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Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
Simpson, EL, Silverberg, JI, Nosbaum, A, Winthrop, KL, Guttman-Yassky, E, Hoffmeister, KM, Egeberg, A, Valdez, H, Zhang, M, Farooqui, SA, et al
American journal of clinical dermatology. 2021;(5):693-707
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Abstract
BACKGROUND Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. OBJECTIVE The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. METHODS Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. RESULTS Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. CONCLUSION Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. TRIAL REGISTRIES ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822.
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Impact of Water Quality, Sanitation, Handwashing, and Nutritional Interventions on Enteric Infections in Rural Zimbabwe: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial.
Rogawski McQuade, ET, Platts-Mills, JA, Gratz, J, Zhang, J, Moulton, LH, Mutasa, K, Majo, FD, Tavengwa, N, Ntozini, R, Prendergast, AJ, et al
The Journal of infectious diseases. 2020;(8):1379-1386
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Abstract
BACKGROUND We assessed the impact of water, sanitation, and hygiene (WASH) and infant and young child feeding (IYCF) interventions on enteric infections in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS We tested stool samples collected at 1, 3, 6, and 12 months of age and during diarrhea using quantitative molecular diagnostics for 29 pathogens. We estimated the effects of the WASH, IYCF, and combined WASH + IYCF interventions on individual enteropathogen prevalence and quantity, total numbers of pathogens detected, and incidence of pathogen-attributable diarrhea. RESULTS WASH interventions decreased the number of parasites detected (difference in number compared to non-WASH arms, -0.07 [95% confidence interval, -.14 to -.02]), but had no statistically significant effects on bacteria, viruses, or the prevalence and quantity of individual enteropathogens after accounting for multiple comparisons. IYCF interventions had no significant effects on individual or total enteropathogens. Neither intervention had significant effects on pathogen-attributable diarrhea. CONCLUSIONS The WASH interventions implemented in SHINE (improved pit latrine, hand-washing stations, liquid soap, point-of-use water chlorination, and clean play space) did not prevent enteric infections. Transformative WASH interventions are needed that are more efficacious in interrupting fecal-oral microbial transmission in children living in highly contaminated environments.
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Infection and Malignancy Outweigh Cardiovascular Mortality in Kidney Transplant Recipients: Post Hoc Analysis of the FAVORIT Trial.
Weinrauch, LA, D'Elia, JA, Weir, MR, Bunnapradist, S, Finn, PV, Liu, J, Claggett, B, Monaco, AP
The American journal of medicine. 2018;(2):165-172
Abstract
OBJECTIVE Now that long-term survival after successful renal transplantation is no longer limited by excessive cardiovascular risk, the primary care physician should consider that infection and malignancy are leading noncardiovascular causes of death even in the recipient with diabetes. METHODS We accessed the National Institutes of Health-sponsored Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) study population (4010 renal transplant recipients with elevated homocysteine levels) studied to determine whether folate and B12 supplementation would reduce cardiovascular end points. This trial had a null result. Patients were classified as being nondiabetic or having type 1 or type 2 diabetes. RESULTS We report an excess (cardiovascular and noncardiovascular) 6-year mortality risk associated with the presence of diabetes mellitus. Two thirds of fatal events in our renal transplant recipients were centrally adjudicated as noncardiovascular. The incidence of noncardiovascular death was 70% higher in the diabetic patient cohort than in the nondiabetic cohort. CONCLUSIONS These results demonstrate that infection (but not malignancy) risks are far higher in diabetic than nondiabetic immunosuppressed individuals (although noncardiovascular death rate in nondiabetic individuals also exceeded cardiovascular deaths) and may play a larger role in the excess mortality populations than previously thought. Given that follow-up in this study was 4 to 10 years after allograft surgery, there was a lesser degree of acute rejection requiring high-dose immunosuppression than in the initial postallograft years. This unique perspective allows transplant recipients to return to primary physicians when taking low doses of immunosuppressive agents and provides focus for follow-up care.
