Short-term Regimen Research Articles

Short-Term Intensified Dosage Regimen of Mycophenolic Acid is Associated with Less Acute Rejection in Kidney Transplantation from Donation after Circulatory Death

Introduction: Whether an early, short-term, adequate exposure to mycophenolic acid (MPA) under tacrolimus-based immunosuppression regimen in kidney transplantation from donation after circulatory death (DCD) was effective and safe is yet unknown. Material and Methods: The study was a single-center, retrospective, cohort study of DCD transplantation in China. Intensified and standard dosage regimens of enteric-coated mycophenolate sodium (EC-MPS) were week 1, 2,160 vs. 1,440 mg/day. The incidences of biopsy-proven acute rejection (BPAR), delayed graft function, infection, and patient and graft survival were compared between the 2 groups. Results: A total of 209 patients (n = 82 in intensified group and n = 127 in standard group) were enrolled from August 2013 to December 2014. The incidence of BPAR at 12 months was significantly lower in the intensified group as compared to that of the standard group. (2.4 vs. 10.2%, p = 0.035). The mean MPA area under curve (AUC) levels at day 7 was significantly higher in the intensified group than that in the standard group (66.18 ± 35.48 vs. 45.30 ± 23.5 mg·h/L, p < 0.001). MPA AUC levels were significantly decreased in patients with BPAR as compared to those with NO-BPAR. Conclusion: An early, short-term regimen of intensified EC-MPS with tacrolimus increased early MPA exposure and achieved a low rate of BPAR in kidney transplantation from DCD.

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

ABSTRACT The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1 ± or Atg4b −/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1 +/- and Atg4b −/- mice, we observed an increase in the toxicity of MTX on Atg4b −/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.

PGI10 - COMPARATIVE EFFECTIVENESS OF PAN-GENOTYPIC THERAPIES FOR THE TREATMENT OF PATIENTS WITH HEPATITIS C VIRUS INFECTION IN BULGARIA

Hepatitis C virus (HCV) is a positive-stranded RNA virus which belongs to the family of flaviviruses, predominantly infecting liver hepatocytes. HCV infection is a major cause for morbidity worldwide. The primary objective of this study was to evaluate the comparative effectiveness of pan-genotypic therapies for the treatment of patients with HCV infection in Bulgaria (sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir). The following databases were searched: MEDLINE, EMBASE, Cochrane Library, PubMed and clinicaltrials.gov to identify studies evaluating the therapeutic efficacy of sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for the treatment of HCV in treatment-naïve/experienced patients with genotypes GT1/2/3/4/5/6. The search was held using keywords: Hepatitis C virus (HCV), sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir clinical trials, comparative, study. The research was mainly focused on the comparison of SVR in patients with genotype GT1b, since, according to local epidemiological data, 90% of HCV positive patients in Bulgaria are carriers of this genotype. The systematic literature review identified 11 studies which evaluated efficacy of pan-genotypic treatments. The range of SVR rates among all the genotypes, achieved after therapy with sofosbuvir/velpatasvir/voxilaprevir in treatment-naïve patients, was 92-100% (8-week therapy) and in experienced patients - 99-100% (12-week therapy), with glecaprevir/pibrentasvir was 91- 100% (12-week therapy), and with sofosbuvir/velpatasvir was 97-100% (12-week therapy). The highest SVR rates for patients with GT1b genotype was achieved in treatment experienced patients receiving 12-week sofosbuvir/velpatasvir/voxilaprevir therapy (99%). The SVR12 rate in patients, receiving sofosbuvir/velpatasvir/voxilaprevir for 8 weeks is comparable with the rate observed in patients treated with sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for 12 weeks thus demonstrating that sofosbuvir/velpatasvir/voxilaprevir is a non-inferior therapy offering simple (administration once daily) and short-term (8- week) treatment regimen with high efficacy, favourable safety profile and good tolerability. This would result in improving the quality of life of patients and contribute significantly to the treatment of HCV infection in Bulgaria.

A Low FODMAP Gluten-Free Diet Improves Functional Gastrointestinal Disorders and Overall Mental Health of Celiac Disease Patients: A Randomized Controlled Trial.

