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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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Cone-beam computed tomography assessment of Schneiderian membranes: Non-infected and infected membranes, and membrane resolution following tooth extraction: A retrospective clinical trial.
Hsu, YH, Pan, WL, Chan, CP, Pan, YP, Lin, CY, Wang, YM, Chang, CC
Biomedical journal. 2019;(5):328-334
Abstract
BACKGROUND Cone-beam computed tomography (CBCT) presurgical assessment on the maxillary sinus can reduce the possibility of Schneiderian membrane perforation. This study examined Schneiderian membrane thickness (SMT) and its relationship with neighboring hard tissues for patients with and without membrane thickening. For patients with sinus infections, we evaluated dimensional changes of the SMT post-extraction relative to pre-extraction SMT and residual bone height (RBH). METHODS CBCT images from 93 patients needing single-tooth implant reconstruction without (n = 83) and with (n = 14) odontogenic infected maxillary sinuses were assessed. SMT, RBH, and lateral wall thickness (LWT) were measured. Causes of extraction, RBH in the infection site, and retrospective post-extraction record of SMT were recorded for the thickened SMT group. RESULTS Mean SMT for normal SMT group was 1.13 ± 0.43 mm, RBH was 6.26 ± 2.38 mm; upper and lower LWT was 1.85 ± 0.95 mm, and 3.07 ± 2.26 mm, respectively. RBH and LWT had no significant relationships with SMT. For thickened SMT group, mean values for SMT and RBH prior to extraction were 4.53 ± 2.46 mm and 1.97 ± 1.43 mm, respectively. Pre-extraction SMT had a moderately negative correlation with pre-extraction RBH. SMT resolution in thickened SMT group was observed by 2.80 ± 1.37 months post-extraction; post-extraction SMT was not significantly different from normal SMT group (p = .187). CONCLUSIONS Within the limitation of the sample size, thickened SMT induced by odontogenic infection subsides about 3 months following tooth extraction, and further sinus lifting implant surgery may be considered.
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Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation.
Norkin, M, Shaw, BE, Brazauskas, R, Tecca, HR, Leather, HL, Gea-Banacloche, J, T Kamble, R, DeFilipp, Z, Jacobsohn, DA, Ringden, O, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019;(2):362-368
Abstract
We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.
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Glycemic control in the infectious diseases ward; role of clinical pharmacist interventions.
Farsaei, S, Karimzadeh, I, Elyasi, S, Hatamkhani, S, Khalili, H
Journal of infection in developing countries. 2014;(4):480-9
Abstract
INTRODUCTION Hyperglycemia is one of the most frequent metabolic complications in hospitalized patients. Increased risk of infection following hyperglycemia has been reported in hospitalized patients and infections may also cause insulin resistance which complicates the control of blood glucose level. In this study the impact of the clinical pharmacist interventions on the glycemic control in patients admitted to infectious diseases ward has been evaluated. METHODOLOGY We conducted a prospective, pre-post interventional study among patients with hyperglycemia. The clinical pharmacist-led multidisciplinary team managed the glycemic profile of patients according to an established insulin protocol commonly used in internal wards. Clinical pharmacists reviewed patients' medical charts for proper insulin administration, evaluated nurses' technique for insulin injection and blood glucose measurement, and educated patients about symptoms of hypoglycemia and the importance of adherence to different aspects of their glycemic management. RESULTS The percentage of controlled random blood sugar increased from 13.8% in the pre-intervention to 22.3% in the post-intervention group (p value < 0.01). On the other hand, the percentage of controlled fasting blood sugars in the post-intervention group was non-significantly higher than in the pre-intervention group. CONCLUSION Pharmacists and additional health care providers from other departments such as nursing and dietary departments need to be devoted to glycemic control service. Collaborative practice agreement between physicians is necessary to promote this service and help to increase the use of such services in different settings for diabetes control.
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Skin toxicity as a risk factor for major infections in breast cancer patients treated with docetaxel.
Poikonen, P, Sjöström, J, Klaar, S, Nittby, LT, Sigurdsson, H, Madsen, EL, Joensuu, H, Blomqvist, C
Acta oncologica (Stockholm, Sweden). 2004;(2):190-5
Abstract
Docetaxel-related skin toxicity, oral and gastrointestinal mucosal toxicity, and changes in blood cell counts were investigated as predictive factors for major infections in 143 women treated with 3-weekly docetaxel (100 mg/m2) as second-line therapy for metastatic breast cancer in a randomized trial. Each patient with a major infection (n = 37) was compared with two controls. Skin toxicity (odds ratio 2.97, 95% CI 1.37-6.47), oral mucositis (1.98, CI 1.30-3.04), and the leukocyte nadir (0.12, CI 0.02-0.51) were significantly associated with a major infection in a univariate logistic regression analysis. In a multivariate analysis, skin toxicity was the only independent factor predictive for grade 3 to 4 infection (2.75, CI 1.00-7.58). A major infection was diagnosed in 62% (8 out of 13) of the docetaxel cycles in severely (grade 4) leukopenic patients who had grade 2 to 4 skin toxicity. Major infections are common in leukopenic patients who develop docetaxel-associated skin toxicity, and leukopenic patients presenting with docetaxel-induced skin toxicity may be candidates for prophylactic anti-infection measures such as prophylactic therapy with hematopoietic growth factors.
