A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types.

Due to activation of fibroblast into cancer-associated fibroblasts, there is often an increased deposition of extracellular matrix and fibrillar collagens, e.g. type III collagen, in the tumor microenvironment (TME) that leads to tumor fibrosis (desmoplasia). Tumor fibrosis is closely associated with treatment response and poor prognosis for patients with solid tumors. To assure that the best possible treatment option is provided for patients, there is medical need for identifying patients with high (or low) fibrotic activity in the TME. Measuring unique collagen fragments such as the pro-peptides released into the bloodstream during fibrillar collagen deposition in the TME can provide a non-invasive measure of the fibrotic activity. Based on data from 8 previously published cohorts, this review provides insight into the prognostic value of quantifying tumor fibrosis by measuring the pro-peptide of type III collagen in serum of a total of 1692 patients with different solid tumor types and discusses the importance of tumor fibrosis for understanding prognosis and for potentially guiding future drug development efforts that aim at overcoming the poor outcome associated with a fibrotic TME.

A retrospective cohort study of the effect of SARS-CoV-2 point of care rapid RT-PCR at the Emergency Department on targeted admission.

BACKGROUND: To prevent nosocomial transmission of SARS-CoV-2, infection prevention control (IPC) measures are implemented for patients with symptoms compatible with COVID-19 until reliable test results are available. This delays admission to the most appropriate ward based on the medical condition. SARS-CoV-2 rapid antigen detection (RAD) tests and point-of-care (POC) rapid RT-PCR (VitaPCR) were introduced at emergency department (ED) at Skåne University Hospital, Sweden in late 2020, but the consequence on patient flow and targeted admission is unknown. METHODS: Patients presenting at the emergency department of a referral hospital (N = 2940) between 13-Nov-2020 and 12-Jan-2021 were included. The study period was delimited into three periods by the introduction of RAD tests and the VitaPCR. Participant data was collected from hospital records, and outcome variables were Length-of-Stay (LoS), intrahospital transfers and targeted admission to COVID-19 ward. RESULTS: Compared to baseline (RT-PCR only), RAD tests reduced ED Length-of-Stay (LoS) for participants with positive tests. Negative VitaPCR results reduced mean hospital LoS by 1.5 (95% CI 0.3-2.7) days and admissions to COVID-19 wards from 34.5 (95% CI 28.9-40.5) to 14.7 (95% CI 11.1-19.1) per 100 admissions and reduced transfers between hospital wards in the first 5 days from 50.0 (95% CI 45.0-55.0) to 34.0 (95% CI 30.3-37.9) per 100 admissions. CONCLUSION: RAD tests enabled prompt detection of SARS-CoV-2 infection which had pronounced effects on LoS at the ED. Negative VitaPCR enabled cessation of IPC measures and a negative test was associated with increased targeted admissions, reduced intrahospital transfers and shorter LoS at the hospital.

Programmed, intermittent boluses versus continuous infusion to the sciatic nerve - a non-inferiority randomized, controlled trial.

BACKGROUND: Trials comparing programmed, intermittent boluses (PIB) and continuous infusion in catheter-based nerve blocks found no analgesic differences. However, as these trials used equal doses of local anesthetic (LA), the time of action of each bolus was not accounted for. Therefore, the dose-sparing benefits of PIB may have been overlooked. We compared the analgesic effect of boluses administered in intervals resembling the time of action of each bolus with continuous infusion. We hypothesized that PIB provided non-inferior analgesia despite consuming less LA. METHODS: Eighty-one patients undergoing fore- and midfoot surgery receiving a catheter-based sciatic nerve block were randomized to ropivacaine 0.2% as PIB of 10 ml every 8th hour or as continuous infusion, 6 ml h-1 . All participants could also receive boluses of 10 ml every 4th hour as needed. A non-inferiority randomized controlled design was used. Primary outcome was pain (VAS, 0-100 mm) for 72 h using area under curve (AUC) calculation. We assumed a linear relationship between mean VAS and AUC-VAS and used a non-inferiority margin of VAS = 20 mm, corresponding to AUC-VAS = 1440 mm h. RESULTS: Mean difference in AUC-VAS was -416 mm h (95% CI -1076 to 244; p = .217) between continuous infusion (mean AUC-VAS 1206 mm h) and PIB (mean AUC-VAS 1621 mm h), establishing non-inferiority. Mean total LA consumption was significantly larger for continuous infusion compared to PIB ((468 ml (95% CI 458 to 478) vs. 136 ml (95% CI 123 to 148); p < 0.0001)). CONCLUSIONS: PIB provided non-inferior analgesia compared to continuous infusion for 72 postoperative hours despite using significantly less LA.