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Effect of vitamin D supplementation, directly or via breast milk for term infants, on serum 25 hydroxyvitamin D and related biochemistry, and propensity to infection: a randomised placebo-controlled trial.
Chandy, DD, Kare, J, Singh, SN, Agarwal, A, Das, V, Singh, U, Ramesh, V, Bhatia, V
The British journal of nutrition. 2016;(1):52-8
Abstract
We assessed the effect of vitamin D supplementation on related biochemistry, infection and dentition of the infant. In a double-blind, placebo-controlled trial conducted in Lucknow, India (latitude 26°N), 230 mother -newborn pairs were randomised to receive, for 9 months, 3000µg/month oral vitamin D3 by the mother (group A) or 10µg/d by the infant (group B) or double placebo (group C). All babies received 15 min of sun exposure (unclothed) during massage. Infants' median 25-hydroxyvitamin D (25(OH)D) was lower in group C (median 45·3; interquartile range (IQR) 22-59·5 nmol/l) than in groups A (median 60·8; IQR 41·3-80·5 nmol/l (P7.5µkat/l) was significantly more frequent in group C babies (16 %) than in group A (4 %) or group B (0 %) babies. The number of days with respiratory or diarrhoeal infection by 9 months of age was higher in group C (median 46·5; IQR 14·8-73·3 d) than in group A (median 18·5; IQR 8·8-31·0 d (P<0·01)) or group B (median 13·0; IQR 7·0-28·5 (P<0·05)). We conclude that monthly maternal or daily infant supplementation with vitamin D along with sun exposure is superior to sun exposure alone in maintaining normal infant 25(OH)D at 3·5 months, and provide protection from elevated alkaline phosphatase and infectious morbidity.
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Comparison of fondaparinux sodium and low molecular weight heparin in the treatment of hypercoagulability secondary to traumatic infection.
Li, B, Wang, K, Zhao, X, Lin, C, Sun, H
Chinese journal of traumatology = Zhonghua chuang shang za zhi. 2015;(3):147-9
Abstract
PURPOSE To compare the effects and side-effects of fondaparinux sodium and low molecular weight heparin in patients with hypercoagulability accompanied with traumatic infection. METHODS Thirty-six patients with post-traumatic infections in our hospital intensive care center were diagnosed with hypercoagulability from February 2012 to February 2013. These patients were randomly divided into 2 groups. In group F (18 patients), the patients were treated with fondaparinux sodium, 2.5 mg, 1/d for 11 d. In group L (18 patients), the patients were treated with low molecular weight heparin, 4100 U, 1/12 h for 11 d. The incidence of deep vein thrombosis, bleeding events and multiple organ dysfunction syndrome (MODS) and mortality of two groups after anticoagulation therapy were analyzed. Fibrinogen, D-dimer level and activity of antithrombin III were measured by the coagulation analyzer. RESULTS The incidence of deep vein thrombosis, MODS incidence and mortality were not significantly different between the two groups. The rate of bleeding evens in group F was lower than group L (p < 0.05). Antithrombin III got an upward trend after anticoagulant therapy, in which it was higher in group F than in group L on the 5th d and 11th d (p<0.05). Fibrinogen levels were gradually increased, and there was no significant difference between two groups (p>0.05). D-dimer was significantly decreased after anticoagulant therapy for 5 d (p<0.01), and there were significant differences between two groups on the 5th d and 7th d (p<0.05). It showed no significant difference on the 11th d (p>0.05). CONCLUSION Fondaparinux sodium and low molecular weight heparin can effectively improve coagulopathy in patients with traumatic infection. Compared with low molecular weight heparin, fondaparinux sodium may reduce the risk of bleeding events in patients with hypercoagulability accompanied by traumatic infection.
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Interventions to increase immunisation coverage among children 12-23 months of age in India through participatory learning and community engagement: pilot study for a cluster randomised trial.
