A nurse- and peer-led psycho-educational intervention to support women with gynaecological cancers receiving curative radiotherapy: The PeNTAGOn randomised controlled trial - ANZGOG 1102.

OBJECTIVE: Radiotherapy for gynaecological cancer is associated with multiple adverse effects. This randomised controlled trial evaluated the impact of a combined nurse- and peer-led psycho-educational intervention on psychological distress, preparation for treatment, quality of life, psychosexual function, unmet needs and vaginal stenosis. METHODS: Eligible women had a confirmed diagnosis of gynaecological cancer, scheduled to receive radiotherapy with curative intent, aged ≥18 years, and able to read and write English. Participants randomly assigned one-to-one to either four nurse-led consultations plus four peer-led telephone sessions, or to usual care. Participants completed study measures at baseline, immediately before first radiotherapy (FU1), and four weeks (FU2), three (FU3), six (FU4), and 12 months (FU5) post radiotherapy. The primary outcomes were psychological distress at FU1 and FU2 measured by the Hospital Anxiety and Depression Scale. RESULTS: Of 840 eligible participants, 625 were approached and 319 (51%) consented; 158 assigned to intervention, 160 to usual care with 1 withdrawing before randomisation. Between-groups differences for primary outcomes were trivial- and small-sized, (both p > 0.05). Notable effects on secondary outcomes favouring the intervention at FU2 included preparation for treatment (sensory/psychological concerns, d = 0.57; and procedural concerns, d = 0.52) and specific needs domains (sexuality needs, d = 0.38; and health system and information needs, d = 0.41). CONCLUSIONS: There was no evidence that a nurse- and peer-led intervention had a beneficial effect on psychological distress compared to usual care. However, improved treatment readiness and lower health system and sexuality needs indicate the intervention may have addressed outcomes known to be important to this population.

The 'dark matter' of ubiquitin-mediated processes: opportunities and challenges in the identification of ubiquitin-binding domains.

Ubiquitin modifications of target proteins act to localise, direct and specify a diverse range of cellular processes, many of which are biomedically relevant. To allow this diversity, ubiquitin modifications exhibit remarkable complexity, determined by a combination of polyubiquitin chain length, linkage type, numbers of ubiquitin chains per target, and decoration of ubiquitin with other small modifiers. However, many questions remain about how different ubiquitin signals are specifically recognised and transduced by the decoding ubiquitin-binding domains (UBDs) within ubiquitin-binding proteins. This review briefly outlines our current knowledge surrounding the diversity of UBDs, identifies key challenges in their discovery and considers recent structural studies with implications for the increasing complexity of UBD function and identification. Given the comparatively low numbers of functionally characterised polyubiquitin-selective UBDs relative to the ever-expanding variety of polyubiquitin modifications, it is possible that many UBDs have been overlooked, in part due to limitations of current approaches used to predict their presence within the proteome. Potential experimental approaches for UBD discovery are considered; web-based informatic analyses, Next-Generation Phage Display, deubiquitinase-resistant diubiquitin, proximity-dependent biotinylation and Ubiquitin-Phototrap, including possible advantages and limitations. The concepts discussed here work towards identifying new UBDs which may represent the 'dark matter' of the ubiquitin system.

Analysis of genetic variation contributing to measured speed in Thoroughbreds identifies genomic regions involved in the transcriptional response to exercise.

Despite strong selection for athletic traits in Thoroughbred horses, there is marked variation in speed and aptitude for racing performance within the breed. Using global positioning system monitoring during exercise training, we measured speed variables and temporal changes in speed with age to derive phenotypes for GWAS. The aim of the study was to test the hypothesis that genetic variation contributes to variation in end-point physiological traits, in this case galloping speed measured during field exercise tests. Standardisation of field-measured phenotypes was attempted by assessing horses exercised on the same gallop track and managed under similar conditions by a single trainer. PCA of six key speed indices captured 73.9% of the variation with principal component 1 (PC1). Verifying the utility of the phenotype, we observed that PC1 (median) in 2-year-old horses was significantly different among elite, non-elite and unraced horses (P < 0.001) and the temporal change with age in PC1 varied among horses with different myostatin (MSTN) g.66493737C>T SNP genotypes. A GWAS for PC1 in 2-year-old horses (n = 122) identified four SNPs reaching the suggestive threshold for association (P < 4.80 × 10-5 ), defining a 1.09 Mb candidate region on ECA8 containing the myosin XVIIIB (MYO18B) gene. In a GWAS for temporal change in PC1 with age (n = 168), five SNPs reached the suggestive threshold for association and defined candidate regions on ECA2 and ECA11. Both regions contained genes that are significantly differentially expressed in equine skeletal muscle in response to acute exercise and training stimuli, including MYO18A. As MYO18A plays a regulatory role in the skeletal muscle response to exercise, the identified genomic variation proximal to the myosin family genes may be important for the regulation of the response to exercise and training.

