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.     

Perceptions of Success in Bariatric Surgery: a Nationwide Survey Among Medical Professionals

Introduction

Various definitions for bariatric surgery (BS) success exist, with weight loss and comorbidity resolution outcomes being the most prominent. The study’s aim was to compare how various healthcare professionals perceive success in BS.

Methods

A 29-item, 10-point Likert scale online survey was distributed via email to Israeli healthcare professionals involved in the different BS aspects using common national professional organizations. These included bariatric surgeons, dietitians, social workers, psychologists, psychiatrists, primary care physicians, gastroenterologists, and nurses. Statement relevancy to BS success was rated. An item was classed as “very important” for BS success if at least 70% of participants rated it 8 or higher in each subgroup. Inter-observer agreement was calculated using kappa statistics. Data on specific occupation, years-in-practice, and major workplace were collected as well.

Results

A total of 155 responses was obtained. The majority of respondents were dietitians (34.8%, n = 54), followed by bariatric surgeons (31.0%, n = 48) and nurses (14.8%, n = 23). Most respondents work mainly at public hospitals (32.9%, n = 51), followed by private hospitals (26.5%, n = 41). The mean years-in-practice among all healthcare professionals was 8.5 ± 8.5 years. Overall inter-observer agreement for prioritized items in accordance to BS success among all health professional subgroups was fair (Fleiss kappa = 0.278, P < 0.001), while dietitians and mental health specialists showed the highest agreement rate (Cohen’s kappa = 0.592, P < 0.001).

Conclusion

The study highlights the various views on defining BS success by different healthcare professionals, although there was some overlap of core outcomes prioritized by all professionals. International uniform definitions for BS success are required.

     

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.     

Autonomous Purkinje cell axonal dystrophy causes ataxia in peroxisomal multifunctional protein‐2 deficiency

Peroxisomes play a crucial role in normal neurodevelopment and in the maintenance of the adult brain. This depends largely on intact peroxisomal β‐oxidation given the similarities in pathologies between peroxisome biogenesis disorders and deficiency of multifunctional protein‐2 (MFP2), the central enzyme of this pathway. Recently, adult patients diagnosed with cerebellar ataxia were shown to have mild mutations in the MFP2 gene, hydroxy‐steroid dehydrogenase (17 beta) type 4 (HSD17B4). Cerebellar atrophy also develops in MFP2 deficient mice but the cellular origin of the degeneration is unexplored. In order to investigate whether peroxisomal β‐oxidation is essential within Purkinje cells, the sole output neurons of the cerebellum, we generated and characterized a mouse model with Purkinje cell selective deletion of the MFP2 gene. We show that selective loss of MFP2 from mature cerebellar Purkinje neurons causes a late‐onset motor phenotype and progressive Purkinje cell degeneration, thereby mimicking ataxia and cerebellar deterioration in patients with mild HSD17B4 mutations. We demonstrate that swellings on Purkinje cell axons coincide with ataxic behavior and precede neurodegeneration. Loss of Purkinje cells occurs in a characteristic banded pattern, proceeds in an anterior to posterior fashion and is accompanied by progressive astro‐ and microgliosis. These data prove that the peroxisomal β‐oxidation pathway is required within Purkinje neurons to maintain their axonal integrity, independent of glial dysfunction.     

ERG alterations and mTOR pathway activation in primary prostate carcinomas developing castration-resistance

Introduction

One of the most common sites of distant metastasization of prostate cancer is bone, but to date reliable biomarkers able to predict the risk and timing of bone metastasization are still lacking.

Insights into the karyotype evolution and speciation of the beetle <Emphasis Type="Italic">Euchroma gigantea</Emphasis> (Coleoptera: Buprestidae)

Euchroma Dejean, 1833 (Buprestidae: Coleoptera) is a monotypic genus comprising the species Euchroma gigantea, with populations presenting a degree of karyotypic variation/polymorphism rarely found within a single taxonomic (specific) unit, as well as drastically incompatible meiotic configurations in populations from extremes of the species range. To better understand the complex karyotypic evolution of E. gigantea, the karyotypes of specimens from five populations in Brazil were investigated using molecular cytogenetics and phylogenetic approaches. Herein, we used FISH with histone genes as well as sequencing of the COI to determine differential distribution of markers and relationships among populations. The analyses revealed new karyotypes, with variability for chromosome number and morphology of multiple sex chromosome mechanisms, occurrence of B chromosome variants (punctiform and large ones), and high dispersion of histone genes in different karyotypes. These data indicate that chromosomal polymorphism in E. gigantea is greater than previously reported, and that the species can be a valuable model for cytogenetic studies. The COI phylogenetic and haplotype analyses highlighted the formation of three groups with chromosomally polymorphic individuals. Finally, we compared the different karyotypes and proposed a model for the chromosomal evolution of this species. The species E. gigantea includes at least three cytogenetically polymorphic lineages. Moreover, in each of these lineages, different chromosomal rearrangements have been fixed. Dispersion of repetitive sequences may have favored the high frequency of these rearrangements, which could be related to both adaptation of the species to different habitats and the speciation process.