A subset of patients with celiac disease (CD) on a gluten-free diet (GFD) reported the persistence of functional gastrointestinal disorders. Foods containing fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can trigger a broad range of gastrointestinal symptoms in sensitive individuals. We evaluated the effects of a low FODMAP diet (LFD) on gastrointestinal and psychological symptomatology in CD patients. A total of 50 celiac patients on GFDs and with persistence of gastrointestinal symptoms were included. The patients were randomly allocated to one of two dietary groups—one on a low FODMAP GFD (LF-GFD, n = 25) and the other on a regular GFD (R-GFD, n = 25)—for 21 days. Psychological symptomatology and quality of life were evaluated by the Symptom Checklist-90-R (SCL-90) and the Short Form (36) Health Survey (SF-36) questionnaires, respectively. Gastrointestinal symptomatology and general well-being were evaluated by visual analogue scale (VAS) scores. After 21 days, 21 and 23 patients completed the dietary treatment on LF-GFD and R-GFD, respectively. A reduced global SCL-90 index (p < 0.0003) was found in the LF-GFD group but not in the R-GFD one. However, the SF-36 scores did not differ between groups after treatment. The VAS for abdominal pain was much lower, and the VAS for fecal consistency enhanced after treatment in the LF-GFD group. General well-being increased in both groups but with a much higher improvement in the LF-GFD (p = 0.03). A short-term LFD regimen helps to improve the psychological health and gastrointestinal symptomatology with enhanced well-being of CD patients with persisting functional gastrointestinal symptomatology. The long-term clinical effects of LFD in particular subgroups of CD patients need further evaluation.

Effect of exercise on metabolic syndrome in black women by family history and predicted risk of breast cancer: The FIERCE Study.

This study examined the effects of supervised and home-based exercise interventions on changes in metabolic syndrome (MetS) according to breast cancer risk (high vs low) in black women enrolled in the Focused Intervention on Exercise to Reduce Cancer (FIERCE) trial. Postmenopausal, obese, metabolically unhealthy black women, 45 to 65 years old, were randomized to supervised aerobic exercise (73 women), home-based walking-based exercise (69 women), or a control arm (71 women). Participants in the exercise arms underwent a 6-month intervention with study assessments conducted at the baseline and 6 months. The primary outcome measure was MetS (fasting glucose, waist circumference, blood pressure, serum triglycerides, and high-density lipoprotein [HDL]). The intervention effects on MetS, stratified by breast cancer risk as measured by the family history of breast cancer and model-based projected breast cancer risk, were examined with intent-to-treat analyses using generalized estimating equation models. Among women with a family history of breast cancer, the exercise arms had lower mean MetS z scores, which suggested an improvement in the metabolic profile, than controls at 6 months (controls, + 0.55; home-based arm, -0.97, P < .01; supervised arm, -0.89, P < .01). Stratified analyses by projected breast cancer risk suggested similar but statistically nonsignificant findings, with those at high risk having more favorable changes in the MetS z score in the exercise arms versus the control arm. These changes were primarily attributable to changes in blood pressure, triglycerides, and HDL. Short-term aerobic activity regimens may improve the metabolic profile and thereby reduce breast cancer risk in obese, metabolically unhealthy black women at high risk for cancer. © 2018 American Cancer Society.

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization.

In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.

Cryopreserved Amniotic Membrane, Autologous Serum Eye Drops, and Tea-Tree Oil Lid Scrubs in combination for the treatment of Keratoconjunctivitis in a Staphylococcus Hypersensitive Teenager