Johri, M, Chandra, D, Koné, GK, Dudeja, S, Sylvestre, MP, Sharma, JK, Pahwa, S
BMJ open. 2015;(9):e007972
Abstract
OBJECTIVE With the aim of conducting a future cluster randomised trial to assess intervention impact on child vaccination coverage, we designed a pilot study to assess feasibility and aid in refining methods for the larger study. TRIAL DESIGN Cluster-randomised design with a 1:1 allocation ratio. METHODS Clusters were 12 villages in rural Uttar Pradesh. All women residing in a selected village who were mothers of a child 0-23 months of age were eligible; participants were chosen at random. Over 4 months, intervention group (IG) villages received: (1) home visits by volunteers; (2) community mobilisation events to promote immunisation. Control group (CG) villages received community mobilisation to promote nutrition. A toll-free number for immunisation was offered to all IG and CG village residents. Primary outcomes were ex-ante criteria for feasibility of the main study related to processes for recruitment and randomisation (50% of villages would agree to participate and accept randomisation; 30 women could be recruited in 70% of villages), and retention of participants (50% of women retained from baseline to endline). Clusters were assigned to IG or CG using a computer-generated randomisation schedule. Neither participants nor those delivering interventions were blinded, but those assessing outcomes were blinded to group assignment. RESULTS All villages contacted agreed to participate and accepted randomisation. 36 women were recruited per village; 432 participants were randomised (IG n=216; CG n=216). No clusters were lost to follow-up. The main analysis included 86% (373/432) of participants, 90% (195/216) from the IG and 82% (178/216) from the CG. CONCLUSIONS Criteria related to feasibility were satisfied, giving us confidence that we can successfully conduct a larger cluster randomised trial. Methodological lessons will inform design of the main study. TRIAL REGISTRATION NUMBER ISRCTN16703097.
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Effects of extended-release niacin with laropiprant in high-risk patients.
, , Landray, MJ, Haynes, R, Hopewell, JC, Parish, S, Aung, T, Tomson, J, Wallendszus, K, Craig, M, Jiang, L, et al
The New England journal of medicine. 2014;(3):203-12
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Abstract
BACKGROUND Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. METHODS After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). RESULTS During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001). CONCLUSIONS Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).
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Local injection of methylprednisolonacetat to prevent seroma formation after mastectomy.
Axelsson, CK, Quamme, GM, Lanng, C, Szecsi, PB, Mortensen, MB, Wegeberg, B, Arpi, M, Lingskov, M, Puglich, MS, Okholm, M
Danish medical journal. 2012;(9):A4482
Abstract
INTRODUCTION This study served the following three purposes: To evaluate the prophylactic effect against seroma of a single dose of steroid in the mastectomy cavity, to evaluate the thesis that there is a connection between subclinical bacterial colonization and seroma formation and to evaluate if a simple urine stix test can detect postmastectomy infection. MATERIAL AND METHODS This was a double-blinded and randomized study of injection of methylprednisolonacetate versus saline in the mastectomy cavity at the time of drain removal. A total of 160 females were enrolled after mastectomy. The study parameters were as follows: seroma volume, number of seroma punctures, frequency of clinical infections, degree and type of subclinical colonization, complications and evaluation of the microbiological results of the stix test with automatically read glucose, ketones, blood, pH, protein, nitrite and leucocytes. The degree of inflammation was monitored by measurement of 15 cytokines in each sample of seroma fluid. The study was initiated in August 2010 and is expected to run for three years. DISCUSSION Some reports have concluded that seroma formation forms part of postsurgical inflammation. Steroids are effective against inflammation and accumulation of fluid at the surgical site after several types of surgery and have also proved valuable in the treatment of seroma formation. In the present study, the prophylactic effect of steroids on seroma formation is investigated. CONCLUSION As the incidence of postmastectomy seroma formation is 80%, there is a need for improvement in the prophylaxis and treatment of this condition. FUNDING not relevant. TRIAL REGISTRATION Medicines Agency The EudraCT number 2009-016650-40 has been issued for your Sponsor's Protocol Code Number 23837. Data protection agency J.no. F.750.75-2. The study is perfomed in collaboration with the GCP Unit, capital Region, Bispebjerg Hospital under the EudraCT number: 2009-016650-40.
