Progressive Resistance Training or Neuromuscular Exercise for Hip Osteoarthritis : A Multicenter Cluster Randomized Controlled Trial.

BACKGROUND: Exercise is recommended as first-line treatment for patients with hip osteoarthritis (OA). However, randomized controlled trials providing evidence for the optimal exercise type are lacking. OBJECTIVE: To investigate whether progressive resistance training (PRT) is superior to neuromuscular exercise (NEMEX) for improving functional performance in patients with hip OA. DESIGN: Multicenter, cluster-randomized, controlled, parallel-group, assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT04714047). SETTING: Hospitals and physiotherapy clinics. PARTICIPANTS: 160 participants with clinically diagnosed hip OA were enrolled from 18 January 2021 to 28 April 2023 and randomly assigned to PRT (n = 82) or NEMEX (n = 78). INTERVENTION: Twelve weeks of PRT or NEMEX with 2 supervised 60-minute group sessions each week. The PRT intervention consisted of 5 high-intensity resistance training exercises targeting muscles at the hip and knee joints. The NEMEX intervention included 10 exercises and emphasized sensorimotor control and functional stability. MEASUREMENTS: The primary outcome was change in the 30-second chair stand test (30s-CST). Key secondary outcomes were changes in scores on the pain and hip-related quality of life (QoL) subscales of the Hip Disability and Osteoarthritis Outcome Score (HOOS). RESULTS: The mean changes from baseline to 12-week follow-up in the 30s-CST were 1.5 (95% CI, 0.9 to 2.1) chair stands with PRT and 1.5 (CI, 0.9 to 2.1) chair stands with NEMEX (difference, 0.0 [CI, -0.8 to 0.8] chair stands). For the HOOS pain subscale, mean changes were 8.6 (CI, 5.3 to 11.8) points with PRT and 9.3 (CI, 5.9 to 12.6) points with NEMEX (difference, -0.7 [CI, -5.3 to 4.0] points). For the HOOS QoL subscale, mean changes were 8.0 (CI, 4.3 to 11.7) points with PRT and 5.7 (CI, 1.9 to 9.5) points with NEMEX (difference, 2.3 [CI, -3.0 to 7.6] points). LIMITATION: Participants and physiotherapists were not blinded. CONCLUSION: In patients with hip OA, PRT is not superior to NEMEX for improving functional performance, hip pain, or hip-related QoL. PRIMARY FUNDING SOURCE: Independent Research Fund Denmark.

Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.

Rebound Hypoglycemia and Hyperglycemia in Type 1 Diabetes.

AIMS: The aim was to investigate rebound hypoglycemic and hyperglycemic events, and describe their relation to other glycemic metrics. METHODS: Data from intermittently scanned continuous glucose monitoring were downloaded for 90 days for 159 persons with type 1 diabetes. A hypoglycemic event was defined as glucose <3.9 mmol/l for at least two 15-minute periods. Rebound hypoglycemia (Rhypo) was a hypoglycemic event preceded by glucose >10.0 mmol/l within 120 minutes and rebound hyperglycemia (Rhyper) was hypoglycemia followed by glucose >10.0 mmol/l within 120 minutes. RESULTS: A total of 10 977 hypoglycemic events were identified of which 3232 (29%) were Rhypo and 3653 (33%) were Rhyper, corresponding to a median frequency of 10.1, 2.5, and 3.0 events per person/14 days. For 1267 (12%) of the cases, Rhypo and Rhyper coexisted. The mean peak glucose was 13.0 ± 1.6 mmol/l before Rhypo; 12.8 ± 1.1 mmol/l in Rhyper. The frequency of Rhyper was significantly (P < .001) correlated with Rhypo (Spearman's rho 0.84), glucose coefficient of variation (0.78), and time below range (0.69) but not with time above range (0.12, P = .13). CONCLUSIONS: The strong correlation between Rhyper and Rhypo suggests an individual behavioral characteristic toward intensive correction of glucose excursions.

