Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label,single‐arm,one‐way crossover study

There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.     

Management of Anemia in Children Receiving Chronic Peritoneal Dialysis

Little information exists regarding the efficacy, modifiers, and outcomes of anemia management in children with CKD or ESRD. We assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing peritoneal dialysis (PD) who were prospectively followed in 30 countries. We noted that 25% of patients had hemoglobin levels below target (<10 g/dl or <9.5 g/dl in children older or younger than 2 years, respectively), with significant regional variation; levels were highest in North America and Europe and lowest in Asia and Turkey. Low hemoglobin levels were associated with low urine output, low serum albumin, high parathyroid hormone, high ferritin, and the use of bioincompatible PD fluid. Erythropoiesis-stimulating agents (ESAs) were prescribed to 92% of patients, and neither the type of ESA nor the dosing interval appeared to affect efficacy. The weekly ESA dose inversely correlated with age when scaled to weight but did not correlate with age when normalized to body surface area. ESA sensitivity was positively associated with residual diuresis and serum albumin and inversely associated with serum parathyroid hormone and ferritin. The prevalence of hypertension and left ventricular hypertrophy increased with the degree of anemia. Patient survival was positively associated with achieved hemoglobin and serum albumin and was inversely associated with ESA dose. In conclusion, control of anemia in children receiving long-term PD varies by region. ESA requirements are independent of age when dose is scaled to body surface area, and ESA resistance is associated with inflammation, fluid retention, and hyperparathyroidism. Anemia and high ESA dose requirements independently predict mortality.Almost three decades after the advent of recombinant erythropoietin, the management of renal anemia has become a recent focus of attention and changing paradigms. Whereas correction of hemoglobin (Hb) levels to near-normal has previously been recommended on the basis of association studies linking more severe anemia to morbidity and mortality with dialysis,^1–3 interventional clinical trials consistently demonstrate that near-normalization of Hb increases the risk of vascular events and mortality in adults receiving maintenance hemodialysis and in those with CKD who are not undergoing dialysis.^4–6 This has prompted ongoing reevaluation and revisions of treatment targets in patients exposed to erythropoiesis-stimulating agents (ESAs).⁷The appropriateness of applying treatment recommendations established in adult hemodialysis populations at high cardiovascular risk and adults with CKD to children undergoing dialysis is questionable because cardiovascular events are far less common in children with CKD. Furthermore, two thirds of children requiring dialysis initially opt for peritoneal dialysis (PD), and there are no systematic studies in the adult PD population to inform the optimal Hb target range in these patients. The risk profile of patients receiving PD may differ from that of the hemodialysis setting because of the absence of dialysis-induced intermittent hemoconcentration and lack of contact activation of the complement and coagulation systems.Further aspects to consider in pediatric anemia management are the greater physical activity of children and the need for optimal cognitive functioning at school.^8,9 The significant physiologic variation of the normal Hb range with age¹⁰ and the relative ESA sensitivity that reportedly increases with age during early childhood are also noteworthy.¹¹The registry of the International Pediatric Peritoneal Dialysis Network (IPPN) prospectively collects detailed clinical, biochemical, dialysis, and medication-related information (including ESA types and doses and modalities of iron supplementation) from a substantial number of children undergoing long-term PD around the world. In-depth analysis of this unique database has allowed us to (1) gain insight into the demographic characteristics of renal anemia and its treatment in the pediatric PD population worldwide, (2) explore the relationship between ESA dose requirements and body dimensions, (3) identify factors contributing to ESA resistance in children, and (4) associate anemia control with patient outcomes.     

Spatial learning and neurogenesis: Effects of cessation of wheel running and survival of novel neurons by engagement in cognitive tasks

Physical exercise stimulates cell proliferation in the adult dentate gyrus and facilitates acquisition and/or retention of hippocampal‐dependent tasks. It is established that regular physical exercise improves cognitive performance. However, it is unclear for how long these benefits last after its interruption. Independent groups of rats received both free access to either unlocked (EXE Treatment) or locked (No‐EXE Treatment) running wheels for 7 days, and daily injections of bromodeoxyuridine (BrdU) in the last 3 days. After a time delay period of either 1, 3, or 6 weeks without training, the animals were tested in the Morris water maze (MWM) either in a working memory task dependent on hippocampal function (MWM‐HD) or in a visible platform searching task, independent on hippocampal function (MWM‐NH). Data confirmed that exposure of rats to 7 days of spontaneous wheel running increases cell proliferation and neurogenesis. In contrast, neurogenesis was not accompanied by significant improvements of performance in the working memory version of the MWM. Longer time delays between the end of exercise and the beginning of cognitive training in the MWM resulted in lower cell survival; that is, the number of novel surviving mature neurons was decreased when this delay was 6 weeks as compared with when it was 1 week. In addition, data showed that while exposure to the MWM‐HD working memory task substantially increased survival of novel neurons, exposure to the MWM‐NH task did not, thus indicating that survival of novel dentate gyrus neurons depends on the engagement of this brain region in performance of cognitive tasks. © 2015 Wiley Periodicals, Inc.     