Abstract&#x0D; Background and Objective: The purpose is to present an interventional case report detailing recurrent bilateral keratoconjunctivitis secondary to Staphylococcus hypersensitivity in a teenage female. At least three times yearly, for five years, the patient has experienced episodes of severe bilateral catarrhal infiltrative or phlyctenular keratoconjunctivitis. Comprehensive corneal and conjunctival cultures had been historically performed, twice, yielding only growth of Staphylococcus aureus and epidermidis. Prior short-term treatment regimens of topical steroids and antibiotics had not prevented recurrences.&#x0D; Methods: This is an interventional case report: In this patient, placement of a topical cryopreserved amniotic membrane, Prokera Slim (PKS by BioTissue), after one week of topical steroid treatment (Durezol (difluroprednate 0.05%) qid) in the right eye (OD) is compared to a steroid (difluroprednate 0.05%) taper in the left eye (OS) over an approximate one-month time period. Both eyes then continue chronic, long-term maintenance therapy with autologous serum eye drops (ASED) dosed six times daily and tea tree oil containing lids scrubs (SteriLid Foam by TheraTears) two times daily, until the present time. Supportive meibomian gland expression for meibomian gland dysfunction was also performed at the three month treatment mark.&#x0D; Results: The PKS treatment in the right eye resulted in superior visual acuity and ocular comfort when compared to a steroid taper in the left eye over an approximate one-month time period. These results were maintained in the left eye at the 12 month- time frame. The right eye experienced a recurrence when the patient self-discontinued all therapy in both eyes at the 4 month mark. With re-initiation of maintenance therapy of ASED and tea tree oil containing lids scrubs, she has remained symptom-free for over eight months in the right eye. &#x0D; Conclusions: Further comparison and study of the treatment modalities above could result in a potentially faster, safer, and superior treatment and prevention protocol for topical ocular inflammation in Staphylococcus hypersensitive keratoconjunctivitis, particularly in pediatric populations.&#x0D;

Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far?

Helicobacter pylori has changed radically gastroenterologic world, offering a new concept in patients' management. Over time, more medical data gave rise to diverse distant, extragastric manifestations and interactions of the "new" discovered bacterium. Special interest appeared within the field of neurodegenerative diseases and particularly Alzheimer's disease, as the latter and Helicobacter pylori infection are associated with a large public health burden and Alzheimer's disease ranks as the leading cause of disability. However, the relationship between Helicobacter pylori infection and Alzheimer's disease remains uncertain. We performed a narrative review regarding a possible connection between Helicobacter pylori and Alzheimer's disease. All accessible relevant (pre)clinical studies written in English were included. Both affected pathologies were briefly analyzed, and relevant studies are discussed, trying to focus on the possible pathogenetic role of this bacterium in Alzheimer's disease. Data stemming from both epidemiologic studies and animal experiments seem to be rather encouraging, tending to confirm the hypothesis that Helicobacter pylori infection might influence the course of Alzheimer's disease pleiotropically. Possible main mechanisms may include the bacterium's access to the brain via the oral-nasal-olfactory pathway or by circulating monocytes (infected with Helicobacter pylori due to defective autophagy) through disrupted blood-brain barrier, thereby possibly triggering neurodegeneration. Current data suggest that Helicobacter pylori infection might influence the pathophysiology of Alzheimer's disease. However, further large-scale randomized controlled trials are mandatory to clarify a possible favorable effect of Helicobacter pylori eradication on Alzheimer's disease pathophysiology, before the recommendation of short-term and cost-effective therapeutic regimens against Helicobacter pylori-related Alzheimer's disease.

Intranasally Delivered Wnt3a Improves Functional Recovery after Traumatic Brain Injury by Modulating Autophagic, Apoptotic, and Regenerative Pathways in the Mouse Brain.