Development and Validation of the Weighted Index for Childhood Adverse Conditions (WICAC).

BACKGROUND: Adverse experiences in childhood are a major public health concern, promoting social inequality in health through biopsychosocial mechanisms. So far, no known measures comprehend the complexity and variations of severity of adverse events. This study aims to develop and validate a new index: the Weighted Index for Childhood Adverse Conditions (WICAC). METHODS: The population consists of 7493 randomly invited men and women aged 18-72 years. Data were collected in 2012-2015 as part of the Danish Study of Functional Disorders (DanFunD). Content and construct validation of the WICAC was performed with the hypothesis testing of multiple biopsychosocial outcomes: cardiovascular disease, cancer, poor health, back pain, BMI, obesity, anxiety, depression, low vitality, subjective social status, lower education, smoking, and alcohol consumption. Data were analysed with binominal and linear regression models with risk ratios (RR) and mean differences (MD). RESULTS: Content validation is fitting for WICAC. The strongest associations observed were for most severe adversity: Poor Health RR = 2.16 (1.19-2.91), Anxiety RR = 3.32 (2.32-4.74), Heavy Drinking RR = 4.09 (1.85-9.04), and Subjective Social Status MD = -0.481 (-0.721-(-0.241)). Similar results were found for the remaining outcomes. Discriminative validation was undecided. CONCLUSIONS: WICAC is an adequate instrument for measuring cumulative adverse life events in childhood and adolescence for research purposes.

Progressive resistance training compared to neuromuscular exercise in patients with hip osteoarthritis and the additive effect of exercise booster sessions: protocol for a multicentre cluster randomised controlled trial (The Hip Booster Trial).

INTRODUCTION: The primary aim of this randomised controlled trial is to investigate the effectiveness of 3 months of progressive resistance training (PRT) compared to neuromuscular exercise (NEMEX) on functional performance in patients with hip osteoarthritis (OA). Secondary aims are to investigate the effectiveness of exercise booster sessions (EBS) in prolonging the effects of the initial exercise interventions as well as to investigate the cost-effectiveness of PRT, NEMEX and EBS at 12-month follow-up. METHODS AND ANALYSIS: This multicentre cluster randomised controlled trial will be conducted at hospitals and physiotherapy clinics across Denmark. A total of 160 participants with clinically diagnosed hip OA will be recruited. Participants will be cluster randomised to a 3-month intervention of either PRT or NEMEX and to receive EBS or not, resulting in four treatment arms.The primary outcome is change in functional performance, measured by the 30 s chair stand test at 3 months for the primary comparison and at 12 months for the EBS comparisons. Secondary outcomes include changes in 40 m fast-paced walk test, 9-step timed stair climb test, leg extensor muscle power and maximal strength, Hip disability and Osteoarthritis Outcome Score subscales, EuroQol Group 5-dimension, global perceived effect, physical activity and pain. Outcomes are measured at baseline, after the initial 3 months of intervention, and at 6-month, 9-month and 12-month follow-up. An intention-to-treat approach will be used for analysing changes in the primary and secondary outcome measures. ETHICS AND DISSEMINATION: The trial has been approved by the Central Denmark Region Committee on Biomedical Research Ethics (Journal No 1-10-72-267-20) and registered at the Danish Data Protection Agency (Journal No 1-16-02-11-21). Results will be published in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04714047.

The Frequency of Intermittently Scanned Glucose and Diurnal Variation of Glycemic Metrics.

