Peripheral nerve morphology and intraneural blood flow in chronic kidney disease with and without diabetes

Introduction/Aims: Sonographic alterations of peripheral nerves in pre-dialytic kidney disease are yet to be determined. We aimed to assess peripheral nerve cross-sectional area (CSA) and intraneural blood flow in patients with pre-dialytic chronic kidney disease (CKD) and diabetic kidney disease (DKD). Methods: Subjects with CKD (n = 20) or DKD (n = 20) underwent ultrasound to assess CSA of the median and tibial nerves as well as intraneural blood flow of the median nerve. Blood flow was quantified using maximum perfusion intensity. Neuropathy was assessed using the Total Neuropathy Score. A 6-m timed walk test was also performed. Healthy controls (n = 28) were recruited for comparison. Results: The DKD group had more severe neuropathy (p =.024), larger tibial nerve CSA (p =.002) and greater median nerve blood flow than the CKD group (p =.023). Blood flow correlated with serum potassium in disease groups (r = 0.652, p =.022). Disease groups had larger tibial nerve CSA than controls (p <.05). No blood flow was detected in controls. Tibial nerve enlargement was associated with slower maximal walking speeds in disease groups (r = −0.389, p =.021). Discussion: Subjects with DKD demonstrated enlarged tibial nerve CSA and increased median nerve blood flow compared to those with CKD. Elevations in serum potassium were associated with increased blood flow. Sonographic alterations were detectable in pre-dialytic kidney disease compared to controls, highlighting the utility of ultrasound in the assessment of nerve pathology in these patient groups

How acceptable are antiretrovirals for the prevention of sexually transmitted HIV? A review of research on the acceptability of oral pre-exposure prophylaxis and treatment as prevention

Recent research has demonstrated how antiretrovirals (ARVs) could be effective in the prevention of sexually transmitted HIV. We review research on the acceptability of oral pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) for HIV prevention amongst potential users. We consider with whom, where and in what context this research has been conducted, how acceptability has been approached, and what research gaps remain. Findings from 33 studies show a lack of TasP research, PrEP studies which have focused largely on men who have sex with men (MSM) in a US context, and varied measures of acceptability. In order to identify when, where and for whom PrEP and TasP would be most appropriate and effective, research is needed in five areas: acceptability of TasP to people living with HIV; motivation for PrEP use and adherence; current perceptions and management of risk; the impact of broader social and structural factors; and consistent definition and operationalisation of acceptability which moves beyond adherence

Effects of Axonal Ion-Channel Dysfunction on Quality of Life in Type 2 Diabetes.

OBJECTIVESPharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium-channel function and ã-aminobutyric acid-minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion-channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion-channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN.RESEARCH DESIGN AND METHODSFifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients.RESULTSNeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545;

The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study

Objective: To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD). Methods: 113 subjects with CKD and 40 matched controls were assessed for peripheral neuropathy using the TNS. An exploratory factor analysis was conducted and internal consistency of the scale was evaluated using Cronbach's alpha. Construct validity of the TNS was tested by comparing scores between case and control groups. Results: Factor analysis revealed valid item correlations and internal consistency of the TNS was good with a Cronbach's alpha of 0.897. Subjects with CKD scored significantly higher on the TNS (CKD: median, 6, interquartile range, 1–13; controls: median, 0, interquartile range, 0–1; p < 0.001). Subgroup analysis revealed construct validity was maintained for subjects with stages 3–5 CKD with and without diabetes. Conclusions: The TNS is a valid measure of peripheral neuropathy in patients with CKD. Significance: The TNS is the first neuropathy scale to be formally validated in patients with CKD

BMJ open: Laser capture microdissection as a tool to evaluate human papillomavirus genotyping and methylation as biomarkers of persistence and progression of anal lesions