Characteristics and Long-term Prognosis of Danish Patients With Varicella Zoster Virus Detected in Cerebrospinal Fluid Compared With the Background Population.

BACKGROUND: Risk factors for, and long-term outcomes following, detection of varicella zoster virus (VZV) DNA in the cerebrospinal fluid (CSF) are unknown. METHODS: We performed a nationwide population-based cohort study of all Danish residents who had VZV DNA detected in the CSF by polymerase chain reaction (PCR) between 1 January 1997 and 1 March 2016 (VZV cohort; n = 517) and an age- and sex- matched comparison cohort from the general Danish population (n = 9823). We examined potential risk factors and mortality, neurologic morbidity, psychiatric morbidity, redemptiom of prescriptions for nervous system medicine prescribed for the nervous system, and social outcomes. RESULTS: Prior hospital admission, redemption of immunosuppressive medicine, comorbidity, and immunosuppressive conditions were associated with detection of VZV DNA in the CSF. Mortality was increased in the VZV cohort, especially during the first year of observation and among patients with encephalitis. Patients in the VZV cohort had an increased risk of dementia and epilepsy. The redemption of antiepileptics and antidepressants was increased in the VZV cohort. CONCLUSIONS: Immunosuppression and comorbidity are associated with increased risk of detection of VZV DNA in the CSF and the condition is associated with increased mortality and neurological morbidity.

High preharvest donor Foxp3 mRNA level predicts late relapse of acute lymphoblastic leukaemia after haematopoietic stem cell transplantation.

OBJECTIVES: The curative effect of allogeneic haematopoietic stem cell transplantation (HSCT) for acute leukaemia is due in part to the donor T cell-mediated graft-versus-leukaemia immune reaction (GvL). Several studies have suggested that donor CD25+CD4+Foxp3+regulator T cells (Tregs) may decrease graft-versus-host disease (GvHD) without abrogating GVL. This notion may need modification in acute lymphoblastic leukaemia (ALL). METHODS: Foxp3 mRNA level was measured by qPCR in preharvest donor blood CD4+ T cells. The study comprised 45 patients with ALL in 1st or 2nd CR who received myeloablative HSCT using T-replete bone marrow grafts. RESULTS: Relapse occurred in 17 patients median 363 days after HSCT. The relapse risk was estimated by Cox univariate and multivariate proportional hazard regression. The proportionality assumption was met by analysing the preharvest donor Foxp3 mRNA level as a time-dependent covariate. Early relapse was not modified by the Foxp3 mRNA level. However, a higher Foxp3 mRNA level was associated with a significantly increased relapse risk after day 363 after transplantation, compatible with inhibition of GvL. In contrast, a higher preharvest donor CD4+ T-cell concentration was associated with reduced relapse risk. CONCLUSION: A higher preharvest donor Foxp3 mRNA level may be predictive of late ALL relapse after HSCT.

Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 µg and above. Doses of 5-40 µg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 µg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Long-Term Survival, Health, Social Functioning, and Education in Patients With an Enterovirus Central Nervous System Infection, Denmark, 1997-2016.