Traumatic brain injury (TBI) is a prevalent disorder, but no effective therapies currently exist. An underlying pathophysiology of TBI includes the pathological elevation of autophagy. β-Catenin, a downstream mediator of the canonical Wnt pathway, is a repressor of autophagy. The Wnt/β-catenin pathway plays a crucial role in cell proliferation and neuronal plasticity/repair in the adult brain. We hypothesized that activation of this pathway could promote neuroprotection and neural regeneration following TBI. In the controlled cortical impact (CCI) model of TBI in C57BL/6 mice (total n = 160), we examined intranasal application of recombinant Wnt3a (2 μg/kg) in a short-term (1 dose/day for 2 days) and long-term (1 dose/day for 7 days) regimen. Immunohistochemistry was performed at 1 to 14 days post-TBI to assess cell death and neurovascular regeneration. Western blotting measured canonical Wnt3a activity, expression of growth factors, and cell death markers. Longitudinal behavior assays evaluated functional recovery. In short-term experiments, Wnt3a treatment with a 60-min delay post-TBI suppressed TBI-induced autophagic activity in neurons (44.3 ± 6.98 and 4.25 ± 2.53 LC3+/NeuN+ double positive cells in TBI+Saline and TBI+Wnt3a mice, respectively; p < 0.0001, n = 5/group), reduced autophagic markers light chain 3 (LC3)-II and Beclin-1, as well as injury markers caspase-3 and matrix metalloproteinase 9 (MMP-9). The Wnt3a treatment reduced cell death and contusion volume (0.72 ± 0.07 mm2 and 0.26 ± 0.04 mm2 in TBI+Saline and TBI+Wnt3a mice, respectively; p < 0.001, n = 5/group). The 7-day Wnt3a treatment increased levels of β-catenin and growth factors glial-derived growth factor (GDNF) and vascular endothelial growth factor (VEGF). This chronic Wnt3a therapy augmented neurogenesis (0.52 ± 0.09 and 1.25 ± 0.13 BrdU+/NeuN+ co-labeled cells in TBI+Saline mice and TBI+Wnt3a mice, respectively; p < 0.01, n = 6/group) and angiogenesis (0.26 ± 0.07 and 0.74 ± 0.13 BrdU+/GLUT1+ co-labeled cells in TBI+Saline and TBI+Wnt3a mice, respectively; p = 0.014, n = 6/group). The treatment improved performance in the rotarod test and adhesive removal test. Targeting the Wnt pathway implements a unique combination of protective and regenerative approaches after TBI.

Rituximab in pemphigus.

Pemphigus is a severe autoimmune blistering disease mediated by pathogenic anti-desmoglein antibodies leading to an inter keratinocyte disjunction. Rituximab is a monoclonal antibody that binds to the CD-20 antigen of B lymphocytes, which causes B-cell depletion and a subsequent reduction in pathogenic autoantibodies. Its therapeutic role in pemphigus has been progressively growing with increasing evidence of successful outcomes. Rituximab was initially off-labeled used as an alternative in patients with recalcitrant or relapsing pemphigus and in patients with contraindications to systemic corticosteroids. Recently, a large randomized clinical trial has shown that first-line use of rituximab combined with short-term prednisone regimen was both more effective and potentially safer than a standard regimen of high doses of corticosteroids in patients with moderate to severe pemphigus.

Delirium tremens and alcohol withdrawal nationally in the Veterans Health Administration.

Alcohol withdrawal-especially delirium tremens (DT)-is a potentially life-threatening condition. While short-term treatment regimens and factors that predispose to more severe symptomatology have been extensively studied, little attention has been paid to the clinical epidemiology and long-term care of the chronic medical, addictive, psychiatric, and psychosocial problems faced by these patients. National Veterans Health Administration data from fiscal year 2012 were examined to identify veterans diagnosed with DT; with withdrawal but not DT (WNDT); and with Alcohol Use Disorder (AUD) but neither DT nor WNDT. They were compared on sociodemographic characteristics, psychiatric and medical co-morbidities, and health service and psychotropic medication use, first with bivariate analyses and then multiple logistic regression. Among the 345,297 veterans diagnosed with AUD, 2,341 (0.7%) were diagnosed with DT and 6,738 (2.0%) with WNDT. Veterans diagnosed with either WNDT or DT were more likely to have been homeless, had more comorbid medical and psychiatric disorders, were more likely to be diagnosed with drug use disorders, utilized more health services, received more psychotropic medications, and were more likely to receive naltrexone. They were more likely to receive specialized legal, housing, vocational, and psychosocial rehabilitation services, as well as intensive case management. Adults with WNDT and DT suffer from multiple chronic conditions and long-term service models are needed to coordinate the work of multiple specialists and to assure continuity of care. This national study identifies sociodemographic characteristics, comorbidities, and service utilization patterns associated with WNDT and DT.(Am J Addict 2017;26:722-730).