Introduction: Anal squamous cell carcinoma is preceded by persistent infection with high-risk human papillomavirus (HPV) and the cancer precursor, highgrade squamous intraepithelial lesion (HSIL). Detection of specific HPV genotypes and HPV-related biomarkers may be an option for primary anal screening. However, more data on the natural history of HPV-related anal lesions are required. The outcomes from this study will enhance our understanding of the clinical and biological behaviour of HPV-related anal lesions and inform the development of future HPV genotype and/or biomarker screening tests. Methods and analysis: HIV-negative and HIV-positive men who have sex with men, aged 35 years and over, recruited from community-based settings in Sydney, Australia, attend 6 clinic visits over 3 years. At the first 5 visits, participants undergo a digital anorectal examination, an anal swab for HPV genotyping and anal cytology, and high-resolution anoscopy with directed biopsy of any visible abnormalities that are suggestive of any abnormality suspicious of SIL. Tissue sections from participants diagnosed with histologically confirmed HSIL at the baseline clinic visit will undergo laser capture microdissection, HPV detection and genotyping, and quantitation of CpG methylation in baseline and followup biopsies. Histological and cytological findings in combination with HPV genotyping data will be used to identify persistent HSIL. HSIL will be stratified as nonpersistent and persistent based on their status at 12 months. The performance of HPV genotype and methylation status in predicting disease persistence at 12 months will be assessed, along with associations with HIV status and other covariates such as age. Ethics and dissemination: The St Vincent's Hospital Ethics Committee granted ethics approval for the study. Written informed consent is obtained from all individuals before any study-specific procedures are performed. Findings from this study will be disseminated to participants and the community through study newsletters, and through peer-reviewed publications and international conferences

Transplant Recipients and Anal Neoplasia Study: Design, Methods, and Participant Characteristics of a Prevalence Study

Kidney recipients have anal cancer rates 3 times higher than the general population in Australia and New Zealand. High-risk human papillomavirus (HPV) genotypes are implicated in the majority of anal cancers. Establishing the epidemiology of anal HPV infection and precursors of anal cancer in transplant recipient populations is 1 consideration in any potential screening program. The Transplant and Anal Neoplasia Study is a cross-sectional study of the prevalence of anal cytological abnormalities and HPV deoxyribonucleic acid in kidney transplant recipients, as well as evaluating the acceptability of an anal cancer screening intervention. The study aims to recruit 100 kidney transplant recipients, older than 18 years, in Australia. Transplant recipients attending for a protocol biopsy at 3 and 12 months and annually posttransplant are approached to participate. Participants undergo an anal swab, which is then analyzed using liquid-based cytological examination and tested for the detection of 37 anogenital HPV deoxyribonucleic acid genotypes. Participants also complete a demographic and behavioral questionnaire that covers sexual behavior, history of anal symptoms, and possible anal cancer risk factors. Associations will be tested using multiple regression analysis. Recruitment for the study began in 2015 and is ongoing. To date, 96 (77%) of 125 kidney transplant recipients approached have consented to the study. The mean age is 48 (median, 47 y; range, 20-76 y), 59% are male, and Northwest European (58%) represented the largest ethnic group. No participants self-identified as Aboriginal or Torres Strait Islander. High consent rates and positive qualitative results suggest that a larger screening program may be well received by kidney transplant recipients, with increased resources and some modification to the timing of approach. Further results of the study will inform the possible implementation of a larger screening trial for prevention of anal cancers in kidney and other solid organ transplant recipients

CpG Methylation Analysis of HPV16 in Laser Capture Microdissected Archival Tissue and Whole Tissue Sections from High Grade Anal Squamous Intraepithelial Lesions: A Potential Disease Biomarker

