 0.05). The average proportion of preoperative opioid prescriptions prescribed by general practitioners ranged between 82% and 86% (41,037 of 49,855 for TKA and 49,137 of 57,289 for THA), between 4% and 6% (2924 of 49,855 for TKA and 2461 of 57,289 for THA), by orthopaedic surgeons, 1% by rheumatologists (409 of 49,855 for TKA and 370 of 57,289 for THA), and between 9% and 11% by other physicians (5485 of 49,855 for TKA and 5321 of 57,289 for THA). Prescriptions by orthopaedic surgeons increased over time, from 3% to 7% for THA (difference 4% [95% CI 3.6 to 4.9]) and 4% to 10% for TKA (difference 6% [95% CI 5% to 7%]; p < 0.001). CONCLUSION: Between 2013 and 2018, preoperative opioid prescriptions increased in the Netherlands, mainly because of a shift to more oxycodone prescriptions. We also observed an increase in opioid prescriptions in the year before surgery. Although general practitioners were the main prescribers of preoperative oxycodone, prescriptions by orthopaedic surgeons also increased during the study period. Orthopaedic surgeons should address opioid use and its associated negative effects in preoperative consultations. More intradisciplinary collaboration seems important to limit the prescribing of preoperative opioids. Additionally, research is necessary to assess whether opioid cessation before surgery reduces the risk of adverse outcomes. LEVEL OF EVIDENCE: Level III, therapeutic study.

Opium as a risk factor for early-onset coronary artery disease: Results from the Milano-Iran (MIran) study.

The spreading of opium use poses new health related concerns. In some areas of Asia its use is believed to protect from cardiovascular disorders, such as coronary artery disease (CAD). However, whether opium use has an association with CAD is unclear. We aimed to investigate the association between non-medical opium use and CAD. We set up a case-control analysis, i.e., the Milano-Iran (MIran) study by enrolling consecutive young patients who underwent a coronary angiography at the Tehran Heart Center, between 2004 and 2011. Incident cases with CAD were contrasted with controls for opium use. Relative risks were calculated in terms of odds ratios (ORs) by logistic regression models adjusted for age, sex, cigarette smoking, body mass index, hypertension, hyperlipidaemia, and diabetes. Interaction analyses were performed between opium and major cardiovascular risk factors. 1011 patients with CAD (mean age 43.6 years) and 2002 controls (mean age 54.3 years) were included in the study. Habitual opium users had a 3.8-fold increased risk of CAD (95%CI 2.4-6.2) compared with non-users. The association was strongest for men, with a fully adjusted OR of 5.5 (95%CI 3.0-9.9). No interaction was observed for the combination of opium addiction and hypertension, or diabetes, but an excess in risk was found in opium users with hyperlipidaemia (OR 16.8, 95%CI 8.9-31.7, expected OR 12.2), suggesting supra-additive interaction. In conclusion, despite common beliefs, we showed that non-medical opium use is associated with an increased risk of CAD, even when other cardiovascular risk factors are taken into account.

Data linkage of two national databases: Lessons learned from linking the Dutch Arthroplasty Register with the Dutch Foundation for Pharmaceutical Statistics.