BACKGROUND: The relation between the frequency of intermittently scanned continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR) and time below range (TBR) is unknown. METHOD: A total of 163 persons with type 1 diabetes who used isCGM had glucose data for 60 days downloaded. Mean TIR and median TBR were calculated for 15-minute periods and presented for daytime and nighttime. The values for tertiles of scanning frequency were compared. RESULTS: The 1st tertile (n = 53) of the population scanned <10 times; the 2nd tertile (n = 56) 10-13 times, and the 3rd tertile (n = 54) >13 per 24 hours. TIR (%, mean ± (SD)) increased significantly from the 1st to the 3rd scan tertile both during the day (43.8 ± 14.8, 52.0 ± 12.3, 62.1 ± 12.8) and the night (44.5 ± 17.3, 52.3 ± 18.5, 64.0 ± 13.9; P < .0001). In contrast, TBR (median, (IQR)) was not significantly associated with scan tertiles during daytime (3.5% (1.1-7.8), 4.4% (1.8-6.1), 3.5% (2.1-6.1); P = .85) or nighttime (3.8% (1.4-13.7), 5.0% (1.6-9.6), 5.7% (3.6-10.9); P = .24). In a multiple regression model, a 50% increase in 24-hour scanning frequency was associated with a 7.8 percentage point increase in TIR (95% CI, 5.6-10.0). CONCLUSIONS: Increased scanning frequency was associated with a higher TIR both during daytime and nighttime with no change in TBR.

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

BACKGROUND: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab. AIMS: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance. RESULTS: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring. CONCLUSIONS: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.

The Effect of Seasonal Priming on Specific Inhalation Challenges With Birch and Grass Allergen Among Persons With Allergic Rhinitis.

Objectives: Allergic diseases are prevalent in the working population, and work-related airborne pollen exposure might be substantial, especially among outdoor workers, resulting in work-exacerbated effects. Seasonal exposure to pollen may induce a priming effect on the allergic bronchial response resulting in exaggerated effects at the end of the natural pollen season. This was previously observed among people with asthma but may also be of importance for persons with allergic rhinitis. In this study, we examined the effect of seasonal priming on bronchial responsiveness among young adults with allergic rhinitis and no or mild asthma. In addition, we explored the association between the baseline characteristics of participants and the severity of bronchoconstriction. Finally, we evaluated the application of a novel non-linear regression model to the log-dose-response curves. Material and methods: In a crossover design, 36 participants underwent specific inhalation challenges (SICs) with either grass or birch allergen outside and at the end of the pollen season. The differences in bronchial response were evaluated by comparing the dose-response profiles and PD20 estimates derived by applying a non-linear regression model. Results: The results showed that 12 of the 19 grass pollen-exposed participants had a lower PD20 at the end of the season compared with the outside season. For birch, this was true for nine out of the 17 participants. However, no statistically significant effects of the seasonal pollen exposure were found on neither the shape nor the magnitude of the modeled dose-response curves for either birch allergen, p = 0.77, or grass allergen, p = 0.45. The model depicted a good fit for the data. Among the baseline characteristics, only the size of the skin prick test for grass allergen was associated with PD20. Conclusion: This study does not support a priming effect of pollen exposure on the bronchial response from the natural seasonal exposure levels of grass or birch allergens among young adults with allergic rhinitis.

High-sensitivity Troponin T in hemodialysis patients: a randomized placebo-controlled sub-study investigating angiotensin-II-blockade, variation over time and associations with clinical outcome.

