Persistent BK Viremia Does Not Increase Intermediate-Term Graft Loss but Is Associated with De Novo Donor-Specific Antibodies

There are limited data regarding intermediate-term outcomes in patients with persistent BK viremia. Other viral infections have been implicated in the development of allosensitization through heterologous immunity, but the relationship between BK viremia and donor-specific antibodies (DSAs) is unexplored. In 2008, we initiated routine post-transplant BK viremia and DSA screening at our center; 785 kidney or kidney–pancreas transplant recipients were included in our study. Of these recipients, 132 (17%) recipients developed BK viremia during the study period. The median duration of BK viremia was 140 days (interquartile range=40–393 days), and persistent BK viremia was defined as lasting ≥140 days. Kaplan–Meier curves were generated to assess differences in patient and allograft survival on the basis of BK viremia status; survival was modeled using Cox proportional hazard regression. After a median follow-up of 3 years, there was no significant difference in terms of patient (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.28 to 2.49) or allograft survival (HR, 0.80; 95% CI, 0.37 to 1.73) between patients with and without BK viremia, which was confirmed in a time-varying analysis. In our logistic regression model, persistent BK viremia was strongly associated with the development of class II (HR, 2.55; 95% CI, 1.30 to 4.98) but not class I (HR, 1.13; 95% CI, 0.46 to 2.77) DSAs. These data suggest that persistent BK viremia does not negatively affect intermediate-term patient or allograft survival but is associated with increased risk for de novo DSA, although the exact mechanism is unclear.     

Do bulk‐fill resins decrease the restorative time in posterior teeth? A systematic review and meta‐analysis of in vitro studies

The aim of the present study was to compare the restorative time for filling cavities in posterior teeth using bulk‐fill and conventional resin composites through a systematic review and meta‐analysis. A search for clinical trials and laboratory studies was performed in PubMed/MEDLINE, Scopus, the Latin American and Caribbean Health Sciences Literature database, the Brazilian Library in Dentistry, Cochrane Library, Clinical Trials, and ReBEC (Registro Brasileiro de Ensaios Clínicos) databases without publication year or language restriction. Two reviewers identified eligible studies according to the inclusion criteria: bulk‐fill compared to conventional resin in class I or II, and the restorative time as an outcome. A meta‐analysis of the restorative time mean difference between composites was performed (inverse variance method, random effects model; Z‐test, P ≤ .05). From the 662 eligible studies, 133 were selected for full‐text analysis; three were included in the systematic review and in the meta‐analysis. Overall, the restorative time was lower when bulk‐fill was used (P = .0007, Z = 3.37), as the subgroup full‐body bulk‐fill (P < .00001, Z = 21.00). There was no difference in restorative time between flowable bulk‐fill and conventional resins (P = .08, Z = 1.76). Moderate‐to‐substantial heterogeneity was detected. Full‐body bulk‐fill composites decrease the restorative time in posterior teeth compared to conventional resins. Full‐body bulk‐fill resins require a shorter restorative time to perform restorations in posterior teeth than conventional resins, but the same is not valid for flowable bulk‐fill resin composites.     

Functional profiling of neurons through cellular neuropharmacology

We describe a functional profiling strategy to identify and characterize subtypes of neurons present in a peripheral ganglion, which should be extendable to neurons in the CNS. In this study, dissociated dorsal-root ganglion neurons from mice were exposed to various pharmacological agents (challenge compounds), while at the same time the individual responses of >100 neurons were simultaneously monitored by calcium imaging. Each challenge compound elicited responses in only a subset of dorsal-root ganglion neurons. Two general types of challenge compounds were used: agonists of receptors (ionotropic and metabotropic) that alter cytoplasmic calcium concentration (receptor-agonist challenges) and compounds that affect voltage-gated ion channels (membrane-potential challenges). Notably, among the latter are K-channel antagonists, which elicited unexpectedly diverse types of calcium responses in different cells (i.e., phenotypes). We used various challenge compounds to identify several putative neuronal subtypes on the basis of their shared and/or divergent functional, phenotypic profiles. Our results indicate that multiple receptor-agonist and membrane-potential challenges may be applied to a neuronal population to identify, characterize, and discriminate among neuronal subtypes. This experimental approach can uncover constellations of plasma membrane macromolecules that are functionally coupled to confer a specific phenotypic profile on each neuronal subtype. This experimental platform has the potential to bridge a gap between systems and molecular neuroscience with a cellular-focused neuropharmacology, ultimately leading to the identification and functional characterization of all neuronal subtypes at a given locus in the nervous system.     