BACKGROUND: To provide guidance on data linkage in case of non-unique identifiers, we present a case study linking the Dutch Foundation for Pharmaceutical Statistics and Dutch Arthroplasty Register to investigate opioid prescriptions before/after arthroplasty. METHODS: Deterministic data linkage was used. Records were linked on: sex, birthyear, postcode, surgery date, or thromboprophylaxis initiation as a proxy for the surgery date. Different postcodes were used, depending on availability: patient postcode (available from 2013 onwards), hospital postcode with codes for physicians/hospitals, and hospital postcode with catchment area. Linkage was assessed in several groups: linked arthroplasties, linked on patient postcode, linked on patient postcode, and low-molecular-weight heparin(LWMH). Linkage quality was assessed by checking prescriptions after death, antibiotics after revision for infection, and presence of multiple prostheses. Representativeness was assessed by comparing the patient-postcode-LMWH group with the remaining arthroplasties. External validation was performed by comparing our opioid prescription rates with those derived from datasets from Statistics Netherlands. RESULTS: We linked 317,899 arthroplasties on patient postcode/hospital postcode(48%). Linkage on the hospital postcode appeared insufficient. Linkage uncertainty ranged from roughly 30% in all arthroplasties to 10-21% in the patient-postcode-LMWH-group. This subset resulted in 166.357(42%) linked arthroplasties after 2013 with somewhat younger age, fewer females, and more often osteoarthritis than other indications compared to the other arthroplasties. External validation showed similar increases in opioid prescription rates. CONCLUSIONS: After identifier selection, checking data availability and internal validity, assessing representativeness, and externally validating our results we found sufficient linkage quality in the patient-postcode-LMWH-group, which consisted of around 42% of the arthroplasties performed after 2013.

Factor V Leiden but not the factor II 20210G>A mutation is a risk factor for premature coronary artery disease: a case-control study in Iran.

Background: Factor V Leiden (FVL) and factor II c.∗97G>A (rs1799963) are genetic risk factors for venous thromboembolism. Their contribution to coronary artery disease (CAD) is less clear. Objectives: This study aimed to investigate the association between FVL, rs1799963, and premature CAD in Iranians. Methods: We performed a genetic case-control study of 944 cases and 1081 controls from the premature CAD Milano-Iran study, including patients aged 18-55 (female) and 18-45 years (male) who underwent coronary angiography at the Tehran Heart Centre (Iran) in 2004-2011. Cases had luminal stenosis ≥50% in at least 1 main coronary artery or branch. Controls were age- and sex-matched with no CAD history. FVL and rs1799963 were genotyped using TaqMan SNP genotyping assays. Association was tested by logistic regression adjusted for matching factors and ethnicity. Effect modification by sex and cardiovascular risk factors (metabolic [obesity, hypertension, hyperlipidemia, and diabetes], and smoking) was assessed. Results: The risk of premature CAD was increased by 50% in FVL carriers (adjusted odds ratio [adjOR] 1.54 [95% CI, 0.95-2.48]) and slightly reduced in rs1799963 carriers (adjOR 0.71 [95% CI, 0.40-1.27]). These effects were more pronounced in women than men (FVL, adjOR 1.66 vs 1.25; rs1799963, adjOR 0.60 vs 1.07). The risk of premature CAD was substantially increased in carriers of FVL with at least 1 metabolic risk factor compared with noncarriers without metabolic risk factors (adjOR 25.14 [95% CI, 12.51-50.52]). Conclusion: FVL but not FII rs1799963 was associated with an increased risk of CAD in young Iranians. This risk increased considerably when combined with metabolic cardiovascular risk factors.

Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: A cohort study.

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow-up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow-up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5-6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT.

The risk of venous thromboembolism after minor surgical procedures: A population-based case-control study.

BACKGROUND: Surgery is a well-known risk factor for venous thromboembolism (VTE). However, for several minor surgical procedures, thromboprophylaxis is not advised. OBJECTIVES: These "low-risk" procedures include a wide variation of interventions for which we estimated the VTE risk to verify their "low-risk" status. PATIENTS/METHODS: We used data from a large population-based case-control study (Multiple Environment and Genetic Assessment study) into causes of VTE, and linked these to the Dutch Hospital Data Registry to identify exposure to surgical procedures. Logistic regression was used to calculate odds ratios for the 90-day and 1-year relative risks of VTE following these procedures, which were adjusted for body mass index (BMI), sex, age, comorbidities, and infection/inflammation. RESULTS: We included 4247 patients with VTE and 5538 control subjects. Median age and BMI were 48.5 years and 25.5 m2/kg, respectively. Nine unique procedures or groups of procedures were analyzed. One hundred twenty-three participants-90 cases and 33 controls-had undergone a minor procedure within 90 days of the index date, resulting in a 3.5-fold (OR, 3.5; 95% CI, 2.3-5.3) overall increased VTE risk. Furthermore, venous stripping (OR, 7.2; 95% CI, 2.4-21.2), open abdominal/inguinal hernia repair (OR, 3.7; 95% CI, 1.2-11.6), and laparoscopic cholecystectomy (OR, 3.2; 95% CI, 1.0-10.6) were associated with an increased risk. Other minor procedures were less strongly or not associated with an increased risk. In the 1-year period before the index date, all odds ratios were lower. CONCLUSION: Of the "low-risk" procedures, we found that venous stripping, open abdominal/inguinal hernia repair, and laparoscopic cholecystectomy were associated with a clearly increased risk of VTE within 90 postoperative days.