BACKGROUND: Troponin T (TnT) is a well-known risk factor for negative outcome in hemodialysis (HD) patients, but little is known about variation over time, and the impact of clinical and dialysis specific factors. This study investigated the effect of angiotensin II receptor blockade (ARB), short and long-term variation in TnT and associations with clinical parameters. METHODS: In this analysis based on the SAFIR-cohort (Clinical Trials ID: NCT00791830) 81 HD patients were randomized double-blind for placebo (n = 40) or angiotensin II receptor blocker (ARB) treatment (n = 41) with irbesartan (150-300 mg) and followed for 12 months with six serial measurements of TnT using a high-sensitivity assay. RESULTS: Fifty-four patients (67%) completed follow-up. Baseline TnT-medians (min-max) were (placebo/ARB): 45(14-295)/46(10-343) ng/L. ARB-treatment did not significantly affect mean TnT-levels over the 12-month study period. Median week-to-week and one-year TnT-variation (5th-95th-percentile range) using all samples regardless of intervention were: 0(- 14-10) ng/L (week-to-week) and 3(- 40-71) ng/L (12 months). Median TnT-amplitude, capturing the change from the lowest to the highest TnT-value observed during the one-year study period was 38% or 20.5 ng/L. Median ratios with 95% limits of agreement were: 1.00(0.73-1.37); P = 0.92 (1 week/baseline; n = 77) and 1.07(0.52-2.25); P = 0.19 (12 months/baseline; n = 54). Baseline TnT was positively correlated with diabetes, ultrafiltration volume, arterial stiffness, change in intradialytic total peripheral resistance and N-terminal pro b-type natriuretic peptide (NT-proBNP) and negatively correlated with hematocrit, residual renal function and change in intradialytic cardiac output. High baseline TnT was associated with a higher risk of admission and cardiovascular (CV) events during follow-up. Increase in TnT over time (ΔTnT = 12-months-baseline) was significantly associated with increase in left ventricular (LV) mass and NT-proBNP and decrease in LV ejection fraction and late intradialytic stroke volume. ΔTnT was not significantly associated with admissions, CV or intradialytic hypotensive events during follow-up. Admissions were significantly more likely with a high (TnT-amplitude> 20.5 ng/L) than a low TnT-amplitude. Peaks in TnT were less frequent in aspirin-treated patients. CONCLUSION: ARB-treatment had no significant effect on TnT-levels. Week-to-week variation was generally low, yet over 12 months individual patients had considerable TnT fluctuations. Rise in TnT over time was significantly correlated with markers of cardiac deterioration. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00791830 . Date of registration: November 17, 2008. EudraCT no: 2008-001267-11.

Criteria for defining interictal epileptiform discharges in EEG: A clinical validation study.

OBJECTIVE: To define and validate criteria for accurate identification of EEG interictal epileptiform discharges (IEDs) using (1) the 6 sensor space criteria proposed by the International Federation of Clinical Neurophysiology (IFCN) and (2) a novel source space method. Criteria yielding high specificity are needed because EEG over-reading is a common cause of epilepsy misdiagnosis. METHODS: Seven raters reviewed EEG sharp transients from 100 patients with and without epilepsy (diagnosed definitively by video-EEG recording of habitual events). Raters reviewed the transients, randomized, and classified them as epileptiform or nonepileptiform in 3 separate rounds: in 2, EEG was reviewed in sensor space (scoring the presence/absence of each IFCN criterion for each transient or classifying unrestricted by criteria [expert scoring]); in the other, review and classification were performed in source space. RESULTS: Cutoff values of 4 and 5 criteria in sensor space and analysis in source space provided high accuracy (91%, 88%, and 90%, respectively), similar to expert scoring (92%). Two methods had specificity exceeding the desired threshold of 95%: using 5 IFCN criteria as cutoff and analysis in source space (both 95.65%); the sensitivity of these methods was 81.48% and 85.19%, respectively. CONCLUSIONS: The presence of 5 IFCN criteria in sensor space and analysis in source space are optimal for clinical implementation. By extracting these objective features, diagnostic accuracy similar to expert scorings is achieved. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that IFCN criteria in sensor space and analysis in source space have high specificity (>95%) and sensitivity (81%-85%) for identification of IEDs.

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

BACKGROUND: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling. METHODS: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression. RESULTS: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided. CONCLUSIONS: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.

Bone, subcutaneous tissue and plasma pharmacokinetics of cefuroxime in total knee replacement patients - a randomized controlled trial comparing continuous and short-term infusion.