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Effect of a multivitamin and mineral supplement on infection and quality of life. A randomized, double-blind, placebo-controlled trial.
Barringer, TA, Kirk, JK, Santaniello, AC, Foley, KL, Michielutte, R
Annals of internal medicine. 2003;(5):365-71
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Abstract
BACKGROUND Use of multivitamin and mineral supplements is common among U.S. adults, yet few well-designed trials have assessed the reputed benefits. OBJECTIVE To determine the effect of a daily multivitamin and mineral supplement on infection and well-being. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Primary care clinics at two medical centers in North Carolina. PARTICIPANTS 130 community-dwelling adults stratified by age (45 to 64 years or >or=65 years) and presence of type 2 diabetes mellitus. INTERVENTION Multivitamin and mineral supplement or placebo taken daily for 1 year. MEASUREMENTS Incidence of participant-reported symptoms of infection, incidence of infection-associated absenteeism, and scores on the physical and mental health subscales of the Medical Outcomes Study 12-Item Short Form. RESULTS More participants receiving placebo reported an infectious illness over the study year than did participants receiving multivitamin and mineral supplements (73% vs. 43%; P < 0.001). Infection-related absenteeism was also higher in the placebo group than in the treatment group (57% vs. 21%; P < 0.001). Participants with type 2 diabetes mellitus (n = 51) accounted for this finding. Among diabetic participants receiving placebo, 93% reported an infection compared with 17% of those receiving supplements (P < 0.001). Medical Outcomes Study 12-Item Short Form scores did not differ between the treatment and placebo groups. CONCLUSIONS A multivitamin and mineral supplement reduced the incidence of participant-reported infection and related absenteeism in a sample of participants with type 2 diabetes mellitus and a high prevalence of subclinical micronutrient deficiency. A larger clinical trial is needed to determine whether these findings can be replicated not only in diabetic persons but also in any population with a high rate of suboptimal nutrition or potential underlying disease impairment.
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The molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) is not useful to assess vitamin A status during infection in hospitalised children.
Donnen, P, Dramaix, M, Brasseur, D, Bitwe, R, Bisimwa, G, Hennart, P
European journal of clinical nutrition. 2001;(12):1043-7
Abstract
OBJECTIVE To assess the usefulness of the molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) to determine vitamin A (VA) status during infection. DESIGN We took advantage of previously collected data during a randomised double-blind, placebo-controlled clinical trial to conduct a secondary analysis of the RBP/TTR ratio and its relationship to infection and VA status. In this clinical trial, children were randomly assigned to one of three groups and received either one single oral high dose of VA (200 000 IU) on the day of admission and subsequently a placebo daily until discharge or daily oral low doses of VA (5000 IU) from admission until discharge or a placebo daily from admission until discharge. SETTING Lwiro pediatric hospital, Province of South Kivu, Democratic Republic of Congo. SUBJECTS A total of 900 children aged 0-72 months hospitalised consecutively between March 1994 and March 1996. MAIN OUTCOME MEASURES RBP/TTR molar ratio after 7 days hospitalisation. RESULTS After 7 days hospitalisation, molar RBP:TTR ratio (mean+/-s.d.) of infected children (C-reactive proteins>10 mg/l) was 0.67+/-0.31 in the high-dose group (n=81), 0.74+/-0.44 in the low dose group (n=71) and 0.73+/-0.39 in the placebo group (n=81). These values did not differ significantly (one-way ANOVA P=0.472). In patients with baseline serum retinol concentrations<0.70 micromol/l, changes in RBP:TTR ratio between admission and day 7 were not statistically different in the three groups (one-way ANOVA P=0.548). CONCLUSIONS In this population of malnourished hospitalised children, molar RBP:TTR ratio does not appear to be useful to assess VA status during infection. SPONSORSHIP Our research was partially supported by a grant from the Fonds de la Recherche Scientifique et Médicale (contract 3.4505.94) and the David and Alice Van Buuren Foundation.
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Localizing infection with a technetium-99m-labeled peptide: initial results.