BACKGROUND: The long-term clinical course of patients with an enterovirus central nervous system infection (ECI) is poorly understood. METHODS: We performed a nationwide population-based cohort study of all Danish patients with ECI diagnosed 1997-2016 (n = 1745) and a comparison cohort from the general population individually matched on date of birth and sex (n = 17 450). Outcomes were categorized into mortality and risk of cancer and likely measures of neurological sequelae: neuropsychiatric morbidities, educational landmarks, use of hospital services, employment, receipt of disability pension, income, number of sick leave days, and nursing home residency. RESULTS: Mortality in the first year was higher among patients with ECI (mortality rate ratio [MRR] = 10.0; 95% confidence interval [CI], 4.17-24.1), but thereafter mortality was not higher (MMR = 0.94; 95% CI, 0.47-1.86). Long-term outcomes for patients with ECI were not inferior to those of the comparison cohort for risk of cancer, epilepsy, mental and behavioral disorders, dementia, depression, school start, school marks, high school education, use of hospital services, employment, receipt of disability pension, income, days of sick leave, or nursing home residency. CONCLUSIONS: Diagnosis of an ECI had no substantial impact on long-term survival, health, or social/educational functioning.

Risk of Neurological Disorders in Patients With European Lyme Neuroborreliosis: A Nationwide, Population-Based Cohort Study.

BACKGROUND: Lyme neuroborreliosis (LNB), caused by the tick-borne spirochetes of the Borrelia burgdorferi sensu lato species complex, has been suggested to be associated with a range of neurological disorders. In a nationwide, population-based cohort study, we examined the associations between LNB and dementia, Alzheimer's disease, Parkinson's disease, motor neuron disease, epilepsy, and Guillain-Barré syndrome. METHODS: We used national registers to identify all Danish residents diagnosed during 1986-2016 with LNB (n = 2067), created a gender- and age-matched comparison cohort from the general population (n = 20 670), and calculated risk estimates and hazard ratios. RESULTS: We observed no long-term increased risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, or epilepsy. However, within the first year, 8 (0.4%) of the LNB patients developed epilepsy, compared with 20 (0.1%) of the comparison cohort (difference, 0.3%; 95% confidence interval, .02-.6%). In the LNB group, 11 (0.5%) patients were diagnosed with Guillain-Barré syndrome within the first year after LNB diagnosis, compared with 0 (0.0%) in the comparison cohort. After the first year, the risk of Guillain-Barré was not increased. CONCLUSIONS: LNB patients did not have increased long-term risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, epilepsy, or Guillain-Barré. Although the absolute risk is low, LNB patients might have an increased short-term risk of epilepsy and Guillain-Barré syndrome.

Volume of ropivacaine 0.2% and sciatic nerve block duration: A randomized, blinded trial in healthy volunteers.

BACKGROUND: Sciatic nerve blocks are used for many orthopaedic procedures on the knee, lower leg, foot and ankle. However, as nerve block durations vary considerably, the timing of supplemental analgesia is challenging. Therefore, knowledge on the effect of local anaesthetic (LA) dose on block duration is important to outweigh the benefits of increasing LA dose against the risk of LA systemic toxicity. In this randomized, double-blind trial, we aimed to explore the relationship between the volume of ropivacaine 0.2% and sciatic nerve block duration. We hypothesized that increasing LA volume would prolong block duration. METHODS: We randomized 60 healthy volunteers to receive one of five volumes of ropivacaine 0.2%: 5, 10, 15, 20, or 30 mL. We used an ultrasound-guided, catheter-based technique targeting the sciatic nerve in the infragluteal region. The primary outcome was sensory block duration defined as the time of insensitivity to a cold stimulus. Intergroup differences were tested using one-way ANOVA. RESULTS: Mean (SD) sensory block durations for the tibial nerve (TN) with increasing volume were: 9.3 hours (1.7), 10.4 hours (1.6), 9.7 hours (2.9), 10.7 hours (2.8) and 9.9 hours (2.6). Mean (SD) sensory block durations for the common peroneal nerve (CPN) were: 10.6 hours (2.7), 11.9 hours (1.5), 11.0 hours (3.3), 13.2 hours (3.7), and 13.5 hours (6.1). There were no intergroup differences (P = .67 [TN]; P = .25 [CPN]). CONCLUSION: We found no effect of increasing the volume of ropivacaine 0.2% from 5 to 30 mL on sensory sciatic nerve block duration.

