Environmental drivers of increased ecosystem respiration in a warming tundra.

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon1,2. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere3,4. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain5-7. This hampers the accuracy of global land carbon-climate feedback projections7,8. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis.

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.

Readmission of older acutely admitted medical patients after short-term admissions in Denmark: a nationwide cohort study.

BACKGROUND: Knowledge of unplanned readmission rates and prognostic factors for readmission among older people after early discharge from emergency departments is sparse. The aims of this study were to examine the unplanned readmission rate among older patients after short-term admission, and to examine risk factors for readmission including demographic factors, comorbidity and admission diagnoses. METHODS: This cohort study included all medical patients aged ≥65 years acutely admitted to Danish hospitals between 1 January 2013 and 30 June 2014 and surviving a hospital stay of ≤24 h. Data on readmission within 30 days, comorbidity, demographic factors, discharge diagnoses and mortality were obtained from the Danish National Registry of Patients and the Danish Civil Registration System. We examined risk factors for readmission using a multivariable Cox regression to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for readmission. RESULTS: A total of 93,306 patients with a median age of 75 years were acutely admitted and discharged within 24 h, and 18,958 (20.3%; 95% CI 20.1 - 20.6%) were readmitted with a median time to readmission of 8 days (IQR 3 - 16 days). The majority were readmitted with a new diagnosis. Male sex (aHR 1.15; 1.11 - 1.18) and a Charlson Comorbidity Index ≥3 (aHR 2.28; 2.20 - 2.37) were associated with an increased risk of readmission. Discharge diagnoses associated with increased risk of readmission were heart failure (aHR 1.26; 1.12 - 1.41), chronic obstructive pulmonary disease (aHR 1.33; 1.25 - 1.43), dehydration (aHR 1.28; 1.17 - 1.39), constipation (aHR 1.26; 1.14 - 1.39), anemia (aHR 1.45; 1.38 - 1.54), pneumonia (aHR 1.15; 1.06 - 1.25), urinary tract infection (aHR 1.15; 1.07 - 1.24), suspicion of malignancy (aHR 1.51; 1.37 - 1.66), fever (aHR 1.52; 1.33 - 1.73) and abdominal pain (aHR 1.12; 1.05 - 1.19). CONCLUSIONS: One fifth of acutely admitted medical patients aged ≥65 were readmitted within 30 days after early discharge. Male gender, the burden of comorbidity and several primary discharge diagnoses were risk factors for readmission.

Long-term comparative safety analysis of the risks associated with adding or switching to a sulfonylurea as second-line Type 2 diabetes mellitus treatment in a US veteran population.

AIM: To examine the risks of all-cause mortality and cardiovascular events associated with adding vs switching to second-line therapies in a comparative safety study of people with Type 2 diabetes mellitus. METHODS: We conducted a retrospective cohort study using an as-treated analysis of people served by the Veterans Health Administration who were on metformin and subsequently augmented this treatment or switched to other oral glucose-lowering treatments between 1998 and 2012. This study included 145 250 people with long follow-up. Confounding was addressed through several strategies, involving weighted propensity score models with rich confounder adjustment and strict inclusion criteria, coupled with an incident-user design. RESULTS: Second-line use of sulfonylureas was related to higher mortality (hazard ratio 1.39, 95% CI 1.14, 1.70) and cardiovascular risks (hazard ratio 1.19, 95% CI 1.09, 1.30) compared with thiazolidinedione therapy. Differential hazards were associated with discontinuing or not discontinuing metformin; switching to sulfonylurea therapy was associated with a higher risk of all-cause mortality and cardiovascular events compared with all other therapies. Furthermore, add-on sulfonylurea therapy was associated with an elevated risk for both outcomes when compared with thiazolidinedione add-on therapy. CONCLUSIONS: The results of the present study may inform decisions on whether to augment or discontinue metformin; when considering the long-term risks, switching to a sulfonylurea appears unfavourable compared with other therapies. Instead, adding a thiazolidinedione to existing metformin therapy appears to be superior to adding or switching to a sulfonylurea.

Preadmission use of antidepressants and risk of complications and death after colorectal cancer surgery: a nationwide population-based cohort study.