Palestro, CJ, Weiland, FL, Seabold, JE, Valdivia, S, Tomas, MB, Moyer, BR, Baran, YM, Lister-James, J, Dean, RT
Nuclear medicine communications. 2001;(6):695-701
Abstract
In vitro-labeled leukocyte imaging is useful for the detection of infection, but an in vivo labeling method is preferable. This study sought to evaluate the safety and efficacy of a leukocyte-avid peptide for the detection of infection, to determine the effects of peptide dose on performance and to compare the peptide with in vitro-labeled leukocytes. A 23-amino acid peptide, P483, containing the platelet factor-4 heparin-binding sequence, was labeled with 99mTc and complexed with heparin (P483H). Thirty patients were injected with 29 microg (n = 11), 145 microg (n = 10) or 290 microg (n = 9) of labeled peptide, and imaged 15 min and 90-120 min later. Early and late images were interpreted individually and jointly. Twenty patients underwent (111)In-labeled leukocyte scintigraphy. Fourteen patients had infection: osteomyelitis (n = 7), vascular graft (n = 2), abscess (n = 2), joint replacement (n = 1), surgical wound (n = 1) and pneumonia (n = 1). There were 10 adverse events in six patients; all were mild and resolved spontaneously, and without any intervention. The sensitivity, specificity and accuracy were the same for both early and late imaging: 0.86, 0.81 and 0.83, respectively. Interpreting early and late images together did not improve the results. No relationship between peptide dose and study accuracy was found. In patients undergoing both examinations, the accuracies of the peptide and in vitro-labeled leukocyte imaging were identical: 0.80. In summary, 99mTc-P483H safely, rapidly and accurately detected focal infection, was comparable with in vitro-labeled leukocyte imaging and therefore merits further investigation.
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Imaging of human infection with (131)I-labeled recombinant human interleukin-8.
Gross, MD, Shapiro, B, Fig, LM, Steventon, R, Skinner, RW, Hay, RV
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2001;(11):1656-9
Abstract
UNLABELLED The chemotactic cytokine interleukin-8 (IL-8) plays an important role in attraction and activation of polymorphonuclear leukocytes in infection and inflammation. A pilot study was conducted to determine if radiolabeled IL-8 would depict infection in humans. METHODS Human recombinant IL-8 (rhIL-8) labeled with (131)I (specific activity, 0.4-0.7 MBq [11-18 microCi] (131)I/microg IL-8) was injected intravenously into 8 diabetic patients with active foot infections and evidence of osteomyelitis, 2 patients with successfully treated osteomyelitis, and 1 patient with cellulitis of the thumb. RESULTS Focal accumulation of (131)I-rhIL-8 was seen in 8 of 8 patients with active foot infection and diffuse uptake was seen in the thumb of the 1 patient with cellulitis. In the 2 patients with successfully treated bone infection, multiphase (99m)Tc-hydroxyethylene diphosphonate bone scans were negative early, but late-phase (>3 h) uptake depicted degenerative lesions that did not image with (131)I-rhIL-8. CONCLUSION (131)I-rhIL-8 accumulates rapidly within infected foci in osteomyelitis and cellulitis but not in successfully treated infections or degenerative joint disease.
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Undernutrition in relation to childhood infections: a prospective study in the Sudan.
Kossmann, J, Nestel, P, Herrera, MG, El Amin, A, Fawzi, WW
European journal of clinical nutrition. 2000;(6):463-72
Abstract
OBJECTIVE The aim of the study was to examine the relationships between nutritional status and diarrhoea and respiratory infections. DESIGN Prospective cohort study within the framework of a randomized double-blind placebo-controlled intervention trial. SETTING In rural communities in the Khartoum and Gezira regions, in Northern Sudan. SUBJECTS 28,753 Sudanese pre-school children between 6 months and 6 y old. METHODS Relative risks of subsequent diarrhoea and respiratory infections in relation to nutritional status measured by anthropometry (Z-scores of height-for-age (H/A), weight-for-height (W/H), and weight-for-age (W/A), which reflect stunting, wasting and underweight, respectively) were estimated using odds ratios from logistic regression adjusting for various covariates. RESULTS H/A, W/H and W/A were significantly and inversely associated with subsequent diarrhoea and febrile diarrhoea (P for trend <0.001) with risks being 2.00 times higher (95% confidence interval, CI (1.64, 2.43)) among children with W/A Z-scores below -4 Z, and 1.75 times higher (95% CI (1.56, 1.96)) among those with a W/A Z-score between -4 and -3 Z compared with children having a W/A Z-score > or =1. Age, gender, region of residence and seasonality modified these associations. Also, febrile cough was inversely associated with W/A and W/H (P<0.03), with risks ranging from 1.41 times higher (95% CI (1.02, 1.97)) to 1.21 times higher (95% CI (1.04, 1.41)) in the group of underweight children with W/A Z-scores below -4 and between -2 and -1 Z, all compared with normally nourished children (> or =-1 Z). CONCLUSIONS The reduction of severe but also mild and moderate undernutrition is necessary through nutrition, health and socio-economic improvement in order to prevent morbidity.