The modified Memorial Symptom Assessment Scale Short Form: a modified response format and rational scoring rules.

PURPOSE: The Memorial Symptom Assessment Scale Short Form (MSAS-SF) is a widely used symptom assessment instrument. Patients who self-complete the MSAS-SF have difficulty following the two-part response format, resulting in incorrectly completed responses. We describe modifications to the response format to improve useability, and rational scoring rules for incorrectly completed items. METHODS: The modified MSAS-SF was completed by 311 women in our Peer and Nurse support Trial to Assist women in Gynaecological Oncology; the PeNTAGOn study. Descriptive statistics were used to summarise completion of the modified MSAS-SF, and provide symptom statistics before and after applying the rational scoring rules. Spearman's correlations with the Functional Assessment for Cancer Therapy-General (FACT-G) and Hospital Anxiety and Depression Scale (HADS) were assessed. RESULTS: Correct completion of the modified MSAS-SF items ranged from 91.5 to 98.7%. The rational scoring rules increased the percentage of useable responses on average 4% across all symptoms. MSAS-SF item statistics were similar with and without the scoring rules. The pattern of correlations with FACT-G and HADS was compatible with prior research. CONCLUSION: The modified MSAS-SF was useable for self-completion and responses demonstrated validity. The rational scoring rules can minimise loss of data from incorrectly completed responses. Further investigation is recommended.

Genetic contributions to precocity traits in racing Thoroughbreds.

Adaptation to early training and racing (i.e. precocity), which is highly variable in racing Thoroughbreds, has implications for the selection and training of horses. We hypothesised that precocity in Thoroughbred racehorses is heritable. Age at first sprint training session (work day), age at first race and age at best race were used as phenotypes to quantify precocity. Using high-density SNP array data, additive SNP heritability (hSNP2) was estimated to be 0.17, 0.14 and 0.17 for the three traits respectively. In genome-wide association studies (GWAS) for age at first race and age at best race, a 1.98-Mb region on equine chromosome 18 (ECA18) was identified. The most significant association was with the myostatin (MSTN) g.66493737C>T SNP (P = 5.46 × 10-12 and P = 1.89 × 10-14 respectively). In addition, two SNPs on ECA1 (g.37770220G>A and g.37770305T>C) within the first intron of the serotonin receptor gene HTR7 were significantly associated with age at first race and age at best race. Although no significant associations were identified for age at first work day, the MSTN:g.66493737C>T SNP was among the top 20 SNPs in the GWAS (P = 3.98 × 10-5 ). Here we have identified variants with potential roles in early adaptation to training. Although there was an overlap in genes associated with precocity and distance aptitude (i.e. MSTN), the HTR7 variants were more strongly associated with precocity than with distance. Because HTR7 is closely related to the HTR1A gene, previously implicated in tractability in young Thoroughbreds, this suggests that behavioural traits may influence precocity.

Evaluation of microRNA expression in plasma and skeletal muscle of thoroughbred racehorses in training.