The skeletal impact of the chemotherapeutic agent etoposide.

Chemotherapeutics target rapidly dividing tumor cells yet also impact hematopoietic and immune cells in an off target manner. A wide array of therapies have negative side effects on the skeleton rendering patients osteopenic and prone to fracture. This study focused on the pro-apoptotic chemotherapeutic agent etoposide and its short- and long-term treatment effects in the bone marrow and skeleton. Six- to 16-week-old mice were treated with etoposide (20-25mg/kg) or vehicle control in short-term (daily for 5-9days) or long-term (3×/week for 17days or 6weeks) regimens. Bone marrow cell populations and their phagocytic/efferocytic functions were analyzed by flow cytometry. Blood cell populations were assessed by CBC analysis. Bone volume and area compartments and osteoclast numbers were measured by microCT, histomorphometry, and TRAP staining. Biomarkers of bone formation (P1NP) and resorption (TRAcP5b) were assayed from serum. Gene expression in bone marrow was assessed using qPCR. Flow cytometric analysis of the bone marrow revealed short-term etoposide reduced overall cell numbers and B220+ cells, with increased marrow apoptotic (AnnexinV+PI-) cells, mesenchymal stem-like cells, and CD68+, CD45+, and CD11b+ monocyte/myeloid cells (as a percent of the total marrow). After 6weeks, the CD68+, Gr1+, CD11b+, and CD45+ cell populations were still relatively increased in etoposide-treated bone marrow. Skeletal phenotyping revealed etoposide decreased bone volume, trabecular thickness, and cortical bone volume. Gene expression in the marrow for the leptin receptor and CXCL12 were reduced with short-term etoposide, and an increased ratio of RANKL/OPG mRNA was observed. In whole bone, Runx2 and osteocalcin gene expressions were reduced, and in serum, P1NP was significantly reduced with etoposide. Treatment with the antiresorptive agent zoledronic acid prior to etoposide increased bone volume and improved the etoposide-induced decrease in skeletal parameters. These data suggest that etoposide induces apoptosis in the bone marrow and significantly reduces parameters of bone formation with rapid reduction in bone volume. Pre-treatment with an antiresorptive agent results in a preservation of bone mass. Preventive approaches to preserving the skeleton should be considered in human clinical studies.

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. French Ministry of Health, French Society of Dermatology, Roche.

Low incidence of acute graft-versus-host disease with short-term tacrolimus in haploidentical hematopoietic stem cell transplantation

Although tacrolimus (Tac) has immunosuppressive properties and exhibits promising efficacy against graft-versus-host disease (GVHD), little is known about Tac in the prophylaxis of GVHD after HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In a multicenter randomized controlled trial, 174 patients received haplo-HSCT with GVHD prophylaxis involving short-term Tac (from −8days to +30days) or cyclosporine (CsA). The 100day cumulative incidences of acute GVHD (aGVHD) and grade III–IV aGVHD with the short-term Tac regimen and CsA regimen were 29.1 (19.5–38.7)% vs. 50.0(39.6–60.4)% (p=0.005) and 3.6(0.0–7.5)% vs. 13.5(6.1–20.9)% (p=0.027), respectively. There were no significant differences in the incidences of chronic GVHD (cGVHD), relapse and cytomegalovirus infection. Lymphocyte subset analysis showed that T cells decreased to lower levels on the short-term Tac regimen within 3 months of transplantation. The disease-free survival and overall survival on the short-term Tac and CsA regimens were 59.3 (48.9–69.7)% vs. 55.7 (45.3–66.1)% (p=0.696) and 65.1 (55.1–75.1)% vs. 61.4 (51.2–71.6)% (p=0.075), respectively. Our findings indicate that the short-term Tac regimen for GVHD prophylaxis in patients undergoing haplo-HSCT is associated with a low incidence and slight severity of aGVHD and did not increase the incidence of relapse and cytomegalovirus infection.

Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling.