Hepatorenal Syndrome: Are We Missing Some Prognostic Factors?

Background  

Hepatorenal syndrome (HRS) is the functional renal failure associated with advanced cirrhosis and has also been described in fulminant hepatic failure. Without liver transplantation its prognosis is dismal. Our study included patients with type 1 HRS associated with cirrhosis, who were not liver transplant candidates.     

Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Context Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas. Objectives To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment. Design/settings/patients Seventy‐eight patients with active acromegaly were included. Long‐term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E‐cadherin and SSTR2a. Protein levels of E‐cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas. Results DG adenomas and the transitional group had higher serum levels of IGF‐1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long‐term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E‐cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG. Conclusions Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E‐cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.     

Sexual activity and function in women with and without pelvic floor disorders

Introduction and hypothesis

We describe differences in sexual activity and function in women with and without pelvic floor disorders (PFDs).

Methods

Heterosexual women ≥40 years of age who presented to either urogynecology or general gynecology clinics at 11 clinical sites were recruited. Women were asked if they were sexually active with a male partner. Validated questionnaires and Pelvic Organ Prolapse Quantification (POP-Q) examinations assessed urinary incontinence (UI), fecal incontinence (FI), and/or pelvic organ prolapse (POP). Sexual activity and function was measured by the Female Sexual Function Index (FSFI). Student’s t test was used to assess continuous variables; categorical variables were assessed with Fisher’s exact test and logistic regression. Univariate and multivariate analyses were used to assess the impact of pelvic floor disorders (PFDs) on FSFI total and domain scores.

Results

Five hundred and five women met eligibility requirements and gave consent for participation. Women with and without PFDs did not differ in race, body mass index (BMI), comorbid medical conditions, or hormone use. Women with PFDs were slightly older than women without PFDs (55.6?+?10.8 vs. 51.6?+?8.3 years, P <0.001); all analyses were controlled for age. Women with PFDs were as likely to be sexually active as women without PFDs (61.6 vs. 75.5 %, P?=?0.09). There was no difference in total FSFI scores between cohorts (23.2?+?8.5 vs. 24.4?+?9.2, P?=?0.23) or FSFI domain scores (all P?=?NS).

Conclusion

Rates of sexual activity and function are not different between women with and without PFDs.     

MicroRT-small animal conformal irradiator

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical 192Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately calculate doses for treatment planning purposes. A series of precisely machined tungsten collimators mounted onto a cylindrical collimator assembly is used to provide the radiation beam portals. The current design allows a source-to-target distance range of 1-8 cm at four beam angles: 0 degrees (beam oriented down), 90 degrees, 180 degrees, and 270 degrees. The animal is anesthetized and placed in an immobilization device with built-in fiducial markers and scanned using a computed tomography, magnetic resonance, or positron emission tomography scanner prior to irradiation. Treatment plans using up to four beam orientations are created utilizing a custom treatment planning system-microRTP. A three-axis computer-controlled stage that supports and accurately positions the animals is programmed to place the animal relative to the radiation beams according to the microRTP plan. The microRT system positioning accuracy was found to be submillimeter. The radiation source is guided through one of four catheter channels and placed in line with the tungsten collimators to deliver the conformal radiation treatment. The microRT hardware specifications, the accuracy of the treatment planning and positioning systems, and some typical procedures for radiobiological experiments that can be performed with the microRT device are presented.     

The denoising of Monte Carlo dose distributions using convolution superposition calculations

Monte Carlo (MC) dose calculations can be accurate but are also computationally intensive. In contrast, convolution superposition (CS) offers faster and smoother results but by making approximations. We investigated MC denoising techniques, which use available convolution superposition results and new noise filtering methods to guide and accelerate MC calculations. Two main approaches were developed to combine CS information with MC denoising. In the first approach, the denoising result is iteratively updated by adding the denoised residual difference between the result and the MC image. Multi-scale methods were used (wavelets or contourlets) for denoising the residual. The iterations are initialized by the CS data. In the second approach, we used a frequency splitting technique by quadrature filtering to combine low frequency components derived from MC simulations with high frequency components derived from CS components. The rationale is to take the scattering tails as well as dose levels in the high-dose region from the MC calculations, which presumably more accurately incorporates scatter; high-frequency details are taken from CS calculations. 3D Butterworth filters were used to design the quadrature filters. The methods were demonstrated using anonymized clinical lung and head and neck cases. The MC dose distributions were calculated by the open-source dose planning method MC code with varying noise levels. Our results indicate that the frequency-splitting technique for incorporating CS-guided MC denoising is promising in terms of computational efficiency and noise reduction.