BACKGROUND: Circulating miRNAs (ci-miRNAs) are endogenous, non-coding RNAs emerging as potential diagnostic biomarkers. Equine miRNAs have been previously identified including subsets of tissue-specific miRNAs. In order to investigate ci-miRNAs as diagnostic tools, normal patterns of expression for different scenarios including responses to exercise need to be identified. Human studies have demonstrated that many ci-miRNAs are up-regulated following exercise with changes in expression patterns in skeletal muscle. However, technical challenges such as haemolysis impact on accurate plasma ci-miRNA quantification, with haemolysis often occurring naturally in horses following moderate-to-intense exercise. The objectives of this study were to identify plasma ci-miRNA profiles and skeletal muscle miRNAs before and after exercise in Thoroughbreds (Tb), and to evaluate for the presence and effect of haemolysis on plasma ci-miRNA determination. Resting and post-exercise plasma ci-miRNA profiles and haemolysis were evaluated in twenty 3 year-old Tbs in sprint training. Resting and post-exercise skeletal muscle miRNA abundance was evaluated in a second cohort of eleven 2 year-old Tbs just entering sprint training. Haemolysis was further quantified in resting blood samples from twelve Tbs in sprint training. A human plasma panel containing 179 miRNAs was used for profiling, with haemolysis assessed spectrophotometrically. Data was analysed using a paired Student's t-test and Pearson's rank correlation. RESULTS: Plasma ci-miRNA data for 13/20 horses and all skeletal muscle miRNA data passed quality control. From plasma, 52/179 miRNAs were detected at both time-points. Haemolysis levels were greater than the threshold for accurate quantification of ci-miRNAs in 18/25 resting and all post-exercise plasma samples. Positive correlations (P < 0.05) between haemolysis and miRNA abundance were detected for all but 4 miRNAs, so exercise-induced changes in plasma ci-miRNA expression could not be quantified. In skeletal muscle samples, 97/179 miRNAs were detected with 5 miRNAs (miR-21-5p, let-7d-3p, let-7d-5p, miR-30b-5p, miR-30e-5p) differentially expressed (DE, P < 0.05) between time-points. CONCLUSIONS: The degree of haemolysis needs to be determined prior to quantifying plasma ci-miRNA expression from horses in high-intensity exercise training. Identification of DE miRNAs in skeletal muscle indicates modification of miRNA expression may contribute to adaptive training responses in Tbs. Using a human plasma panel likely limited detection of equine-specific miRNAs.

Does the Presence of Scrapie Affect the Ability of Current Statutory Discriminatory Tests To Detect the Presence of Bovine Spongiform Encephalopathy?

Current European Commission (EC) surveillance regulations require discriminatory testing of all transmissible spongiform encephalopathy (TSE)-positive small ruminant (SR) samples in order to classify them as bovine spongiform encephalopathy (BSE) or non-BSE. This requires a range of tests, including characterization by bioassay in mouse models. Since 2005, naturally occurring BSE has been identified in two goats. It has also been demonstrated that more than one distinct TSE strain can coinfect a single animal in natural field situations. This study assesses the ability of the statutory methods as listed in the regulation to identify BSE in a blinded series of brain samples, in which ovine BSE and distinct isolates of scrapie are mixed at various ratios ranging from 99% to 1%. Additionally, these current statutory tests were compared with a new in vitro discriminatory method, which uses serial protein misfolding cyclic amplification (sPMCA). Western blotting consistently detected 50% BSE within a mixture, but at higher dilutions it had variable success. The enzyme-linked immunosorbent assay (ELISA) method consistently detected BSE only when it was present as 99% of the mixture, with variable success at higher dilutions. Bioassay and sPMCA reported BSE in all samples where it was present, down to 1%. sPMCA also consistently detected the presence of BSE in mixtures at 0.1%. While bioassay is the only validated method that allows comprehensive phenotypic characterization of an unknown TSE isolate, the sPMCA assay appears to offer a fast and cost-effective alternative for the screening of unknown isolates when the purpose of the investigation was solely to determine the presence or absence of BSE.

Rapid biodiagnostic ex vivo imaging at 1 µm pixel resolution with thermal source FTIR FPA.

A recent upgrade to the optics configuration of a thermal source FTIR microscope equipped with a focal plane array detector has enabled rapid acquisition of high magnification spectrochemical images, in transmission, with an effective geometric pixel size of ∼1 × 1 µm(2) at the sample plane. Examples, including standard imaging targets for scale and accuracy, as well as biomedical tissues and microorganisms, have been imaged with the new system and contrasted with data acquired at normal magnification and with a high magnification multi-beam synchrotron instrument. With this optics upgrade, one can now conduct rapid biodiagnostic ex vivo tissue imaging in-house, with images collected over larger areas, in less time (minutes) and with comparable quality and resolution to the best synchrotron source FTIR imaging capabilities.

Adolescents and young adult cancer survivors: exercise habits, quality of life and physical activity preferences.

