Meeting report: FDA public meeting on patient‐focused drug development and medication adherence in solid organ transplant patients

The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients’ daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.     

The biology of stem cell factor,a new hematopietic growth factor involved in stem cell regulation

Summary Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The gene for this factor or for its receptor are deleted in two well know series of mice mutants which display pleiotropic stem cell defects. Therefore, this factor supposedly plays an important role in stem cell biology. This paper reviews some of the elegant genetic work which led to the discovery of the factor and of its receptor, the biological effects that this factor exerts in the hematopoietic system in normal individuals and in patients with Diamond-Blackfan anemia and speculates on some of its potential clinical applications.     

Acidic Sphingomyelinase (ASM) Is Necessary for Fas-induced GD3 Ganglioside Accumulation and Efficient Apoptosis of Lymphoid Cells

Ceramides deriving from sphingomyelin hydrolysis are important mediators of apoptotic signals originating from Fas (APO-1/CD95). However, definitive evidence for the role played by individual sphingomyelinases is still lacking. We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene. NPD lymphoblasts, which display normal neutral sphingomyelinase activity, fail to activate ASM in response to Fas cross-linking, unlike normal lymphoblasts. NPD lymphoblasts also fail to accumulate GD3 ganglioside, a downstream mediator of ceramide-induced cell death (De Maria, R., L. Lenti, F. Malisan, F. D'Agostino, B. Tomassini, A. Zeuner, M.R. Rippo, R. Testi. 1997. Science. 277:1652–1655), and display a substantially inefficient apoptosis after Fas cross-linking. Inefficient apoptosis is due to lack of ASM activity, because proximal signaling from Fas in NPD lymphoblasts is not impaired and apoptosis can be efficiently triggered by passing the ASM defect with exogenous ceramides. Moreover, mannose receptor–mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking. These results provide definitive genetic evidence for the role of ASM in the progression of apoptotic signals originating from Fas.     

Fatigue, level of everyday physical activity and quality of life after liver transplantation.

OBJECTIVE: To assess whether liver transplant recipients have a hypoactive (sedentary) lifestyle and whether the level of everyday physical activity is related to complaints of fatigue. In addition, we explored the relationship between activity level and health-related quality of life. DESIGN: Case comparison. SUBJECTS: Eight persons 6-36 months after liver transplantation with varying severity of fatigue and 8 persons without known impairments (matched for gender, age, social situation and employment). METHODS: Activity levels were assessed during 2 randomly selected consecutive weekdays with an accelerometry-based Activity Monitor. In the transplantation group, severity of fatigue (Fatigue Severity Scale) and health-related quality of life (RAND-36) were also assessed. RESULTS: Five liver transplant recipients had a hypoactive lifestyle, but there was no significant difference in activity level between the transplantation group and comparison group. Severity of fatigue was correlated (p=0.01) with both duration of dynamic activities and intensity of everyday activity (r(s)=-0.81 and -0.84, respectively). Activity level was correlated (p< or =0.05) with several domains of health-related quality of life (r(s)=0.72-0.78). CONCLUSION: As a group, liver transplant recipients were not significantly less active than comparison subjects. Activity level was related with severity of fatigue and health-related quality of life. These findings have implications for the development of interventions needed to rehabilitate persons after liver transplantation.     

Lack of agreement between the revised criteria of impaired fasting glucose and impaired glucose tolerance in children with excess body weight

OBJECTIVE: The aim of this study was to describe the agreement between impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) in children with excess body weight using the original and the revised definitions of IFG. RESEARCH DESIGN AND METHODS: Obese and overweight children aged 4-17 years were included (n = 533). Anthropometric parameters and biochemical tests (fasting and 2-h glucose tests after an oral glucose load [1.75 g/kg]) were performed. Case subjects with a fasting plasma glucose >/=126 mg/dl were excluded. The diagnostic parameters of the original and the revised definitions of IFG for detecting IGT were estimated. The analysis of agreement between these categories was made using the kappa test. RESULTS: The prevalence of IFG increased from 6.2 to 13.3% using the new criteria. The prevalence of IFG became closer to the prevalence of IGT (14.8%). The revised criteria increased the sensitivity from 26.6 to 36.7%. However, the new IFG definition was not useful for identifying IGT cases. Of the 71 case subjects with IFG, only 29 (40.8%) had IGT. In addition, 50 case subjects with IGT (9.4%) and 13 with diabetes (2.4%) had a fasting glycemia <100 mg/dl. A poor agreement was found between the 2003 IFG definition and abnormal 2-h postchallenge plasma glucose (kappa = 0.359). The proportion of false-positive cases increased (36.3-59.1%) under the new definition. CONCLUSIONS: The new definition modestly increases the sensitivity of IFG for detecting IGT in children with excess body weight. Despite this, more than one-half of these cases are not detected. In addition, the false-positive rate was increased by 61%.     

