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Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease.
Mahadevan, U, Long, MD, Kane, SV, Roy, A, Dubinsky, MC, Sands, BE, Cohen, RD, Chambers, CD, Sandborn, WJ, ,
Gastroenterology. 2021;(4):1131-1139
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Abstract
BACKGROUND & AIMS Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child. METHODS Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest. RESULTS Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51). CONCLUSIONS Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.
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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.
Sevransky, JE, Rothman, RE, Hager, DN, Bernard, GR, Brown, SM, Buchman, TG, Busse, LW, Coopersmith, CM, DeWilde, C, Ely, EW, et al
JAMA. 2021;(8):742-750
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IMPORTANCE Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. OBJECTIVE To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. INTERVENTIONS Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. MAIN OUTCOMES AND MEASURES The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. RESULTS Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. CONCLUSIONS AND RELEVANCE Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03509350.
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Nebulised hypertonic saline in moderate-to-severe bronchiolitis: a randomised clinical trial.
Jaquet-Pilloud, R, Verga, ME, Russo, M, Gehri, M, Pauchard, JY
Archives of disease in childhood. 2020;(3):236-240
Abstract
OBJECTIVES To investigate whether nebulised hypertonic saline (HS) treatment would decrease length of hospital stay (LOS) among infants with moderate-to severe-bronchiolitis compared with standard supportive care (SC). METHODS We conducted an open, multicentre, randomised clinical trial from 1 April 2013 to 31 March 2016, in Swiss children's hospitals. Patients aged 6 weeks to 24 months with a primary diagnosis of moderate or severe bronchiolitis were included. Children with previous episodes of wheezing, cardiac disease, chronic respiratory disease, immunodeficiency, prematurity (gestational age <34 weeks), corticotherapy in the preceding 2 weeks or inhaled bronchodilators within 24 hours before presentation were excluded. Patients were randomised to receive standard SC with nebulisation of 4 mL of 3% sodium chloride every 6 hours versus SSC. Main outcomes and measures were LOS duration of oxygen therapy, transfer to intensive care unit (ICU), readmission within 7 days following discharge and adverse events. RESULTS 121 children were randomised. No statistically significant differences were found between treatment groups at baseline (age, Wang Score, atopic history, smoking exposure). Children in the HS group had a non-significant difference in length of stay -2.8 hours (-10; 16) compared with the SC group. There were no differences in oxygen therapy duration, transfer to ICU, readmission rate or adverse events. The intervention was discontinued at the parents' request in 16% of the cases. CONCLUSION Our study does not support the use of HS nebulisation in children with moderate to severe bronchiolitis. TRIAL REGISTRATION NUMBER NCT01812525.
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PCSK9 Antibody Alirocumab Attenuates Arterial Wall Inflammation Without Changes in Circulating Inflammatory Markers.
Hoogeveen, RM, Opstal, TSJ, Kaiser, Y, Stiekema, LCA, Kroon, J, Knol, RJJ, Bax, WA, Verberne, HJ, Cornel, JH, Stroes, ESG
JACC. Cardiovascular imaging. 2019;(12):2571-2573
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Safety and Impact of Low-dose Methotrexate on Endothelial Function and Inflammation in Individuals With Treated Human Immunodeficiency Virus: AIDS Clinical Trials Group Study A5314.
Hsue, PY, Ribaudo, HJ, Deeks, SG, Bell, T, Ridker, PM, Fichtenbaum, C, Daar, ES, Havlir, D, Yeh, E, Tawakol, A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(11):1877-1886
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BACKGROUND Chronic inflammation in treated HIV infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV. METHODS This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD). RESULTS The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T cells at week 24 and CD8+ T cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo. CONCLUSIONS Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation. CLINICAL TRIALS REGISTRATION NCT01949116.
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Real-World Assessment of Dexamethasone Intravitreal Implant in DME: Findings of the Prospective, Multicenter REINFORCE Study.
Singer, MA, Dugel, PU, Fine, HF, Capone, A, Maltman, J
Ophthalmic surgery, lasers & imaging retina. 2018;(6):425-435
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BACKGROUND AND OBJECTIVE Dexamethasone intravitreal implant (DEX) (Ozurdex; Allergan plc, Dublin, Ireland) is approved for the treatment of diabetic macular edema (DME). This study assessed the real-world effectiveness, safety, and reinjection interval of DEX in adult patients with DME. PATIENTS AND METHODS This was a phase 4, prospective, multicenter (18 U.S. sites), observational study. RESULTS The study population comprised 177 patients (180 eyes; 93.8% previously treated). Baseline mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were 54.4 letters and 424.6 μm, respectively. DEX was administered as monotherapy or with other DME therapy (55%/45%). The mean reinjection interval was 5.0 months. Mean maximum BCVA change from baseline after the first three DEX injections was +9.1 letters, +7.7 letters, and +7.0 letters, respectively (P < .001); 36.0% of eyes achieved 15-letter or greater BCVA improvement. Mean maximum CRT change from baseline was -137.7 μm (P < .001). CONCLUSION DEX used alone or with other DME therapy improved visual and anatomic outcomes in DME patients in clinical practice, with no new safety concerns. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:425-435.].