INTRODUCTION: Given the decades of survivorship for adolescent and young adult (AYA) cancer survivors, it is important to promote behaviours that enhance physical and mental well-being and quality of life (QoL). The purpose of this study was to explore the exercise programming preferences and information needs of AYA survivors and to examine the impact of a cancer diagnosis on physical activity behavior and QoL. METHODS: Participants aged 15-25 years at time of diagnosis and referred to a specialist AYA cancer service between January 2008 and February 2012 were recruited. Eligible participants were mailed a self-administered questionnaire assessing demographic and disease-related information, physical activity levels over time and exercise information preferences. QoL was measured using the Assessment of Quality of Life-6D (AQoL-6D). RESULTS: Seventy-four (response rate 52 %) participants completed the questionnaire. The mean age was 23 years with 54 % female, with prevalent diagnoses included hematological malignancy (45 %) and sarcoma (24 %). Results indicated a significant reduction in the average minutes of physical activity post diagnosis (p =< 0.001) and during treatment (p = < 0.001). AYA who met public health physical activity guidelines (n = 36) at questionnaire completion had significantly higher QoL than those not meeting the guidelines (n = 38) (median (Mdn) = 0.87, interquartile range (IQR) = 0.73 to 0.98 and Mdn = 0.81, IQR = 0.57 to 0.93, respectively; p = 0.034). Most participants wanted exercise information at some point after diagnosis (85 %) but many did not receive any information (45 %). CONCLUSIONS: Findings suggest that AYA with cancer experience a significant impact on physical activity levels and QoL. Moreover, survivors experience considerable difficulty returning to premorbid levels of activity. Our study suggests that interventions promoting physical activity and healthy lifestyle behaviours would be well accepted within this population and may be essential to improve their long-term health and QoL during survivorship.

Study protocol for a single-site feasibility study evaluating the adoption and fidelity of Prep-4-RT: prehabilitation for head and neck cancer patients undergoing radiotherapy.

INTRODUCTION: Prep-4-RT is a co-designed stepped-care multimodal prehabilitation program for people scheduled to receive radiotherapy for head and neck cancer (HNC). Prehabilitation, which occurs between diagnosis and treatment commencement, aims to improve a patient's health to reduce the incidence and severity of current and future impairments. HNC treatment can be distressing and has detrimental impacts on function and quality of life. HNC patients have increased social vulnerabilities including higher rates of socio-economic disadvantage and engagement in lifestyle habits which increase cancer risk. High levels of physical and psychological impacts of HNC treatment and increased social vulnerabilities of this population warrant investigation of optimal pathways of care, such as prehabilitation. This paper describes a research protocol to evaluate the feasibility of Prep-4-RT, which was designed to prepare HNC patients for the physical and psychological impacts of radiotherapy. METHODS AND ANALYSIS: At least sixty adult HNC patients, scheduled to receive radiotherapy (with or without chemotherapy), will be recruited over a five-month period. All participants will receive access to Prep-4-RT self-management resources. Participants identified through screening as high-risk will also be offered individualised interventions with relevant allied health professionals prior to the commencement of radiotherapy (psychologists, dietitians, speech pathologists and physiotherapists). Participants will complete evaluation surveys assessing their experiences with Prep-4-RT resources and interventions. Clinicians will also complete program evaluation surveys. Primary feasibility outcomes include adoption (uptake and intention to try) and fidelity (adherence to the specialist prehabilitation pathway). Secondary feasibility outcomes include acceptability (patient and clinician) of and satisfaction (patient) with Prep-4-RT as well as operational costs. Feasibility outcome data will be analysed using exact binomial and one-sample t tests, as appropriate. ETHICS AND DISSEMINATION: Ethics approval has been obtained at the Peter MacCallum Cancer Centre in Melbourne, Australia. Results will be presented at national conferences and published in peer-reviewed journal(s) so that it can be accessed by clinicians involved in the care of HNC patients receiving radiotherapy. If the model of care is found to be feasible and acceptable, the transferability and scalability to other cancer centres, or for other cancer types, may be investigated. REGISTRATION DETAILS: ANZCTA (Australian New Zealand Clinical Trials Registry) ACTRN12623000770662.

Haemostatic discs demonstrate physical efficacy against microbes commonly associated with central-line-associated bloodstream infections.

BACKGROUND: Vascular access devices form an essential component in the management of acute and chronic medical conditions. Introduction and ongoing management of these devices are linked with bundles of care aimed at reducing associated risks including bleeding and infection. AIM: To evaluate the antimicrobial potential of the potassium ferrate haemostatic disc on Gram-positive (Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae, Pseudomonas aeruginosa) bacteria and on Candida albicans. METHODS: The impact of the potassium ferrate disc was compared with the often-used chlorhexidine gluconate (CHG) impregnated disc to evaluate the potential efficacy of the potassium ferrate disc as an alternative to CHG in cases with an increased risk of active bleeding. RESULTS: In the presence of anticoagulated blood, we observed an inhibitory effect of the haemostatic disc on microbial growth for microbial strains commonly associated with vascular access device related infections. CONCLUSION: Our results indicate that the potassium ferrate disc may provide dual clinical benefits with both haemostatic and antimicrobial action observed during in-vitro testing.