A phase Ib,open‐label,single arm study to assess the safety,pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end‐stage renal disease

The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin‐based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end‐stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow‐up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non‐ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) C_max, T_max, AUC, and half‐life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti‐HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals.     

Effectiveness of transcutaneous electrical nerve stimulation on postoperative pain with movement.

This study tested the effectiveness of episodic transcutaneous electrical nerve stimulation (TENS) as a supplement to pharmacologic analgesia on pain with movement and at rest after abdominal surgery and evaluated whether its use during walking and vital capacity maneuvers enhances performance of these activities. TENS, with a modulated frequency, intensity as high as the subject could tolerate, and electrodes placed on either side and parallel to the incision, was compared to placebo TENS and pharmacologic analgesia alone (control) by using a crossover design. Self-report of pain intensity, walking function, and vital capacity were assessed on 33 subjects. TENS resulted in significantly less pain than the control during both walking (P <.5) and vital capacity activities (P <.1) and significantly less pain than placebo TENS during vital capacity (P <.01). TENS also produced significantly better gait speeds than the control (P <.05) and greater gait distances (P <.01) than the control and placebo TENS. Vital capacity and pain intensity at rest were not significantly different among the 3 treatments. These results suggest TENS reduces pain intensity during walking and deep breathing and increases walking function postoperatively when used as a supplement to pharmacologic analgesia. The lack of effect on pain at rest supports the hypothesis that TENS works through reducing hyperalgesia.     

Apical vertebral derotation and translation (AVDT) for adolescent idiopathic scoliosis using screws and sublaminar bands: a safer concept for deformity correction

Purpose

To assess the efficacy and safety of a new deformity correction philosophy treatment for AIS called apical vertebral derotation and translation (AVDT).

Methods

It is a retrospective study of prospectively collected data concerning two different scoliosis correction techniques used in our department. A total of 81 patients (22M, 59F) with a mean age of 15.5 years and minimum follow-up of 2 years were reviewed. Patients were divided into two groups according to the correction technique: 36 patients underwent single-rod derotation using all screws construct (AS), while 45 patients underwent apical vertebral derotation and translation using screws and sublaminar bands (SB).

Results

The mean improvement of the MT curve was 70% in the AS group and 60.6% in the SB group, while the mean improvement of the TL/L curve was 65.5 and 72.4%, respectively. PT increased in both groups after surgery with a mean amount of 2.5° in the AS group and only 1° in the SB group. We observed also a greater amount of cervical lordosis reduction in the AS group (4.5°) compared with the SB group (only 1°). The SB group had less operative time and less blood loss.

Conclusion

There was no significant difference between the two groups at the final follow-up and both techniques led to an excellent correction in the frontal plane; in the sagittal plane, the AVDT technique seemed to give less sagittal imbalance with better cervical profile; the surgical procedure is easy with less operative time, less blood loss and less risk of potential complications.

Graphical abstract

These slides can be retrieved under Electronic Supplementary Material.

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Effect of Ku80 Deficiency on Mutation Frequencies and Spectra at a LacZ Reporter Locus in Mouse Tissues and Cells

Non-homologous end joining (NHEJ) is thought to be an important mechanism for preventing the adverse effects of DNA double strand breaks (DSBs) and its absence has been associated with premature aging. To investigate the effect of inactivated NHEJ on spontaneous mutation frequencies and spectra in vivo and in cultured cells, we crossed a Ku80-deficient mouse with mice harboring a lacZ-plasmid-based mutation reporter. We analyzed various organs and tissues, as well as cultured embryonic fibroblasts, for mutations at the lacZ locus. When comparing mutant with wild-type mice, we observed a significantly higher number of genome rearrangements in liver and spleen and a significantly lower number of point mutations in liver and brain. The reduced point mutation frequency was not due to a decrease in small deletion mutations thought to be a hallmark of NHEJ, but could be a consequence of increased cellular responses to unrepaired DSBs. Indeed, we found a substantial increase in persistent 53BP1 and γH2AX DNA damage foci in Ku80^−/− as compared to wild-type liver. Treatment of cultured Ku80-deficient or wild-type embryonic fibroblasts, either proliferating or quiescent, with hydrogen peroxide or bleomycin showed no differences in the number or type of induced genome rearrangements. However, after such treatment, Ku80-deficient cells did show an increased number of persistent DNA damage foci. These results indicate that Ku80-dependent repair of DNA damage is predominantly error-free with the effect of alternative more error-prone pathways creating genome rearrangements only detectable after extended periods of time, i.e., in young adult animals. The observed premature aging likely results from a combination of increased cellular senescence and an increased load of stable, genome rearrangements.