Intra- and inter-Individual variability in nerve block duration: A randomized cross-over trial in the common peroneal nerve of healthy volunteers.

BACKGROUND: The reported variation in nerve block duration is considerable. To individualize nerve block therapy, knowledge of the intra- vs inter-individual variability is essential. We investigated the relative contribution of these 2 parameters to the overall nerve block duration variability. METHODS: With ethics committee approval, we conducted a randomized cross-over trial where 20 healthy volunteers received 8 common peroneal nerve blockades with lidocaine 0.5% on 4 consecutive days. Allocations were 5 mL to either the right or left side and 10 mL to the opposite side on day 1 and 2 and vice versa on day 3 and 4. With fixed needle entry and nerve target, we repeated local anaesthetic deposition for each blockade. The primary outcome was variation in duration of sensory nerve block defined as insensitivity to a cold stimulus. Data were analysed using linear mixed model regression. RESULTS: The mean sensory block duration of 380 (95% CI = [342; 418]) minutes on day one was 55 [33; 77] minutes longer than on day two (P < .001), but there were no differences in mean duration between days 2, 3 and 4. The ratios with 2.5; 97.5 percentiles between inter- and intra-individual variation were 2.4 [0.8; 5.2] for the 5 mL blockades and 3.0 [0.9; 6.7] for the 10 mL blockades. The probabilities of inter- to intra-individual variation-ratios >1 were 96% and 97%. CONCLUSION: The intra-individual variability is a substantially minor contributor to the overall variability in sensory nerve block duration compared with the inter-individual variability.

The effect of ropivacaine concentration on common peroneal nerve block duration using a fixed dose: A randomised, double-blind trial in healthy volunteers.

BACKGROUND: The effect of local anaesthetic concentration on peripheral nerve block duration is unclear. Recent clinical trials found nerve blocks of equivalent duration despite changing local anaesthetic concentration but with a fixed local anaesthetic dose. A criticism of these studies is that the local anaesthetic doses used were above the proposed local anaesthetic dose-duration ceiling level, masking any potential effect of different local anaesthetic concentrations on nerve block duration. OBJECTIVE: We investigated the effect of local anaesthetic concentration on nerve block duration using a fixed local anaesthetic dose below the local anaesthetic dose-duration ceiling level. We hypothesised that changing local anaesthetic concentration would affect nerve block duration. DESIGN: Randomised, double-blind trial. SETTING: Single-centre, academic hospital. PARTICIPANTS: Healthy volunteers. INTERVENTIONS: Each participant received an ultrasound-guided common peroneal nerve block with a fixed dose of 10 mg of ropivacaine dissolved in either 2.5, 5, 10, 15 or 20 ml of 0.9% saline according to group allocation, yielding local anaesthetic concentrations of 4, 2, 1, 0.67 and 0.5 mg ml. MAIN OUTCOME MEASURES: The primary outcome was duration of sensory block defined as altered or no sensitivity to a cold stimulus. The secondary outcome was duration of motor block defined as either paresis or paralysis. Intergroup differences were tested using one-way Analysis of variance . RESULTS: All participants had sensory block, and 56 out of 60 participants had motor block. From the highest to the lowest concentration groups, mean ±â€ŠSD sensory block durations were 13.1 ±â€Š2.7, 13.4 ±â€Š3.3, 12.6 ±â€Š3.9, 10.4 ±â€Š2.9 and 11.0 ±â€Š2.1 h (P = 0.073), and mean ±â€ŠSD motor block durations were 8.5 ±â€Š2.0, 7.9 ±â€Š3.0, 6.1 ±â€Š3.1, 5.9 ±â€Š3.5, 4.0 1.9 h (P = 0.002). CONCLUSION: In contrast to our hypothesis, we found no changes in mean sensory nerve block duration. However, local anaesthetic dilution resulted in reduced motor block duration. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03326609.