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Long-term Efficacy and Safety of Adalimumab in Pediatric Patients with Crohn's Disease.
Faubion, WA, Dubinsky, M, Ruemmele, FM, Escher, J, Rosh, J, Hyams, JS, Eichner, S, Li, Y, Reilly, N, Thakkar, RB, et al
Inflammatory bowel diseases. 2017;(3):453-460
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BACKGROUND IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohn's disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. METHODS Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohn's Disease Activity Index remission (Pediatric Crohn's Disease Activity Index ≤ 10) and response (Pediatric Crohn's Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. RESULTS Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. CONCLUSIONS Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohn's disease were consistent with IMAgINE 1 and adult Crohn's disease adalimumab trials.
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Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation.
Williams, KM, Cheng, GS, Pusic, I, Jagasia, M, Burns, L, Ho, VT, Pidala, J, Palmer, J, Johnston, L, Mayer, S, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016;(4):710-716
Abstract
Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.
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β-Glucan-based cream (containing pleuran isolated from pleurotus ostreatus) in supportive treatment of mild-to-moderate atopic dermatitis.
Jesenak, M, Urbancek, S, Majtan, J, Banovcin, P, Hercogova, J
The Journal of dermatological treatment. 2016;(4):351-4
Abstract
BACKGROUND Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases with serious impact on quality of life. β-Glucans are natural substances with potent immunomodulatory and anti-inflammatory activity. METHODS In a multicentre open split-body study, we studied the effect of Imunoglukan P4H® cream in a group of 105 patients with AD (39 males, 37%). Evaluation of subjective (visual analogue scale, VAS) and objective (EASI score, eczema area and severity index) characteristics of AD was carried out. RESULTS In total, 80 patients (76.2%) completed the study. Topical β-glucan application resulted in the significant improvement of both objective and subjective symptoms of AD. On the application side, significant decline in the number of days with AD exacerbation and its severity was observed. Moreover, the subjects experienced decline of pruritus on the β-glucan half of the body (VAS score: 1.68 vs. 1.95, p < 0.001). During the study, the continual and significant decline of EASI scores on the site of β-glucan application was observed (V4: 1.57 vs. 1.85, p < 0.001). The preparation was in general well tolerated. CONCLUSIONS This is the first study evaluating and confirming the potential use of β-glucan-based cream as a supportive complementary therapy of atopic dermatitis.
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Treatment of Meniere's disease with intratympanic dexamethazone plus high dosage of betahistine.
Albu, S, Nagy, A, Doros, C, Marceanu, L, Cozma, S, Musat, G, Trabalzini, F
American journal of otolaryngology. 2016;(3):225-30
Abstract
PURPOSE The aim of the present study was to assess if the combined therapy of intratympanic dexamethasone (ITD) and high dosage of betahistine (HDBH) is able to provide increased vertigo control compared to ITD alone in patients suffering from definite unilateral Meniere's disease (MD). MATERIALS AND METHODS Consecutive MD patients were enrolled and randomly divided in two groups, each comprising 33 cases. Group A received a combination of ITD and identical-appearing placebo pills while Group B received a combination of ITD and HDBH. ITD protocol consisted of three consecutive daily injections. HDBH comprised 144mg/day (48mg tid). The main outcome measures were: 1) vertigo class, pure tone average (PTA), speech discrimination score (SDS) and Functional Level Score (FLS) according to the American Academy of Otolaryngology-Head and Neck Surgery criteria; 2) complete and substantial vertigo control according to the Kaplan-Meier survival method. RESULTS Sixty two patients completed the 24-month follow-up. A complete vertigo control was achieved in 14 patients (44%) from Group A and in 22 patients (73.3%) from Group B, statistically significant (p=0.01). Complete vertigo relief is also significant according to the Kaplan-Meier method: p=0.027, log rank test. Substantial vertigo control was obtained in 21 patients (65.6%) in Group A and 27 patients (90%) in Group B. The difference is statistically significant, p=0.02. The difference is significant according to the Kaplan-Meier method: p=0.035, log rank test. No significant differences between hearing levels and tinnitus scores were demonstrated between the groups. CONCLUSIONS Our preliminary results demonstrate that complete and substantial vertigo control is significantly higher in patients treated with a combination of HDBH and ITD.