Predictors of distress associated with altered appearance and function in people treated surgically for oral cancers: a cross-sectional study.

This cross-sectional study was performed to examine sources of variation in distress associated with altered appearance and fundamental functions in oral cancer patients at 2 months, 12-15 months, 24-36 months, and ≥ 5 years post-definitive treatment. Eligible patients completed six scales from the FACE-Q Head and Neck Cancer Module. Pre-specified regression models were used to examine sources of variation in study outcomes for 145 patients. Patient self-reports indicated that distress associated with altered appearance and fundamental functions was highly variable, and distress was present beyond 5 years post-definitive treatment in some patients. Associations between distress scores and time post-definitive treatment, reconstructive surgery, and adjuvant therapy were not statistically significant. There was, however, moderate to strong evidence against the null hypothesis of no association between eating distress scores and sex, primary cancer site, and T-stage; smiling distress scores and age and primary cancer site; appearance distress scores and geographical remoteness and primary cancer site; and speaking distress scores and primary cancer site. Primary cancer site was the only significant independent predictor of multiple distress scores. These findings suggest that predicting the psychological impact of oral cancer treatment remains a challenge for the multidisciplinary team. Screening and interventions for psychological distress are essential beyond the preoperative and acute care settings.

Comparison of ventilatory and oxygen consumption measurements of yearling Thoroughbred colts and fillies exercising unridden on an all-weather track.

Sex effects on ventilatory and oxygen consumption (V̇O2) measurements during exercise have been identified in humans. This study's aim was to evaluate the hypothesis that there are sex effects on ventilatory and V̇O2 measurements in exercising, untrained yearling Thoroughbreds (Tb). Forty-one Tbs (16 colts, 25 fillies; 19.8 ± 1.4 months old) were recruited. Physiological, ventilatory and exercise data were gathered from horses exercising unridden at high intensity on an all-weather track from a global positioning-heart rate unit and a portable ergospirometry system. Data were analysed with an unpaired Student's t-test and the Benjamini-Hochberg correction for multiple testing (P ≤ 0.05 significant). Mean bodyweight (BW, P = 0.002) and wither height (P = 0.04) were greater for colts than fillies. There were no differences in physiological and exercise data and absolute peak V̇O2 between groups. However, fillies had a higher mass specific peak V̇O2 (P = 0.03) than colts (121.5 ± 21.6 mL/kg.min vs. 111.9 ± 27.4 mL/kg.min). The peak breathing frequency was greater for fillies (P < 0.001) while the peak inspiratory (P < 0.001) and expiratory air flow (P < 0.001), peak expiratory tidal volume (VTE; P < 0.001) and peak minute ventilation (V̇E; P = 0.01) were greater for colts; there were no differences for peak VTE and V̇E when adjusted for BW. Differences in BW explain the differences in mass specific peak V̇O2 between groups. Given their morphological differences, it is likely that lung volumes and airway diameters are smaller for fillies, resulting in greater resistance and lower air flows and volumes. Further research is required to investigate the ventilatory differences and how they may change with maturation and impact performance.

Biochemical label-free tissue imaging with subcellular-resolution synchrotron FTIR with focal plane array detector.

The critical questions into the cause of neural degeneration, in Alzheimer disease and other neurodegenerative disorders, are closely related to the question of why certain neurons survive. Answers require detailed understanding of biochemical changes in single cells. Fourier transform infrared microspectroscopy is an excellent tool for biomolecular imaging in situ, but resolution is limited. The mid-infrared beamline IRENI (InfraRed ENvironmental Imaging) at the Synchrotron Radiation Center, University of Wisconsin-Madison, enables label-free subcellular imaging and biochemical analysis of neurons with an increase of two orders of magnitude in pixel spacing over current systems. With IRENI's capabilities, it is now possible to study changes in individual neurons in situ, and to characterize their surroundings, using only the biochemical signatures of naturally-occurring components in unstained, unfixed tissue. We present examples of analyses of brain from two transgenic mouse models of Alzheimer disease (TgCRND8 and 3xTg) that exhibit different features of pathogenesis. Data processing on spectral features for nuclei reveals individual hippocampal neurons, and neurons located in the proximity of amyloid plaque in TgCRND8 mouse. Elevated lipids are detected surrounding and, for the first time, within the dense core of amyloid plaques, offering support for inflammatory and aggregation roles. Analysis of saturated and unsaturated fatty acid ester content in retina allows characterization of neuronal layers. IRENI images also reveal spatially-resolved data with unprecedented clarity and distinct spectral variation, from sub-regions including photoreceptors, neuronal cell bodies and synapses in sections of mouse retina. Biochemical composition of retinal layers can be used to study changes related to disease processes and dietary modification.