AIM: Few studies have evaluated how preadmission use of antidepressants affects outcomes in colorectal cancer (CRC) patients after they have undergone surgery. Therefore, our aim is to examine whether preadmission use of antidepressants increased the risk of complications and death in patients who underwent CRC surgery. METHOD: Using the Danish Colorectal Cancer Group Database we identified patients who underwent CRC surgery in Denmark from 2005 to 2012. We identified prescriptions for antidepressants redeemed within 1 year prior to surgery and categorized patients as current users (≤ 90 days), former users (91-365 days) and nonusers. All patients were followed from surgery to 30 days thereafter or to death. We calculated 30-day rates of complications, intensive care unit (ICU) admission and mortality and compared these between users and nonusers using logistic and Cox regression adjusting for potential confounders. RESULTS: Of 27 374 patients, 8.9% were current users and 3.0% were former users. Antidepressant users were older and had more comorbidity but a similar cancer stage. Compared with nonusers, current users had a higher risk of postoperative reoperation [adjusted odds ratio (aORs) = 1.15 (95% CI 1.02-1.30)], medical complications [aORs = 1.41 (95% CI 1.25-1.60)] and increased ICU admission rate [adjusted hazard ratio (aHR) = 1.32 (95% CI 1.21-1.45)]. The 30-day mortality was 11.4% for current users, 9.1% for former users and 6.2% for nonusers [aHR = 1.34 (95% CI 1.17-1.53) for current vs nonusers]. CONCLUSION: Patients with preadmission use of antidepressants had a higher risk of complications and ICU admission, and higher 30-day mortality following CRC surgery than nonusers.

Out-of-hours intensive care unit admission and 90-day mortality: a Danish nationwide cohort study.

BACKGROUND: Mortality rates in critically ill adult patients admitted to the intensive care unit (ICU) remains high, and numerous patient- and disease-related adverse prognostic factors have been identified. In recent years, studies in a variety of emergency conditions suggested that outcome is dependent on the time of hospital admission. The importance of out-of-hours admission to the ICU has been sparsely evaluated and with ambiguous findings. We assessed the association between out-of-hours (16:00 to 07:00) and weekend admission to the ICU, respectively, and 90-day mortality in a nationwide cohort. METHODS: We included all Danish adult patients admitted to the ICU between 1 January 2011 and 30 June 2014, with an ICU stay > 24 h. The crude and adjusted association between out-of-hours and weekend admission and 90-day mortality was assessed (odds ratio (ORs) with 95% confidence intervals (CI)). RESULTS: A total of 44,797 patients were included, 53.3% were admitted out-of-hours, and 22.6% during weekends. Median age was 67 years (interquartile range (IQR) 55-76), and median SAPS II was 42 (IQR 30-54). Patients admitted in-hours vs. out-of-hours displayed a 90-day mortality rate of 41.0% vs. 44.2%. The adjusted association (OR with 95% CI) between out-of-hours admission and 90-day mortality was 1.07 (1.02-1.11), and the adjusted association (OR with 95% CI) between weekend admission and 90-day mortality was 1.10 (1.05-1.15). CONCLUSION: This nationwide study suggests that critically ill adult patients admitted to the ICU during weekends and out-of-hours, and with an ICU stay > 24 h are at slightly increased risk of mortality.

Volume of ropivacaine 0.2% and common peroneal nerve block duration: a randomised, double-blind cohort trial in healthy volunteers.

The volume-duration relationship using low concentrations of ropivacaine for peripheral nerve blocks is unknown, even though low concentrations of ropivacaine are increasingly used clinically. We investigated the effect of ropivacaine 0.2% on common peroneal nerve block duration. With ethical committee approval, 60 consenting, healthy volunteers were randomly allocated to receive one of five volumes of ropivacaine 0.2% (2.5, 5.0, 10, 15 or 20 ml) administered by ultrasound-guided, catheter-based injection (at 10 ml.min-1 ) near the common peroneal nerve. Our primary outcome was duration of sensory block, defined by insensitivity to a cold stimulus. Our secondary outcome was duration of motor block. Outcomes were assessed every hour from onset of block to complete remission. Intergroup differences were tested using one-way ANOVA followed by regression analyses using the 20 ml intervention group as reference. Block durations varied significantly (p < 0.0001) between groups. Mean (SD) sensory block durations were 9.2 (3.3), 12.5 (3.0), 15.5 (4.4), 17.3 (3.5) and 17.3 (4.6) h. Mean (SD) motor block durations were 3.3 (2.1), 7.2 (2.5), 9.2 (2.2), 12.7 (2.5) and 12.5 (2.5) h. Regression analysis showed that the effect of volume on block duration was progressively smaller with increasing volume, reaching a threshold volume above which there was no effect on nerve block duration (10 ml for sensory block and 15 ml for motor block). We conclude that there is a ceiling effect of increasing volume of ropivacaine 0.2% on both sensory and motor block duration of the common peroneal nerve.