Renal fibrosis contributes to declining renal function in the elderly. What is unclear however, is whether epithelial-mesenchymal transition (EMT) contributes to this age-related renal fibrosis. Here, we analyzed indicators of EMT during kidney aging and investigated the protective effects and mechanisms of short-term regimens of caloric restriction (CR) or caloric restriction mimetics (CRMs), including resveratrol and metformin. High glucose was used to induce premature senescence and EMT in human primary proximal tubular cells (PTCs) in vitro. To test the role of AMPK-mTOR signaling, siRNA was used to deplete AMPK. Cellular senescence and AMPK-mTOR signaling markers associated with EMT were detected. CR or CRMs treatment alleviated age-related EMT in aging kidneys, which was accompanied by activation of AMPK-mTOR signaling. High glucose induced premature senescence and EMT in PTCs in vitro, which was accompanied by down-regulation of AMPK/mTOR signaling. CRMs alleviated high glucose-induced senescence and EMT via stimulation of AMPK/mTOR signaling. Activation of AMPK/mTOR signaling protected PTCs from high glucose-induced EMT and cellular senescence. Short-term regimens of CR and CRMs alleviated age-related EMT via AMPK-mTOR signaling, suggesting a potential approach to reducing renal fibrosis during aging.

HOW LONG SHOULD THE TREATMENT OF COMMUNITY-ACQUIRED PNEUMONIA CONTINUE? FOCUS ON SHORT-COURSE ANTIMICROBIAL THERAPY

Till today, the duration of antibiotic therapy for community-acquired pneumonia (EP) remains a subject of debate. In different clinical guidelines the duration of antibiotic administration varies. Meanwhile, there is growing evidence that short-term antibiotic regimens for non-severe respiratory infections of the lower respiratory tract seem attractive and promising.

Influence of a Shorter Duration of Post-Operative Antibiotic Prophylaxis on Infectious Complications in Patients Undergoing Elective Liver Resection.

Antibiotic prophylaxis has been recommended to reduce post-operative infectious complications. Discontinuation of post-operative antibiotic administration within 24 hours of operation is currently recommended. Many surgeons, however, conventionally tend to extend the duration of prophylactic antibiotic use. In this study, we performed a retrospective analysis to assess the efficacy of extended post-operative antibiotic use in patients who underwent elective liver resection. A total of 208 consecutive patients who underwent liver resection without biliary reconstruction were investigated. Patients were divided into two groups according to the duration of post-operative antibiotic use: Only once after the operation (the post-operative day [POD] 0 group) and until three days after the operation (the POD 3 group). Post-operative complications in the two groups were analyzed and compared. Incisional surgical site infections (SSIs) were observed in 5% of the POD 0 group and 3% of the POD 3 group (p = 0.517). Organ/space SSIs were observed in 2% of the POD 0 group and 3% of the POD 3 group (p = 0.694). Overall infectious complications including SSIs and remote site infections were observed in 12% of the POD 0 group and 11% of the POD 3 group. Multi-variable analyses revealed that the short-term post-operative antibiotic regimen did not confer additional risk for infectious complications. In elective liver resection, the administration of prophylactic antibiotics on the operative day alone appears to be sufficient, because no additional benefit in the incidence of post-operative infectious complications was conferred on patients given antibiotic agents for three days.

How do short-term prophylactic antibiotic regimens compare with long-term or preoperative regimens in people undergoing orthognathic surgery?

How do short-term prophylactic antibiotic regimens compare with long-term or preoperative regimens in people undergoing orthognathic surgery?

PERBANDINGAN ANTARA PEMBERIAN ANTIBIOTIKA PROFILAKSIS PADA SEKSIO SESAR SESUAI ALUR KLINIS RSUP DR SARDJITO DENGAN ANTIBIOTIKA DOSIS MULTIPEL TERHADAP KEJADIAN INFEKSI LUKA OPERASI