Impact of a novel nurse-led prechemotherapy education intervention (ChemoEd) on patient distress, symptom burden, and treatment-related information and support needs: results from a randomised, controlled trial.

BACKGROUND: High levels of distress and need for self-care information by patients commencing chemotherapy suggest that current prechemotherapy education is suboptimal. We conducted a randomised, controlled trial of a prechemotherapy education intervention (ChemoEd) to assess impact on patient distress, treatment-related concerns, and the prevalence and severity of and bother caused by six chemotherapy side-effects. PATIENTS AND METHODS: One hundred and ninety-two breast, gastrointestinal, and haematologic cancer patients were recruited before the trial closing prematurely (original target 352). ChemoEd patients received a DVD, question-prompt list, self-care information, an education consultation≥24 h before first treatment (intervention 1), telephone follow-up 48 h after first treatment (intervention 2), and a face-to-face review immediately before second treatment (intervention 3). Patient outcomes were measured at baseline (T1: pre-education) and immediately preceding treatment cycles 1 (T2) and 3 (T3). RESULTS: ChemoEd did not significantly reduce patient distress. However, a significant decrease in sensory/psychological (P=0.027) and procedural (P=0.03) concerns, as well as prevalence and severity of and bother due to vomiting (all P=0.001), were observed at T3. In addition, subgroup analysis of patients with elevated distress at T1 indicated a significant decrease (P=0.035) at T2 but not at T3 (P=0.055) in ChemoEd patients. CONCLUSIONS: ChemoEd holds promise to improve patient treatment-related concerns and some physical/psychological outcomes; however, further research is required on more diverse patient populations to ensure generalisability.

What mothers know, and want to know, about the complications of general anaesthesia.

BACKGROUND: Informed consent should be sought when performing anaesthesia on pregnant patients. There is no standard for consent for general anaesthesia on the delivery suite. This study was designed to assess post-partum women's awareness of the complications of general anaesthesia and the level of risk at which they felt these risks should be discussed. METHODS: One hundred and fifty parturients from two London hospitals who had undergone uncomplicated vaginal deliveries were asked on the first post-partum day about their knowledge of the potential complications of general anaesthesia for obstetrics. They were also asked about the level of risk at which they would wish to be informed before consenting to a general anaesthetic procedure. RESULTS: The knowledge of the risks of general anaesthesia among the parturients was poor, with awareness, allergy, nausea and vomiting being known by over 50%. Knowledge of difficult intubation and its consequences, dental damage, malignant hyperpyrexia and suxamethonium apnoea was known by less than 30% of the respondents. The level of risk at which mothers felt they should be informed was variable, with 50% wishing to know all risks up to 1 : 1000, and 19% wishing to know risks of greater than 1 : 1,000,000. All known risks were wished by nearly 30% of those questioned. CONCLUSIONS: Anaesthetists must be flexible when providing information to mothers about general anaesthesia and should provide more information to mothers if they wish it.

Prions are secreted in milk from clinically normal scrapie-exposed sheep.

The potential spread of prion infectivity in secreta is a crucial concern for prion disease transmission. Here, serial protein misfolding cyclic amplification (sPMCA) allowed the detection of prions in milk from clinically affected animals as well as scrapie-exposed sheep at least 20 months before clinical onset of disease, irrespective of the immunohistochemical detection of protease-resistant PrP(Sc) within lymphoreticular and central nervous system tissues. These data indicate the secretion of prions within milk during the early stages of disease progression and a role for milk in prion transmission. Furthermore, the application of sPMCA to milk samples offers a noninvasive methodology to detect scrapie during preclinical/subclinical disease.

Virologic and immunologic effectiveness of tipranavir/ritonavir (TPV/r)- versus darunavir/ritonavir (DRV/r)-based regimens in clinical practice.

BACKGROUND: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. OBJECTIVE: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). METHODS: Multicenter, retrospective cohort study. RESULTS: The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). CONCLUSION: No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.