Impact of body mass index on risk of acute kidney injury and mortality in elderly patients undergoing hip fracture surgery.

The literature is limited regarding risk factors for acute kidney injury (AKI) and mortality in hip fracture patients, although AKI is common in these patients. While obese patients were at increased risk of AKI, underweight patients with and without AKI had elevated mortality for up to 1 year after hip fracture surgery, compared with normal-weight patients. INTRODUCTION: This study aimed to examine risk of postoperative AKI and subsequent mortality, by body mass index (BMI) level, in hip fracture surgery patients aged 65 and over. METHODS: A regional cohort study using medical databases was used. We included all patients who underwent surgery to repair a hip fracture during the years 2005-2011 (n = 13,529) at hospitals in Northern Denmark. We calculated cumulative risk of AKI by BMI level during 5 days postsurgery and subsequent short-term (6-30 days postsurgery) and long-term (31-365 days post-surgery) mortality. We calculated crude and adjusted hazard ratios (aHRs) for AKI and death with 95% confidence intervals (CIs), comparing underweight, overweight, and obese patients with normal-weight patients. RESULTS: Risks of AKI within five postoperative days were 11.9, 10.1, 12.5, and 17.9% for normal-weight, underweight, overweight, and obese patients, respectively. Among those who developed AKI, short-term mortality was 14.1% for normal-weight patients compared to 23.1% for underweight (aHR 1.7 (95% CI 1.2-2.4)), 10.7% for overweight (aHR 0.9 (95% CI 0.6-1.1)), and 15.2% for obese (aHR 0.9 (95% CI 0.6-1.4)) patients. Long-term mortality was 24.5% for normal-weight, 43.8% for underweight (aHR 1.6 (95% CI 1.0-2.6)), 20.5% for overweight (aHR 0.8 (95% CI 0.6-1.2)), and 21.4% for obese (aHR 1.1 (95% CI 0.7-1.8) AKI patients. Similar associations between BMI and mortality were observed among patients without postoperative AKI, although the absolute mortality risk estimates by BMI were considerably lower in patients without than in those with AKI. CONCLUSIONS: Obese patients were at increased risk of AKI compared with normal-weight patients. Among patients with and without postoperative AKI, overweight and obesity were not associated with mortality. Compared to normal-weight patients, underweight patients had elevated mortality for up to 1 year after hip fracture surgery irrespective of the presence of AKI. The absolute mortality risks were higher in all BMI groups with the presence of AKI.

Metformin use and risk of lactic acidosis in people with diabetes with and without renal impairment: a cohort study in Denmark and the UK.

AIMS: To assess risk of lactic acidosis among metformin users compared with other glucose-lowering agent users, according to renal function. METHODS: Using routine registries and databases, we conducted a cohort study. Of 43 580 metformin and 37 788 other glucose-lowering agent users in northern Denmark and 102 688 metformin and 28 788 other glucose-lowering agent users in the UK during 2001-2011, we identified lactic acidosis using diagnostic codes. We calculated the incidence rates of lactic acidosis in metformin and other glucose-lowering agent users overall and according to baseline estimated GFR (eGFR) levels. RESULTS: In Denmark, the incidence rates of lactic acidosis were 11.6 (95% CI 7.0-18.1) and 1.8 (95% CI 0.4-5.4) per 100 000 person-years of metformin use and of other glucose-lowering agent use, respectively. In the UK, the corresponding lactic acidosis incidence rates were 6.8 (95% CI 4.6-9.6) and 1.0 (95% CI 0.01-5.7) per 100 000 person-years of metformin use and of other glucose-lowering agent use. The incidence rates increased with decreasing baseline eGFR in both countries. Of the metformin-exposed people with lactic acidosis, 37% in Denmark and 34% in the UK experienced a decline in renal function in the year before the diagnosis. CONCLUSIONS: Risk of lactic acidosis was higher in metformin users than in other glucose-lowering agent users, and increased with decreasing eGFR, although this could be attributable to surveillance bias; however, diagnosed lactic acidosis was rare and can occur regardless of renal function.