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Effect of vitamin D supplementation of low birth weight term Indian infants from birth on cytokine production at 6 months.
Trilok-Kumar, G, Arora, H, Rajput, M, Chellani, H, Singh, V, Raynes, J, Arya, S, Aggarwal, S, Srivastava, N, Sachdev, HP, et al
European journal of clinical nutrition. 2012;(6):746-50
Abstract
BACKGROUND/OBJECTIVES Vitamin D deficiency has been associated with impaired resistance to infection, which may be mediated by alterations in cytokine responses. We investigated the effect of vitamin D supplementation to infants on whole blood in-vitro cytokine production and on the inflammatory marker, plasma C-reactive protein (CRP). SUBJECTS/METHODS Blood samples were taken at 6 months of age from infants participating in the DIVIDS (Delhi Infant Vitamin D Supplementation) randomized controlled trial of weekly vitamin D supplements (1400 IU = recommended intake) from birth to 6 months with the aim of decreasing mortality and severe morbidity. We measured plasma CRP and whole blood in-vitro production of tumour necrosis factor-α (TNFα), interferon-γ (INFγ), interleukin (IL)-10 and IL-13 following no stimulation or stimulation with lipopolysaccharide or phytohemagglutinin. RESULTS Although the intervention improved vitamin D status in a severely deficient population, there were no differences between treatment groups in plasma CRP or in the production of any of the cytokines in either unstimulated or stimulated cultures. Recent illness had limited association with immunological markers. Plasma 25-hydroxyvitamin D levels were not associated with CRP or production of any cytokines. CONCLUSIONS Vitamin D supplementation did not affect plasma CRP or whole blood cytokine production of vitamin D-deficient low birth weight infants. This is consistent with the lack of effect of vitamin D on mortality and severe morbidity among infants in the DIVIDS trial.
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A formula containing galacto- and fructo-oligosaccharides prevents intestinal and extra-intestinal infections: an observational study.
Bruzzese, E, Volpicelli, M, Squeglia, V, Bruzzese, D, Salvini, F, Bisceglia, M, Lionetti, P, Cinquetti, M, Iacono, G, Amarri, S, et al
Clinical nutrition (Edinburgh, Scotland). 2009;(2):156-61
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BACKGROUND & AIM: The addition of prebiotics to infant formula modifies the composition of intestinal microflora. Aim of the study was to test the hypothesis that prebiotics reduce the incidence of intestinal and respiratory infections in healthy infants. METHODS A prospective, randomized, placebo-controlled, open trial was performed. Healthy infants were enrolled and randomized to a formula additioned with a mixture of galacto- and fructo-oligosaccharides or to a control formula. The incidence of intestinal and respiratory tract infections and the anthropometric measures were monitored for 12 months. RESULTS Three hundred and forty two infants (mean age 53.7+/-32.1 days) were enrolled. The incidence of gastroenteritis was lower in the supplemented group than in the controls (0.12+/-0.04 vs. 0.29+/-0.05 episodes/child/12 months; p=0.015). The number of children with more than 3 episodes tended to be lower in prebiotic group (17/60 vs. 29/65; p=0.06). The number of children with multiple antibiotic courses/year was lower in children receiving prebiotics (24/60 vs. 43/65; p=0.004). A transient increase in body weight was observed in children on prebiotics compared to controls during the first 6 months of follow-up. CONCLUSIONS Prebiotic administration reduce intestinal and, possibly, respiratory infections in healthy infants during the first year of age.