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Suppression of active, but not total MMP-3, is associated with treatment response in a phase III clinical study of rheumatoid arthritis.

OBJECTIVE: Biologics for rheumatoid arthritis (RA) patients with moderate to severe disease may preserve joint function. Matrix metalloproteinase 3 (MMP-3), a key tissue degrading protease, is highly elevated in RA. MMP-3, which measures the total pool of circulating MMP-3 species (cMMP3), is a commonly measured biomarker in rheumatology. The aim was to investigate the association of activated MMP-3 (actMMP3) species with treatment response compared to cMMP-3. METHODS: The LITHE biomarker study (n=741) was a 1-year phase III, double-blind, placebo-controlled, parallel group study of TCZ in RA patients on stable methotrexate. cMMP-3 and actMMP-3 were assessed in fasting serum at baseline, week 4, 16, 24 and 52. Patients not achieving ACR20 remission at week 16 or 28 received rescue treatment (escapers). Spearman's correlation was analysed between biomarker baseline level or biomarker delta and clinical measures. Changes in biomarker levels were studied as a function of time and treatment. RESULTS: ActMMP-3 16-week change in treatment groups was predictive of 1-year radiographic progression; a small change in actMMP3 was equal to worsening radiographics. Baseline cMMP-3 was associated with 52-weeks' radiographic status and cMMP3 16-weeks' change was predictive of 1-year change in disease activity. ActMMP-3 was dose-dependently decreased by TCZ, and escapers decreased in actMMP-3 upon treatment. CONCLUSIONS: ActMMP-3 and cMMP-3 were found to be efficacy biomarkers of TCZ and actMMP-3 were able to differentiated doses. Moreover, the suppression of actMMP3, but not cMMP3 was associated with treatment response. This study illustrates that two biomarkers of the same protein may have different predictive capacities.

Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis.

BACKGROUND: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). METHODS: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. RESULTS: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. CONCLUSIONS: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. TRIAL REGISTRATION: NCT00486434 (trial 1) and NCT00704847 (trial 2).

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes.

AIMS/HYPOTHESIS: The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio. METHODS: The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis. RESULTS: Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA1c and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA1c for individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p < 0.01, and 3.85 (95% CI 1.94, 7.61) p < 0.001, respectively. Endotrophin levels correlated with adipose tissue mass, insulin resistance and fatty liver index. Notably, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile. CONCLUSIONS/INTERPRETATION: Elevated endotrophin serum levels predict response to two insulin sensitisers and reduce the risk of associated adverse effects, thereby, identifying patients with type 2 diabetes who may profit from PPARγ agonist treatment.

Weight change and risk of hyperglycaemia in elderly women.