Initial placement and secondary displacement of a new suture-method catheter for sciatic nerve block in healthy volunteers: a randomised, double-blind pilot study.

We performed a randomised double-blind pilot study in 16 healthy volunteers to investigate the success rate for placing a new suture-method catheter for sciatic nerve block. A catheter was inserted into both legs of volunteers and each was randomly allocated to receive 15 ml lidocaine 2% through the catheter in one leg and 15 ml saline in the other leg. Successful placement of the catheter was defined as a 20% decrease in maximum voluntary isometric contraction for dorsiflexion of the ankle. Secondary outcomes were maximum voluntary isometric contraction for plantar flexion at the ankle, surface electromyography and cold sensation. After return of motor and sensory function, volunteers performed standardised physical exercises; injection of the same study medication was repeated in the same leg and followed by motor and sensory assessments. Fifteen of 16 (94%; 95%CI 72-99%) initial catheter placements were successful. The reduction in maximum voluntary isometric contraction and surface electromyography affected the peroneal nerve more often than the tibial nerve. Eleven of 15 (73%; 95%CI 54-96%) catheters remained functional with motor and sensory block after physical exercise, and the maximal displacement was 5 mm. Catheters with secondary block failure were displaced between 6 and 10 mm. One catheter was displaced 1.8 mm that resulted in a decrease in maximum voluntary isometric contraction of less than 20%. After repeat test injection, 14 of the 16 volunteers had loss of cold sensation. Neither motor nor sensory functions were affected in the legs injected with placebo. We conclude that the suture-method catheter can be placed with a high success rate, but that physical exercise may cause displacement.

Preadmission use of selective serotonin reuptake inhibitors and short-term mortality in diabetic patients hospitalized due to stroke.

BACKGROUND: Patients with diabetes have an increased risk of stroke with a poor prognosis. Moreover, diabetic patients are at increased risk of depression and therefore likely to use selective serotonin reuptake inhibitors (SSRIs). We examined whether preadmission SSRI use was associated with increased mortality in diabetic patients hospitalized due to stroke. METHODS: Population-based medical databases were used to identify all first-time stroke-related hospitalizations and subsequent mortality in diabetic patients in Denmark between 2004 and 2012 (n = 12 620). Based on redeemed prescriptions, SSRI use was categorized as current (new or long term), former or nonuse, and absolute 30-day mortality and mortality rate ratios (MRRs) were computed using Cox regression controlling for confounding factors. RESULTS: Amongst SSRI nonusers, 30-day stroke mortality was 15.8% (10.4% for ischaemic stroke, 41.8% for intracerebral haemorrhage and 27.3% for subarachnoid haemorrhage). Amongst current SSRI users, 30-day stroke mortality was 23.3% (17.1% for ischaemic stroke, 50.7% for intracerebral haemorrhage and 28.6% for subarachnoid haemorrhage). Current SSRI use was associated with increased 30-day stroke mortality compared with nonuse [adjusted MRR 1.3, 95% confidence interval (CI) 1.1-1.5], with the highest risk observed amongst new users (MRR 1.5, 95% CI 1.2-1.8). Overall stroke mortality was driven by increased mortality due to ischaemic stroke, with adjusted MRRs of 1.3 (95% CI 1.1-1.7) for current users and 1.7 (95% CI 1.2-2.4) for new users. Propensity score-matched results were similar and robust across subgroups. CONCLUSION: In patients with diabetes, preadmission SSRI use was associated with increased mortality following ischaemic stroke, compared with nonuse.

Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future.

Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.

Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment?