Change in Hematoma Size after Dexamethasone Therapy in Chronic Subdural Hematoma Subtypes: A Prospective Study in Symptomatic Patients.

The main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy is applied. Recent trials revealed dexamethasone therapy to be an ineffective treatment in symptomatic patients with chronic subdural hematoma. Whether the efficacy of dexamethasone therapy differs in radiological hematoma subtypes is unknown. The aim of this substudy was to identify which hematoma subtype might be favorable for dexamethasone therapy. As part of a randomized controlled trial, symptomatic chronic subdural hematoma patients received 19-days dexamethasone therapy. The primary outcome measure was the change in hematoma size as measured on follow-up computed tomography (CT) after 2 weeks of dexamethasone in six hematoma (architectural and density) subtypes: homogeneous total, laminar, separated and trabecular architecture types, and hematoma without hyperdense components (homogeneous hypodense, isodense) and with hyperdense components (homogeneous hyperdense, mixed density). We analyzed hematoma thickness, midline shift, and volume using multi-variable linear regression adjusting for age, sex and baseline value of the specific radiological parameter. From September 2016 until February 2021, 85 patients were included with a total of 114 chronic subdural hematoma. The mean age was 76 years and 25% were women. Larger decrease in hematoma thickness and midline shift was revealed in hematoma without hyperdense components compared with hematoma with hyperdense components (adjusted [adj.] b -2.2 mm, 95% confidence interval [CI] -4.1 to -0.3 and adj. b -1.3 mm, 95% CI -2.7 to 0.0 respectively). Additional surgery was performed in 57% of patients with the highest observed rate (81%) in separated hematoma. Largest hematoma reduction and better clinical improvement was observed in chronic subdural hematoma without hyperdense components after dexamethasone therapy. Evaluation of these parameters can be part of an individualized treatment strategy.

Agreement between nicotine metabolites in blood and self-reported smoking status: The Netherlands Epidemiology of Obesity study.

Introduction: Self-report and nicotine detection are methods to measure smoking exposure and can both lead to misclassification. It is important to highlight discrepancies between these two methods in the context of epidemiological research. Objective: The aim of this cross-sectional study is to assess the agreements between self-reported smoking status and nicotine metabolite detection. Methods: Data of 599 participants from the Netherlands Epidemiology of Obesity study were used to compare serum metabolite levels of five nicotine metabolites (cotinine, hydroxy-cotinine, cotinine N-Oxide, norcotinine, 3-hydroxy-cotinine-glucuronide) between self-reported never smokers (n = 245), former smokers (n = 283) and current smokers (n = 71). We assessed whether metabolites were absent or present and used logistic regression to discriminate between current and never smokers based on nicotine metabolite information. A classification tree was derived to classify individuals into current smokers and non/former smokers based on metabolite information. Results: In 94% of the self-reported current smokers, at least one metabolite was present, versus in 19% of the former smokers and in 10% of the never smokers. In none of the never smokers, cotinine-n-oxide, 3-hydroxy-cotinine-n-glucorinide or norcotinine was present, while at least one of these metabolites was detected in 68% of the self-reported current smokers. The classification tree classified 95% of the participants in accordance to their self-reported smoking status. All self-reported smokers who were classified as non-smokers according to the metabolite profile, had reported to be occasional smokers. Conclusion: The agreement between self-reported smoking status and metabolite information was high. This indicates that self-reported smoking status is generally reliable.