Incidence and mortality rates of anal cancer are increasing globally. More than 90% of anal squamous cell carcinomas (ASCC) are associated with human papillomavirus (HPV). Studies on HPV-related anogenital lesions have shown that patterns of methylation of viral and cellular DNA targets could potentially be developed as disease biomarkers. Lesion-specific DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissues from existing or prospective patient cohorts may constitute a valuable resource for methylation analysis. However, low concentrations of DNA make these samples technically challenging to analyse using existing methods. We therefore set out to develop a sensitive and reproducible nested PCR-pyrosequencing based method to accurately quantify methylation at 10 CpG sites within the E2BS1, E2BS2,3,4 and Sp1 binding sites in the viral upstream regulatory region of HPV16 genome. Methylation analyses using primary and nested PCR-pyrosequencing on 52 FFPE tissue [26 paired whole tissue sections (WTS) and laser capture microdissected (LCM) tissues] from patients with anal squamous intraepithelial lesions was performed. Using nested PCR, methylation results were obtained for the E2BS1, E2BS2,3,4 and Sp1 binding sites in 86.4% of the WTS and 81.8% of the LCM samples. Methylation patterns were strongly correlated within median values of matched pairs of WTS and LCM sections, but overall methylation was higher in LCM samples at different CpG sites. High grade lesions showed low methylation levels in the E2BS1 and E2BS2 regions, with increased methylation detected in the E2BS,3,4/Sp1 regions, showing the highest methylation at CpG site 37. The method developed is highly sensitive in samples with low amounts of DNA and demonstrated to be suitable for archival samples. Our data shows a possible role of specific methylation in the HPV16 URR for detection of HSIL

Papillary immature metaplasia of the anal canal: A low-grade lesion that can mimic a high-grade lesion

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. In a natural history study of anal human papillomavirus (HPV) infection and HPV-related lesions among homosexual men in Sydney, Australia, we identified 15 examples of papillary immature metaplasia (PIM) in anal biopsy samples. PIM has previously been described in the cervix, but not in the anal canal. PIM is a form of exophytic low-grade squamous intraepithelial lesion (eLSIL) also known as condyloma. In contrast to the maturing keratinocytes and koilocytosis seen in conventional eLSIL, the slender papillary structures of PIM have a surface population of immature squamous cells. In our anal samples PIM was characterized by close proximity to conventional eLSIL, was negative for p16 INK4A (p16) expression, and revealed the presence of a single low-risk HPV genotype (either 6 or 11) in laser capture microdissected lesions. The clinical significance of recognizing PIM lies in preventing misdiagnosis as high-grade squamous intraepithelial lesion, (the presumed precursor to anal cancer), due to the morphologic immaturity of the cell population. In routine practice, awareness of anal canal PIM and p16 immunostaining will prevent this. Further study of the natural history of anal canal PIM is needed

High reproducibility of histological diagnosis of human papillomavirus-related intraepithelial lesions of the anal canal

In a natural history study of anal human papillomavirus (HPV) infection and HPV-related lesions, we examined the reproducibility of histological high-grade squamous intraepithelial lesion (HSIL). Three expert anogenital pathologists share the reporting of histological specimens from the Study of the Prevention of Anal Cancer (SPANC), utilising Lower Anogenital Squamous Terminology (LAST) criteria. In total, 194 previously reported biopsies were randomly chosen within diagnostic strata [50 HSIL–anal intraepithelial neo-plasia (AIN) 3; 45 HSIL–AIN 2; 49 ‘flat’ low-grade squamous intraepithelial lesion (LSIL); 50 ‘exophytic’ LSIL; and 50 negative for squamous intraepithelial lesion] and reviewed by each of these three pathologists. Consensus was defined as agreement between at least two review diagnoses, using a binary classification of HSIL and non-HSIL, or if consensus was not obtained in this way, it was achieved through a multiheader microscope session by the three pathologists. We found very high agreement between original and consensus diagnoses (Kappa = 0.886) and between each pathologist's review and consensus (Kappas = 0.926, 0.917 and 0.905). Intra-observer agreement for the three pathologists was 0.705, 1.000 and 0.854. This high level of diagnostic reproducibility indicates that the findings of SPANC should be robust and provide reliable information about HPV-related anal canal disease