The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients might benefit from anti-inflammatory treatment is a topic of intense research in the OA field. We have reviewed the current literature on OA, with an emphasis on inflammation in OA, biochemical markers of structural damage, and anti-inflammatory treatments for OA. The literature suggests that the OA patient population is diverse, consisting of several subpopulations, including one associated with inflammation. This inflammatory subpopulation may be identified by a combination of novel serological inflammatory biomarkers. Preliminary evidence from small clinical studies suggests that this subpopulation may benefit from anti-inflammatory treatment currently reserved for other inflammatory arthritides.

Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials.

PURPOSE: To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural damage classified as Kellgren and Lawrence (KL)2-3. METHODS AND DESIGN: This is the combined reporting of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral sCT in patients with painful knee OA with structural manifestations, enrolling 1176 and 1030 patients, respectively. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo (PBO) for 24 months. The primary efficacy objectives were to examine the treatment effect compared to placebo on change over 24 months in joint space width (JSW) in the signal knee measured by X-ray, and to examine the change in pain and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. Other study parameters included patient and physician global assessment, and biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II). RESULTS: At the 24 month endpoint there was no statistically significant treatment effect on joint space narrowing (JSN) in any of the two studies. In CSMC021C2301 there was a treatment effect on WOMAC (sum of pain, function, stiffness, and total scores) as well as on the biomarkers of bone and joint metabolism, but due to the hierarchical testing procedure the treatment effect was not claimed statistically significant. CONCLUSIONS: The present formulation of oral sCT did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847).

OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA.

BACKGROUND/PURPOSE: The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI. METHODS: Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA). RESULTS: There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner. CONCLUSION: These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.

Preadmission use of ACE inhibitors or angiotensin receptor blockers and short-term mortality after stroke.

BACKGROUND AND AIM: The prognostic impact of ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on stroke mortality remains unclear. We aimed to examine whether prestroke use of ACE-Is or ARBs was associated with improved short-term mortality following ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH). METHODS: We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all first-time stroke patients during 2004-2012 and their comorbidities. We defined ACE-I/ARB use as current use (last prescription redemption <90 days before admission for stroke), former use and non-use. Current use was further classified as new or long-term use. We used Cox regression modelling to compute 30-day mortality rate ratios (MRRs) with 95% CIs, controlling for potential confounders. RESULTS: We identified 100 043 patients with a first-time stroke. Of these, 83 736 patients had ischaemic stroke, 11 779 had ICH, and 4528 had SAH. For ischaemic stroke, the adjusted 30-day MRR was reduced in current users compared with non-users (0.85, 95% CI 0.81 to 0.89). There was no reduction in the adjusted 30-day MRR for ICH (0.95, 95% CI 0.87 to 1.03) or SAH (1.01, 95% CI 0.84 to 1.21), comparing current users with non-users. No association with mortality was found among former users compared with non-users. No notable modification of the association was observed within sex or age strata. CONCLUSIONS: Current use of ACE-Is/ARBs was associated with reduced 30-day mortality among patients with ischaemic stroke. We found no association among patients with ICH or SAH.

Common variant at 16p11.2 conferring risk of psychosis.

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

The VGF-Derived Neuropeptide TLQP-21 Shows No Impact on Hormone Secretion in the Isolated Perfused Rat Pancreas.

TLQP-21 is a VGF-derived neuropeptide proposed to be involved in regulation of metabolism. More specifically it has been suggested that TLQP-21 has the ability to enhance glucose stimulated insulin secretion, making it a candidate for treatment of patients with type 2 diabetes.In this study, we investigated the impact of TLQP-21 on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. We found that administration of 5 and 50 nM TLQP-21 had no impact on pancreatic hormone secretion at 3.5 or 8 mM glucose levels. Increasing TLQP-21 (200 nM) and glucose concentration (3.5 and 16 mM) led to a nonsignificant decrease in glucagon secretion, though insulin and somatostatin secretory patterns remained unaffected. In a final set of experiments, perfusions were performed with infusion of 50 and 1 000 nM TLQP-21 to ensure sufficient stimulation. However, administration of TLQP-21 under this setup showed no impact on the pancreatic hormone secretion either. In conclusion, the outcome of this study does not concur with previous findings, suggesting that the effect of TLQP-21 does not directly involve silent hormone secretion.