Background: Clinical pathway recommend the use of short-term prophylaxis antibiotics for cesarean section. Long-term antibiotics or multiple doses was found in clinical practice. There are differences in the mode of administration and the number of doses administered at sardjito hospital.Objective: To determine the effectiveness of short-term antibiotic prophylaxis in cesarean section appropriate to clinical pathway in the prevention of surgical site infection (ssi), the incidence of fever, dysuria events, length of stay.Method: The study used randomized clinical trial. The study subjects who underwent cesarean section and meet the inclusion and exclusion criteria in the period July 2013 to January 2014 divided into an intervention group (n = 52) who received ampicillin 2 gram pre and post-cesarean section, and a control group (n = 54) who received ampicillin 2 gram pre cesarean section and 1 gram every 8 hours for 6 times. Observed on days 3 and 10 post-cesarean section. The primary outcomes assessed were the incidence of surgical wound infection based on the criteria of surgical site infection from Centers for Disease Controland Prevention. Secondary outcomes assessed were the incidence of fever, dysuria events, length of stay. Homogeneity analysis were conducted on subject. Outcome analysis performed bivariate with t test and chi squared test.Results and Discussion : A total of 106 subjects can be analyzed. SSI events in the intervention group at day 3 was 3.8% (n = 52) and control group was 1.84% (n = 54) with p&gt;0.05 RR 2.077 (95% CI 0.194 to 22.219). SSI on day 10 of 7.7% (n = 52) in the intervention group versus 9.3% (n = 54) in controls with p&lt;0.05 RR 0.831 (CI 95%, 0.236 to 2.924). Fever events on day 3 by 5.8% in the intervention group versus 3.7% incontrols with p&gt;0.05 RR 1.558 (95% CI 0.271 to 8.948) and on day 10 was 3.8% versus 3.7 % with p&gt;0.05 RR 1.038 (95% CI 0.152 to 7.102). Dysuria not found on day 3 and but on 10 found 5.8% in the intervention group versus 11.1% with p&gt;0.05 RR 0.519 (IK95% 0.137 to 1.968). Length of stay after cesarean section for 3.21 ± 0.412 days in the intervention group and 3.26 ± 0.442 days in the control group with p&gt;0.05 (95% CI -0.213 - 0.117).Conclusion: There is no significant difference in the incidence of surgical wound infections, the incidence of fever, dysuria, length of stay between short-term prophylaxis antibiotics ampicillin appropriate to clinical pathway and long-term or multiple doses prophylaxis antibiotics. Short term antibiotics prophylaxis are more efficiently with the same effectiveness in preventing outcomes research.Keywords: prophylaxis antibiotics, ampicillin, short term regimen, long term regimen, cesarean section, surgical site infection.

Efficacy and safety of short-term dual- versus mono-antiplatelet therapy in patients with ischemic stroke or TIA: a meta-analysis of 10 randomized controlled trials

Stroke is still a primary disease for death and disability all over the world. The optimal antiplatelet therapy for treatment of stroke is under controversy. We performed a meta-analysis to justify whether short-term (≤1year) dual-antiplatelet therapy (DAPT) has advantages over mono-antiplatelet therapy. We systematically searched the databases of Cochrane library, Pubmed and Embase up to July 2016. Randomized controlled trials (RCTs) comparing DAPT with mono-antiplatelet therapy were included in our meta-analysis. Totally ten trials involving 8969 patients were satisfied with our inclusion criteria. At the end of follow-up, DAPT is associated with a significant reduction in recurrent stroke [risk ratio (RR) 0.65, 95% confidence interval (CI) 0.56-0.76, P<0.00001] and the net clinical outcome (ischemic stroke (IS) recurrence plus major bleeding) (RR 0.67, 95% CI 0.58-0.79, P<0.00001). In terms of safety outcomes of major bleeding (RR 1.44, 95% CI 0.72-2.88, P=0.30) and intracranial hemorrhage (RR 1.29, 95% CI 0.56-2.93, P=0.55), DAPT has a homologous safety profile compared with mono-antiplatelet therapy. The subgroup analysis according to different races, antiplatelet combinations or initiation time produced similar outcomes as comprehensive outcomes. Given short-term treatment regimen, DAPT can be superior to mono-antiplatelet therapy in treating IS or transient ischemic attack (TIA). No matter in acute or non-acute phase of IS, short-term DAPT has more efficacy than mono-antiplatelet therapy and has equivalent safety as mono-antiplatelet therapy.