Spontaneity as predictive factor for well-being

The study discusses the construct of spontaneity and its causal relationship with psychological well-being. It develops a preview phase of validation of the SAI-R and its correlation with the Clinical Outcomes for Routine Evaluation-Outcome Measure (CORE-OM) and the Beck Depression Inventory (BDI-II) and assumes the hypothesis that a high level of spontaneity is correlated negatively with low level of well-being and positively with depression. The research involved Italian and Austrian participants, consisting of 166 Italian and 146 Austrian university students. The findings suggested a causal relationship between low spontaneity and psychological suffering. The results obtained confirm the hypothesized model, showing significant negative causal relationship. The verification of this theoretical model on non-clinical samples allows us to set the ground for future use in clinical samples. Furthermore, this result encourages the development of further research into the use of SAI-R.     

Slings in surgery of genuine stress incontinence

Purpose

To summarize the available evidence concerning efficacy and safety of standard mid-urethral sling (SMUS) operations for the treatment of stress urinary incontinence (SUI).

Methods and results

A non-systematic literature review was carried out in order to collect the available evidence concerning efficacy and safety of SMUS operations for the treatment of SUI. According to the data of our prior meta-analysis, patients receiving SMUS had significantly higher overall and objective cure rates than those receiving Burch colposuspension, although they had a higher risk of bladder perforations. Patients undergoing SMUS and pubovaginal slings had similar cure rates, although the latter were slightly more likely to experience storage lower urinary tract symptoms and had a higher reoperation rate. Patients treated with retropubic SMUS had slightly higher objective cure rates than those treated with transobturator tape (TOT); however, subjective cure rates were similar, and patients treated with TOT had a much lower risk of some complications. Meta-analysis demonstrated similar outcomes for TOTs. With regard to the novel mini-sling, another meta-analysis from Abdel-fattah et al. demonstrated that repeat continence surgery and de novo urgency incontinence were significantly higher in the patients treated with mini-slings.

Conclusion

Patients treated with retropubic tape (RT) experienced slightly higher continence rates than those treated with Burch colposuspension, but they faced a much higher risk of intraoperative complications. RT and pubovaginal slings were similarly effective. The use of RT was followed by objective cure rates slightly higher than TOT and by higher risk of complications. The novel mini-slings do not seem to be more effective than the SMUS.     

Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease

BACKGROUND: End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver-organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). METHODS: Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille's syndrome (n=12), Byler's disease (n=8), and other cholestatic diseases (n=8). RESULTS: Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. CONCLUSIONS: SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.     

Experimental arthritis induced by a clinical Mycoplasma fermentans isolate

Background  

Mycoplasma fermentans has been associated with rheumatoid arthritis. Recently, it was detected in the joints and blood of patients with rheumatoid arthritis, but it is not clear yet how the bacteria enter the body and reach the joints. The purpose of this study was to determine the ability of M. fermentans to induce experimental arthritis in rabbits following inoculation of the bacteria in the trachea and knee joints.     

Oral streptococcal strains isolated from odontogenic infections and their susceptibility to antibiotics

The aim of this study was to identify at species level and to investigate the antibiotic susceptibility of oral streptococcal strains isolated from 100 pus samples collected from Romanian patients with different odontogenic infections. The isolates were identified at species level using the Rapid ID 32 STREP system and their susceptibility was testing by the Etest, against: penicillin G, ampicillin, erythromycin, clindamycin and tetracycline. For the investigation of erythromycin resistance phenotype the disk diffusion test was used. The isolates belonged to several species, with Streptococcus anginosus and Streptococcus oralis predominating. Reduced susceptibility to beta-lactam antibiotics was found only among the isolates belonging to S. mitis and S. sanguinis groups. Resistance to erythromycin was detected among all species, except for: S. constellatus, S. intermedius and S. gordonii, and the M phenotype was established, while resistance to tetracycline was detected within all species but S. gordonii. In contrast, clindamycin was fully active. As most odontogenic infections are mixed infections, often involving strictly anaerobic bacteria, which are frequently beta-lactamase producers, the association of a penicillin and a beta-lactamase inhibitor, like Amoxiclav, is recommended when the antimicrobial treatment is necessary.     

Elastin density: Link between histological and biomechanical properties of vaginal tissue in women with pelvic organ prolapse?

Introduction and hypothesis

The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP).

Methods

Tissue samples were collected from the anterior [point Ba; POP Questionnaire (POP-Q)] and/or posterior (point Bp; POP-Q) vaginal wall of 15 women who underwent vaginal surgery for POP. Both histological and biomechanical assessments were performed from the same tissue samples in 14 of 15 patients. For histological assessment, the density of collagen and elastin fibers was determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. For biomechanical testing, uniaxial tension tests were performed to evaluate vaginal tissue stiffness at low (C₀) and high (C₁) deformation rates.

Results

Biomechanical testing highlights the hyperelastic behavior of the vaginal wall. At low strains (C₀), vaginal tissue appeared stiffer when elastin density was low. We found a statistically significant inverse relationship between C₀ and the elastin/collagen ratio (p?=?0.048) in the lamina propria. However, at large strain levels (C₁), no clear relationship was observed between elastin density or elastin/collagen ratio and stiffness, likely reflecting the large dispersion of the mechanical behavior of the tissue samples.

Conclusion

Histological and biomechanical properties of the vaginal wall vary from patient to patient. This study suggests that elastin density deserves consideration as a relevant factor of vaginal stiffness in women with POP.