Spare non-occupational HIV post-exposure prophylaxis by active contacting and testing of the source person.

OBJECTIVE: HIV-1 post-exposure prophylaxis (PEP) is frequently prescribed after exposure to source persons with an undetermined HIV serostatus. To reduce unnecessary use of PEP, we implemented a policy including active contacting of source persons and the availability of free, anonymous HIV testing ('PEP policy'). METHODS: All consultations for potential non-occupational HIV exposures i.e. outside the medical environment) were prospectively recorded. The impact of the PEP policy on PEP prescription and costs was analysed and modelled. RESULTS: Among 146 putative exposures, 47 involved a source person already known to be HIV positive and 23 had no indication for PEP. The remaining 76 exposures involved a source person of unknown HIV serostatus. Of 33 (43.4%) exposures for which the source person could be contacted and tested, PEP was avoided in 24 (72.7%), initiated and discontinued in seven (21.2%), and prescribed and completed in two (6.1%). In contrast, of 43 (56.6%) exposures for which the source person could not be tested, PEP was prescribed in 35 (81.4%), P < 0.001. Upon modelling, the PEP policy allowed a 31% reduction of cost for management of exposures to source persons of unknown HIV serostatus. The policy was cost-saving for HIV prevalence of up to 70% in the source population. The availability of all the source persons for testing would have reduced cost by 64%. CONCLUSION: In the management of non-occupational HIV exposures, active contacting and free, anonymous testing of source persons proved feasible. This policy resulted in a decrease in prescription of PEP, proved to be cost-saving, and presumably helped to avoid unnecessary toxicity and psychological stress.

More on Testing for Validity Instead of Looking for It

Using Monte Carlo simulations and reanalyzing the data of a validation study of the AEIM emotional intelligence test, we demonstrated that an atheoretical approach and the use of weak statistical procedures can result in biased validity estimates. These procedures included stepwise regression-and the general case of failing to include important theoretical controls-extreme scores analysis, and ignoring heteroscedasticity as well as measurement error. The authors of the AEIM test responded by offering more complete information about their analyses, allowing us to further examine the perils of ignoring theory and correct statistical procedures. In this paper we show with extended analyses that the AEIM test is invalid.

MALDI-TOF MS-based drug susceptibility testing of pathogens: The example of Candida albicans and fluconazole.

MALDI-TOF MS can be used for the identification of microorganism species. We have extended its application to a novel assay of Candida albicans susceptibility to fluconazole, based on monitoring modifications of the proteome of yeast cells grown in the presence of varying drug concentrations. The method was accurate, and reliable, and showed full agreement with the Clinical Laboratory Standards Institute's reference method. This proof-of-concept demonstration highlights the potential for this approach to test other pathogens.

Patients with AIDS-defining cancers are not universally screened for HIV: a 10-year retrospective analysis of HIV-testing practices in a Swiss university hospital.

OBJECTIVES: Kaposi's sarcoma (KS), invasive cervical carcinoma (ICC) and non-Hodgkin lymphoma (NHL) have been listed as AIDS-defining cancers (ADCs) by the Centers for Disease Control and Prevention since 1993. Despite this, HIV screening is not universally mentioned in ADC treatment guidelines. We examined screening practices at a tertiary centre serving a population where HIV seroprevalence is 0.4%. METHODS: Patients with KS, ICC, NHL and Hodgkin lymphoma (HL), treated at Lausanne University Hospital between January 2002 and July 2012, were studied retrospectively. HIV testing was considered part of the oncology work-up if performed between 90 days before and 90 days after the cancer diagnosis date. RESULTS: A total of 880 patients were examined: 10 with KS, 58 with ICC, 672 with NHL and 140 with HL. HIV testing rates were 100, 11, 60 and 59%, and HIV seroprevalence was 60, 1.7, 3.4 and 5%, respectively. Thirty-seven patients (4.2%) were HIV-positive, of whom eight (22%) were diagnosed at oncology work-up. All newly diagnosed patients had CD4 counts < 200 cells/μL and six (75%) had presented to a physician 12-236 weeks previously with conditions warranting HIV testing. CONCLUSIONS: In our institution, only patients with KS were universally screened. Screening rates for other cancers ranged from 11 to 60%. HIV seroprevalence was at least fourfold higher than the population average. As HIV-positive status impacts on cancer patient medical management, HIV screening should be included in oncology guidelines. Further, we recommend that opt-out screening should be adopted in all patients with ADCs and HL.

Cardiovascular and metabolic responses during isokinetic shoulder rotators strength testing in healthy subjects

Background: Although there have been many studies on isokinetic shoulder exercises in evaluation and rehabilitation programs, the cardiovascular and metabolic responses of those modes of muscle strength exercises have been poorly investigated. Objective: To analyze cardiovascular and metabolic responses during a standardized test used to study the internal (IR) and external (ER) rotators maximal isokinetic strength. Methods: Four days after an incremental exercise test on cycle ergometer, ten healthy subjects performed an isokinetic shoulder strength evaluation with cardiovascular (Heart rate, HR) and metabolic gas exchange (&Vdot;O_{2}) analysis. The IR and ER isokinetic strength, measured in seated position with 45° of shoulder abduction in scapular plane, was evaluated concentrically at 60, 120 and 240°/s and eccentrically at 60°/s, for both shoulder sides. An endurance test with 30 repetitions at 240°/s was performed at the end of each shoulder side testing. Results: There was a significant increase of mean HR with isokinetic exercise (P< 0.05). Increases of HR was 42-71% over the resting values. During endurance testing, increases of HR was 77-105% over the resting values, and corresponded to 85-86% of the maximal HR during incremental test. Increase of &Vdot;O_{2} during isokinetic exercises was from 6-11 ml/min/kg to 20-43 ml/min/kg. Conclusion: This study performed significant cardiovascular and metabolic responses to isokinetic exercise of rotators shoulder muscles. A warm-up should be performed before maximal high-intensity isokinetic shoulder testing. Our results indicated that observation and supervision are important during testing and/or training sessions, especially in subjects with risk for cardiovascular disorders.

Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T-lymphocyte responses against a melanoma tumor antigen.

Cytotoxic T cells represent a powerful strategy for antitumor treatment. Depending on the route of injection, an important role for CD4 T cell-mediated help was observed in the induction of this response. For this reason, we investigated whether induction of a CTL response to the HLA-A2-restricted immunodominant peptide melanoma antigen Melan-A was improved by using rVVs expressing the CTL-defined epitope alone or in combination with an SAg. In the latter case, the few infected dendritic cells simultaneously presented an SAg and an antigen, i.e., peptide. Here, we show that the anti-Melan-A response was efficiently induced but not significantly improved by coexpression of the SAg.

Tricky and terrible T-cell tumors: these are thrilling times for testing: molecular pathology of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) encompass a group of rare and usually clinically aggressive diseases. The classification and diagnosis of these diseases are compounded by their marked pathological heterogeneity and complex clinical features. With the exception of ALK-positive anaplastic large cell lymphoma (ALCL), which is defined on the basis of ALK rearrangements, genetic features play little role in the definition of other disease entities. In recent years, hitherto unrecognized chromosomal translocations have been reported in small subsets of PTCLs, and genome-wide array-based profiling investigations have provided novel insights into their molecular characteristics. This article summarizes the current knowledge on the best-characterized genetic and molecular alterations underlying the pathogenesis of PTCLs, with a focus on recent discoveries, their relevance to disease classification, and their management implications from a diagnostical and therapeutical perspective.

Candida species distribution and antifungal susceptibility testing according to European Committee on Antimicrobial Susceptibility Testing and new vs. old Clinical and Laboratory Standards Institute clinical breakpoints: a 6-year prospective candidaemia survey from the fungal infection network of Switzerland.

We analyzed the species distribution of Candida blood isolates (CBIs), prospectively collected between 2004 and 2009 within FUNGINOS, and compared their antifungal susceptibility according to clinical breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2013, and the Clinical and Laboratory Standards Institute (CLSI) in 2008 (old CLSI breakpoints) and 2012 (new CLSI breakpoints). CBIs were tested for susceptiblity to fluconazole, voriconazole and caspofungin by microtitre broth dilution (Sensititre(®) YeastOne? test panel). Of 1090 CBIs, 675 (61.9%) were C. albicans, 191 (17.5%) C. glabrata, 64 (5.9%) C. tropicalis, 59 (5.4%) C. parapsilosis, 33 (3%) C. dubliniensis, 22 (2%) C. krusei and 46 (4.2%) rare Candida species. Independently of the breakpoints applied, C. albicans was almost uniformly (>98%) susceptible to all three antifungal agents. In contrast, the proportions of fluconazole- and voriconazole-susceptible C. tropicalis and F-susceptible C. parapsilosis were lower according to EUCAST/new CLSI breakpoints than to the old CLSI breakpoints. For caspofungin, non-susceptibility occurred mainly in C. krusei (63.3%) and C. glabrata (9.4%). Nine isolates (five C. tropicalis, three C. albicans and one C. parapsilosis) were cross-resistant to azoles according to EUCAST breakpoints, compared with three isolates (two C. albicans and one C. tropicalis) according to new and two (2 C. albicans) according to old CLSI breakpoints. Four species (C. albicans, C. glabrata, C. tropicalis and C. parapsilosis) represented >90% of all CBIs. In vitro resistance to fluconazole, voriconazole and caspofungin was rare among C. albicans, but an increase of non-susceptibile isolates was observed among C. tropicalis/C. parapsilosis for the azoles and C. glabrata/C. krusei for caspofungin according to EUCAST and new CLSI breakpoints compared with old CLSI breakpoints.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.

BACKGROUND: We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting. METHODS: We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods. RESULTS: From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment. CONCLUSIONS: HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.

Prioritizing genetic testing in patients with kallmann syndrome using clinical phenotypes.

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

Test-retest reliability of thermal quantitative sensory testing on two sites within the L5 dermatome of the lumbar spine and lower extremity.

INTRODUCTION: Quantitative sensory testing (QST) is widely used in human research to investigate the integrity of the sensory function in patients with pain of neuropathic origin, or other causes such as low back pain. Reliability of QST has been evaluated on both sides of the face, hands and feet as well as on the trunk (Th3-L3). In order to apply these tests on other body-parts such as the lower lumbar spine, it is important first to establish reliability on healthy individuals. The aim of this study was to investigate intra-rater reliability of thermal QST in healthy adults, on two sites within the L5 dermatome of the lumbar spine and lower extremity. METHODS: Test-retest reliability of thermal QST was determined at the L5-level of the lumbar spine and in the same dermatome on the lower extremity in 30 healthy persons under 40 years of age. Results were analyzed using descriptive statistics and intraclass correlation coefficient (ICC). Values were compared to normative data, using Z-transformation. RESULTS: Mean intraindividual differences were small for cold and warm detection thresholds but larger for pain thresholds. ICC values showed excellent reliability for warm detection and heat pain threshold, good-to-excellent reliability for cold pain threshold and fair-to-excellent reliability for cold detection threshold. ICC had large ranges of confidence interval (95%). CONCLUSION: In healthy adults, thermal QST on the lumbar spine and lower extremity demonstrated fair-to-excellent test-retest reliability.