Reference intervals of urinary kidney injury biomarkers for middle-aged men and women determined by quantitative protein mass spectrometry.

BACKGROUND AND AIMS: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins neutrophil-gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), C-X-C motif chemokine 9 (CXCL9), transforming growth factor-beta 1 (TGF-ß1), solute carrier family 22 member 2 (SLC22A2), nephrin, cubilin, and uromodulin (UMOD) have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. MATERIALS AND METHODS: The 24 h urine samples from 1443 Caucasian middle-aged men and women were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24 h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. RESULTS: NGAL, IGFBP7, TIMP2, KIM-1, and UMOD could be quantified in this population, whereas nephrin, SLC22A2, and CXCL9 were below their detection limits. Urine creatinine and osmolality were correlated to urine volume (r = -0.71; -0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, body mass index, smoking, kidney function, or common comorbid conditions. The reference intervals (men; women) were 18-108; 21-131 pmol IGFBP7/mmol creatinine, 1-63; 4-224 pmol NGAL/mmol creatinine, 7-48; 7-59 pmol TIMP2/mmol creatinine, <1-9; <1-12 pmol KIM-1/mmol creatinine, and 0.1-1.2; 0.1-1.7 mg UMOD/mmol creatinine. CONCLUSION: We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population.

Adherence to the healthy lifestyle guideline in relation to the metabolic syndrome: Analyses from the 2013 and 2018 Indonesian national health surveys.

In this study, we aimed to investigate differences in lifestyle factors and prevalence of metabolic syndrome (MetS) in the Indonesian population between 2013 and 2018. In addition, we investigated whether adherence to the 2015-released national healthy lifestyle guideline ('GERMAS') is associated with MetS in different sex, age, urban/rural, and BMI categories. We performed cross-sectional analyses in individuals aged >15 of the 2013 (n = 34,274) and 2018 (n = 33,786) Indonesian National Health Surveys. A stratified, multi-stage, systematic random sampling design and the probability proportional to size method were used to select households in the 34 provinces across the country. MetS was defined according to the Joint Interim Statement Criteria, and adherence to 'GERMAS' guideline was defined as fulfilling the national healthy lifestyle recommendations of ≥150 min/week physical activity (PA), ≥5 portions/day fruit and vegetable (FV), no smoking (NS), and no alcohol consumption (NA). We examined the associations of each lifestyle factor with MetS using logistic regression categorised by sex, age groups, urban/rural, and BMI, and adjusted for sociodemographic factors. We observed that men who adhered to the guideline had lower odds ratio of MetS [OR(95%CI) associated with PA: 0.85(0.75-0.97); NA: 0.75(0.56-1.00)] than non-adherent men. Middle-aged adults who adhered to the guideline had lower OR of MetS [PA: 0.85(0.72-1.01); FV: 0.78(0.62-0.99); NA: 0.66(0.46-0.93)] than non-adherent adults <45 years. The adherent urban population had lower OR of MetS [FV: 0.85(0.67-1.07); NA: 0.74(0.52-1.07)] than the non-adherent urban population. Those with overweight or obesity who adhered to the guideline had relatively lower odds of MetS than those who did not. In conclusion, in this nationally representative study, adherence to the 'GERMAS' guideline may confer cardiometabolic health benefits to several groups of the Indonesian population, particularly men, middle-aged, those with overweight and obesity, and potentially urban population.

Association between cardiovascular risk factors and venous thromboembolism in the elderly.