BACKGROUND: Hyperglycaemia increases the risk of type 2 diabetes, heart disease and stroke, and is influenced by weight. However, the impact of preceding weight change on blood glycemia levels in late-life is less well understood. AIM: We studied the interplay between weight change and risk of hyperglycaemia in a prospective cohort of elderly women. METHODS: Elderly Caucasian women (age: 67.1 years at baseline, n = 1173) enrolled in the Prospective Epidemiological Risk Factor study with baseline and 13-year follow-up measurements of BMI and fasting glucose levels (FPG) and no previous history of diabetes or impaired fasting glucose. Multivariate logistic regression was used to determine risk of hyperglycaemia (FPG ≥ 5.6 mmol/L or HbA1c ≥ 42 mmol/mol) in normalweight (BMI ≤ 25 kg/m2), overweight (BMI = 25-29.9 kg/m2) and obese (BMI ≥ 30 kg/m2) women who either lost weight, were weight-stable or had gained weight at follow-up. RESULTS: Overweight and obese elderly women who had gained weight at follow-up presented an increased risk of hyperglycaemia, OR = 2.7 (1.6-4.6) and OR = 3.2 (1.5-6.8), compared to weight-stable normalweight women. Overweight and obese women who lost weight decreased their risk of hyperglycaemia to a level comparable to weight-stable normalweight women. Overweight and obese women with stable weight presented a two-fold increased risk of hyperglycaemia compared to normalweight weight-stable women. CONCLUSIONS: Losing weight in late life had a positive effect on the risk of hyperglycaemia in overweight and obese women, while further, weight gain increased the risk of hyperglycaemia. The study highlights that strategies to reduce weight in obese and overweight elderly women could have a positive influence on disease burden in late-life.

Severe Human Parechovirus Infections in Infants and the Role of Older Siblings.

Human parechovirus (HPeV) is a cause of severe morbidity among infants and young children. To evaluate the associations between early environmental risk factors and HPeV infections, we carried out a nationwide cohort study linking registry data on birth and sibship characteristics with a laboratory surveillance database, covering all HPeV infections detected in Denmark during 2009-2012 among children <5 years of age. Incidence rate ratios were calculated in log-linear Poisson regression analyses. Overall, 133 HPeV infections, 85 caused by human parechovirus type 3 (HPeV-3) and 48 by human parechovirus other than type 3 (non-HPeV-3), were detected among 132 children. Neither birth weight, mode of delivery, Apgar score, nor gestational age was associated with the risk of HPeV infections. Compared with firstborn children, secondborn children were at a 9-fold increased risk (incidence rate ratio = 8.68, 95% confidence interval: 3.85, 19.53) of contracting HPeV-3 infections, but at no increased risk of contracting non-HPeV-3 infections. However, the shorter the age gap to the nearest older sibling, the higher the risk of HPeV-3 as well as non-HPeV-3 infections, although the trend was strongest for HPeV-3 infections. Our study is the first to suggest that having a slightly older sibling increases the risk for severe neonatal HPeV infections. This new knowledge might lead to new preventive measures.

Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy.

There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation.

Dynamic Cerebral Autoregulation after Cardiopulmonary Bypass.

Background Cerebral hemodynamic disturbances in the peri- or postoperative period may contribute to postoperative cognitive dysfunction (POCD) in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We therefore examined dynamic cerebral autoregulation (dCA) post-CPB and changes in neurocognitive function in patients that had undergone CABG. Materials and Methods We assessed dCA by transfer function analysis of spontaneous oscillations between arterial blood pressure and middle cerebral artery blood flow velocity measured by transcranial Doppler ultrasound in eight patients 6 hours after the cessation of CPB; 10 healthy volunteers served as controls. Neurocognitive function was assessed by four specific tests 1 day prior to and 3 days after CPB. Results Even though patients exhibited systemic inflammation and anemic hypoxemia, dCA was similar to healthy volunteers (gain: 1.24 [0.94-1.49] vs. 1.22 [1.06-1.34] cm mm Hg-1 s-1, p = 0.97; phase: 0.33 [0.15-0.56] vs. 0.69 [0.50-0.77] rad, p = 0.09). Neurocognitive testing showed a perioperative decline in the Letter Digit Coding Score (p = 0.04), while weaker dCA was associated with a lower Stroop Color Word Test (rho = - 0.90; p = 0.01). Discussion and Conclusion We found no changes in dCA 6 hours after CPB. However, based on the data at hand, it cannot be ruled out that changes in dCA predispose to POCD, which calls for larger studies that assess the potential impact of dCA in the early postoperative period on POCD.