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.
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.
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.
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.
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.
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.
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.
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.
IntroductionThe 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 analysisThis 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 disseminationThe 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 numberNCT04714047.
Summary
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.
Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones.
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.
To ...investigate whether progressive resistance training (PRT) is superior to neuromuscular exercise (NEMEX) for improving functional performance in patients with hip OA.
Multicenter, cluster-randomized, controlled, parallel-group, assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT04714047).
Hospitals and physiotherapy clinics.
160 participants with clinically diagnosed hip OA were enrolled from 18 January 2021 to 28 April 2023 and randomly assigned to PRT (
= 82) or NEMEX (
= 78).
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.
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).
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).
Participants and physiotherapists were not blinded.
In patients with hip OA, PRT is not superior to NEMEX for improving functional performance, hip pain, or hip-related QoL.
Independent Research Fund Denmark.
The kidneys account for about 10% of the whole body oxygen consumption, whereas only 0.5% of the total body mass. It is known that intrarenal hypoxia is present in several diseases associated with ...development of kidney disease, including diabetes, and when renal blood flow is unaffected. The importance of deranged oxygen metabolism is further supported by deterioration of kidney function in patients with diabetes living at high altitude. Thus, we argue that reduced oxygen availability alters renal energy metabolism. Here, we introduce a novel magnetic resonance imaging (MRI) approach to monitor metabolic changes associated with diabetes and oxygen availability. Streptozotocin diabetic and control rats were given reduced, normal, or increased inspired oxygen in order to alter tissue oxygenation. The effects on kidney oxygen metabolism were studied using hyperpolarized 1-13Cpyruvate MRI. Reduced inspired oxygen did not alter renal metabolism in the control group. Reduced oxygen availability in the diabetic kidney altered energy metabolism by increasing lactate and alanine formation by 23% and 34%, respectively, whereas the bicarbonate flux was unchanged. Thus, the increased prevalence and severity of nephropathy in patients with diabetes at high altitudes may originate from the increased sensitivity toward inspired oxygen. This increased lactate production shifts the metabolic routs toward hypoxic pathways.
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