BACKGROUND: The preponderance of the evidence supports no association between traditional cardiovascular risk factors and venous thromboembolism (VTE), other than obesity. There are limited data in older people. OBJECTIVES: To investigate whether cardiovascular risk factors (body mass index, smoking, alcohol intake, hypertension, and diabetes) are associated with the risk of VTE in elderly and to assess the combined effect between cardiovascular risk factors and genetic risk factors for VTE (factor V Leiden/prothrombin 20210A, positive family history of VTE, and non-O blood group). METHODS: The Age and Thrombosis, Acquired and Genetic risk factors in the Elderly study is a multicenter case-control study performed in Vermont, USA and Leiden, the Netherlands, comprising 401 cases with first VTE and 431 control subjects, all aged ≥70 years. To assess the risk of VTE, odds ratios (OR) with 95% confidence intervals (CIs) were calculated, adjusting for potential confounders. RESULTS: Both height and weight were positively associated with VTE risk: the ORs were 2.2 (95% CI, 1.2-3.9) and 1.5 (95% CI, 1.0-2.4) in the top quartile for height and weight separately. This risk was more pronounced for unprovoked VTE. Smoking, alcohol intake, and diabetes were not associated with VTE. Higher systolic and diastolic blood pressure and hypertension were associated with a decreased risk of VTE. In the presence of a genetic predisposition, height and weight further increased the risk of VTE. CONCLUSIONS: In the elderly, height and weight are positively associated with the risk of VTE. With genetic predisposition, higher levels of height and weight further increase the risk of VTE.

Targeted proteomics for evaluating risk of venous thrombosis following traumatic lower-leg injury or knee arthroscopy.

INTRODUCTION: Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis use, and individual risk factors for developing VT are often ignored. To assist in VT risk stratification and guide thromboprophylaxis use, various prediction models have been developed. These models depend largely on clinical factors and provide reasonably good C-statistics of around 70%. We explored using protein levels in blood plasma measured by multiplexed quantitative targeted proteomics to predict VT. Our aim was to assess whether a VT risk prediction model based on absolute plasma protein quantification is possible. METHODS: We used internal standards to quantify proteins in less than 10 µl plasma. We measured 270 proteins in samples from patients scheduled for knee arthroscopy or with lower-leg cast immobilization. The two prospective POT-(K)CAST trails allow complementary views of VT signature in blood, namely pre and post trauma, respectively. From approximately 3000 patients, 31 patients developed VT who were included and matched with double the number of controls. RESULTS: Top discriminating proteins between cases and controls included APOC3, APOC4, APOC2, ATRN, F13B, and F2 in knee arthroscopy patients and APOE, SERPINF2, B2M, F13B, AFM, and C1QC in patients with lower-leg cast. A logistic regression model with cross-validation resulted in C-statistics of 88.1% (95% CI: 85.7-90.6%) and 79.6% (95% CI: 77.2-82.0%) for knee arthroscopy and cast immobilization groups respectively. CONCLUSIONS: Promising C-statistics merit further exploration of the value of proteomic tests for predicting VT risk upon additional validation.

Association of smoking and cancer with the risk of venous thromboembolism: the Scandinavian Thrombosis and Cancer cohort.

Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993-1997 to 2008-2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12-1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96-1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.

Prediction or causality? A scoping review of their conflation within current observational research.

Etiological research aims to uncover causal effects, whilst prediction research aims to forecast an outcome with the best accuracy. Causal and prediction research usually require different methods, and yet their findings may get conflated when reported and interpreted. The aim of the current study is to quantify the frequency of conflation between etiological and prediction research, to discuss common underlying mistakes and provide recommendations on how to avoid these. Observational cohort studies published in January 2018 in the top-ranked journals of six distinct medical fields (Cardiology, Clinical Epidemiology, Clinical Neurology, General and Internal Medicine, Nephrology and Surgery) were included for the current scoping review. Data on conflation was extracted through signaling questions. In total, 180 studies were included. Overall, 26% (n = 46) contained conflation between etiology and prediction. The frequency of conflation varied across medical field and journal impact factor. From the causal studies 22% was conflated, mainly due to the selection of covariates based on their ability to predict without taking the causal structure into account. Within prediction studies 38% was conflated, the most frequent reason was a causal interpretation of covariates included in a prediction model. Conflation of etiology and prediction is a common methodological error in observational medical research and more frequent in prediction studies. As this may lead to biased estimations and erroneous conclusions, researchers must be careful when designing, interpreting and disseminating their research to ensure this conflation is avoided.