Cefuroxime is widely used as antibiotic prophylaxis for orthopaedic procedures. We evaluated bone, subcutaneous tissue (SCT) and plasma pharmacokinetics of cefuroxime in male patients undergoing total knee replacement (TKR) after both traditional short-term infusion (STI) and continuous infusion (CI). Eighteen male patients undergoing TKR were randomly assigned to STI or CI of 1.5 g of cefuroxime. Measurements were obtained in plasma, SCT, cancellous and cortical bone every 30 min for 8 h following surgery. For sampling in solid tissues, microdialysis was applied. Population pharmacokinetic modelling was performed in order to estimate pharmacokinetic parameters, and to assess the probability of attaining cefuroxime concentrations above clinically relevant minimal inhibitory concentrations (MICs) for 65% and 90% of the 8 h dosing interval. Low SCT and cortical bone penetration were found in both the STI and the CI group, but the findings were only significant in the STI group. Irrespective of MIC, tissue and target, CI leads to improved probability of attaining relevant pharmacokinetic targets compared with STI. For the Staphylococcus aureus MIC breakpoint (4 µg/mL), STI leads to inadequate probability of target attainment. CI of 1.5 g of cefuroxime leads to improved probability of attaining relevant pharmacokinetic targets in male TKR patients compared with traditional STI. These findings suggest that application of CI may improve antibiotic prophylaxis for male TKR patients.

Long-term effects of angiotensin II blockade with irbesartan on inflammatory markers in hemodialysis patients: A randomized double blind placebo controlled trial (SAFIR study).

INTRODUCTION: Low-grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti-inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. METHODS: Adult HD patients were randomized for double-blind treatment with the ARB irbesartan 150-300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1ß, IL-6, IL-8, IL-18, and transforming growth factor-ß (TGF-ß) were measured using Luminex and enzyme-linked immunosorbent assay (ELISA) technology. FINDINGS: Eighty-two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2-23.4)/2.7(0.2-29.6) µg/mL; IL-1ß 1.1(0.0-45.9)/1.1(0.0-7.2) pg/mL; IL-6 10(1-90)/12(1-84) pg/mL; IL-8 31(9-134)/34(5-192) pg/mL; IL-18 364(188-1343)/377(213-832) pg/mL; TGF-ß 3.2(0.8-13.9)/3.6(1.3-3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL-6, IL-8, and TGF-ß between placebo and ARB-treated patients during the study period, and hsCRP, IL-6, IL-8, and TGF-ß were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL-1ß level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL-18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB-treated (P ≥ 0.51 in tests for parallel curves and equal levels). DISCUSSION: Inflammatory biomarkers were neither acutely, nor in the long-term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti-inflammatory effects.

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.

BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02). CONCLUSIONS: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Effect of degree of hydrolysis of whey protein on in vivo plasma amino acid appearance in humans.

Whey protein is generally found to be faster digested and to promote faster and higher increases in plasma amino acid concentrations during the immediate ~60 min following protein ingestion compared to casein. The aim of the present study was to compare three different whey protein hydrolysates with varying degrees of hydrolysis (DH, % cleaved peptide bonds) to evaluate if the degree of whey protein hydrolysis influences the rate of amino acid plasma appearance in humans. A casein protein was included as reference. The three differentially hydrolysed whey proteins investigated were: High degree of hydrolysis (DH, DH = 48 %), Medium DH (DH = 27 %), and Low DH (DH = 23 %). The casein protein was intact. Additionally, since manufacturing of protein products may render some amino acids unavailable for utilisation in the body the digestibility and the biological value of all four protein fractions were evaluated in a rat study. A two-compartment model for the description of the postprandial plasma amino acid kinetics was applied to investigate the rate of postprandial total amino acid plasma appearance of the four protein products. The plasma amino acid appearance rates of the three whey protein hydrolysates (WPH) were all significantly higher than for the casein protein, however, the degree of hydrolysis of the WPH products did not influence plasma total amino acid appearance rate (estimates of DH and 95 % confidence intervals [CI] (mol L(-1) min(-1)): High DH 0.0585 [0.0454, 0.0754], Medium DH 0.0594 [0.0495, 0.0768], Low DH 0.0560 [0.0429, 0.0732], Casein 0.0194 [0.0129, 0.0291]). The four protein products were all highly digestible, while the biological value decreased with increasing degree of hydrolysis. In conclusion, the current study does not provide evidence that the degree of whey protein hydrolysis is a strong determinant for plasma amino acid appearance rate within the studied range of hydrolysis and protein dose.