Objectively Measured Physical Activity and Body Fatness: Associations with Total Body Fat, Visceral Fat, and Liver Fat.

PURPOSE: It remains unclear to what extent habitual physical activity and sedentary time (ST) are associated with visceral fat and liver fat. We studied the substitution of ST with time spent physically active and total body fat (TBF), visceral adipose tissue (VAT), and hepatic triglyceride content (HTGC) in middle-age men and women. DESIGN: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, physical activity was assessed in 228 participants using a combined accelerometer and heart rate monitor. TBF was assessed by the Tanita bioelectrical impedance, VAT by magnetic resonance imaging, and HTGC by proton-MR spectroscopy. Behavioral intensity distribution was categorized as ST, time spent in light physical activity (LPA), and moderate to vigorous physical activity (MVPA). To estimate the effect of replacing 30 min·d-1 of ST with 30 min·d-1 LPA or MVPA, we performed isotemporal substitution analyses, adjusted for sex, age, ethnicity, education, the Dutch Healthy Diet index, and smoking. RESULTS: Included participants (41% men) had a mean ± SD age of 56 ± 6 yr and spent 88 ± 56 min in MVPA and 9.0 ± 2.1 h of ST. Replacing 30 min·d-1 of ST with 30 min of MVPA was associated with 1.3% less TBF (95% confidence interval = -2.0 to -0.7), 7.8 cm2 less VAT (-11.6 to -4.0), and 0.89 times HTGC (0.82-0.97). Replacement with LPA was not associated with TBF (-0.03%; -0.5 to 0.4), VAT (-1.7 cm2; -4.4 to 0.9), or HTGC (0.98 times; 0.92-1.04). CONCLUSIONS: Reallocation of time spent sedentary with time spent in MVPA, but not LPA, was associated with less TBF, visceral fat, and liver fat. These findings contribute to the development of more specified guidelines on ST and physical activity.

Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study.

BACKGROUND: Statins are a potential treatment for venous thromboembolism (VTE) prophylaxis complementary to conventional anticoagulants without associated bleeding complications. This study aimed to compare pro-thrombotic activities of different classes of lipid-lowering drugs in an active comparator design and determine whether there is a relation between statin versus fibrate/niacin use and pro-coagulant factor outcomes. METHODS: This is a cross-sectional analysis of participants from the Netherlands Epidemiology of Obesity study using any class of lipid-lowering drugs, including any types of statins, niacin, and fibrates. We performed linear regression analyses to determine fibrinogen, factor (F) VIII, FIX, and FXI activity in statins versus fibrate/niacin users and adjusted for age, sex, tobacco smoking, body mass index (BMI), hypertension, diabetes, and prevalent cardiovascular disease. RESULTS: Among 1043 participants, the mean age was 58.4 ± 5.2 years, 61% were men, and the mean BMI was 31.3 ± 4.5 kg/m2. Clinical characteristics were balanced between statin and fibrate/niacin users. Statin users had lower mean FXI (18.3 IU/dL, 95% confidence interval (CI) 9.4 to 27.3) levels compared to fibrate/niacin users. The level of FVIII (15.8 IU/dL, 95% CI - 0.003 to 31.6), and FIX (11.3 IU/dL, 95% CI - 0.4 to 23.2) were lower in statin users than fibrate/niacin users with marginal statistical significance. CONCLUSION: Current statin use was associated with lower plasma levels of FXI than fibrate/niacin use. The effects on coagulation factors may, in part, explain the benefit of statin therapy rendered in primary and secondary prevention of VTE.