Effects of facial tooth movement on the periodontium in rats: a comparison between conventional and low force.

BACKGROUND: Bone dehiscences and gingival recession have been associated with orthodontic arch expansion. The aim of this study was to assess and compare periodontal modelling during application of two force levels. METHODS: The second and third upper molars were orthodontically moved buccally with conventional or low forces for 60 or 90 days in 32 rats. Ten non-treated animals were used as controls. The influence of force level and time on dental, skeletal and periodontal parameters (i.e. height and thickness of gingiva and bone) was assessed on histomicrographs using a mixed linear model. RESULTS: Facial tooth position (725 µm, CI 379-1072 µm, distal root of the third molar) and maxillary skeletal width (295 µm, CI 168-421 µm) differed significantly between force groups. Despite bone apposition at the facial aspects of the moved roots, bone dehiscences were developing and bone thickness was decreasing during facial tooth movement. Development of gingival recession was scarce and in cases with extreme facial tooth movement. No remarkable differences between force levels were found for any of the periodontal parameters. CONCLUSIONS: Facial tooth movement with conventional or low forces resulted in similar modelling of facial alveolar bone and gingiva.

The development of a sense of control scale.

In the past decades, sense of control-the feeling that one is in control of one's actions has gained much scientific interests. Various scales have been used to measure sense of control in previous studies, yet no study has allowed participants to create a scale for rating their control experiences despite advances in the neighboring field of conscious vision has been linked to this approach. Here, we examined how participants preferred to rate sense of control during a simple motor control task by asking them to create a scale to be used to describe their sense of control experience during the task. Scale with six steps was most frequently created. Even though some variability was observed in the number of preferred scale steps, descriptions were highly similar across all participants when scales were converted to the same continuum. When we divided participants into groups based on their number of preferred scale steps, mean task performance and sense of control could be described as sigmoid functions of the noise level, and the function parameters were equivalent across groups. We also showed that task performance increased exponentially as a function of control rating, and that, again, function parameters were equivalent for all groups. In summary, the present study established a participant-generated 6-point sense of control rating scale for simple computerized motor control tasks that can be empirically tested against other measures of control in future studies.

Remote ischaemic conditioning on recipients of deceased renal transplants, effect on immediate and extended kidney graft function: a multicentre, randomised controlled trial protocol (CONTEXT).

INTRODUCTION: Delayed graft function due to ischaemia-reperfusion injury is a frequent complication in deceased donor renal transplantation. Experimental evidence indicates that remote ischaemic conditioning (RIC) provides systemic protection against ischaemia-reperfusion injury in various tissues. METHODS AND ANALYSIS: 'Remote ischaemic conditioning in renal transplantation--effect on immediate and extended kidney graft function' (the CONTEXT study) is an investigator initiated, multicentre, randomised controlled trial investigating whether RIC of the leg of the recipient improves short and long-term graft function following deceased donor kidney transplantation. The study will include 200 kidney transplant recipients of organ donation after brain death and 20 kidney transplant recipients of organ donation after circulatory death. Participants are randomised in a 1:1 design to RIC or sham-RIC (control). RIC consists of four cycles of 5 min occlusion of the thigh by a tourniquet inflated to 250 mm Hg, separated by 5 min of deflation. Primary end point is the time to a 50% reduction from the baseline plasma creatinine, estimated from the changes of plasma creatinine values 30 days post-transplant or 30 days after the last performed dialysis post-transplant. Secondary end points are: need of dialysis post-transplant, measured and estimated-glomerular filtration rate (GFR) at 3 and 12 months after transplantation, patient and renal graft survival, number of rejection episodes in the first year, and changes in biomarkers of acute kidney injury and inflammation in plasma, urine and graft tissue. ETHICS AND DISSEMINATION: The study is approved by the local ethical committees and national data security agencies. Results are expected to be published in 2016. TRIAL REGISTRATION NUMBER: NCT01395719.