HIV testing strategies outside of health care settings in the European Union (EU)/European Economic Area (EEA): a systematic review to inform European Centre for Disease Prevention and Control guidance.

OBJECTIVES: In recent years, new technologies and new approaches to scale up HIV testing have emerged. The objective of this paper was to synthesize the body of recent evidence on strategies aimed at increasing the uptake and coverage of HIV testing outside of health care settings in the European Union (EU)/European Economic Area (EEA). METHODS: Systematic searches to identify studies describing effective HIV testing interventions and barriers to testing were run in five databases (2010-2017) with no language restrictions; the grey literature was searched for similar unpublished studies (2014-2017). Study selection, data extraction and critical appraisal were performed by two independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Eighty studies on HIV testing in non-health care settings were identified, the majority set in Northern Europe. Testing was implemented in 65 studies, with men who have sex with men the risk group most often targeted. Testing coverage and positivity/reactivity rates varied widely by setting and population group. However, testing in community and outreach settings was effective at reaching people who had never previously been tested and acceptability of HIV testing, particularly rapid testing, outside of health care settings was found to be high. Other interventions aimed to increase HIV testing identified were: campaigns (n = 8), communication technologies (n = 2), education (n = 3) and community networking (n = 1). CONCLUSIONS: This review has identified several strategies with potential to achieve high HIV testing coverage outside of health care settings. However, the geographical spread of studies was limited, and few intervention studies reported before and after data, making it difficult to evaluate the impact of interventions on test coverage.

HIV testing strategies employed in health care settings in the European Union/European Economic Area (EU/EEA): evidence from a systematic review.

OBJECTIVES: Despite the availability of HIV testing guidelines to facilitate prompt diagnosis, late HIV diagnosis remains high across Europe. The study synthesizes recent evidence on HIV testing strategies adopted in health care settings in the European Union/European Economic Area (EU/EEA). METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and systematic searches were run in five databases (2010-2017) to identify studies describing HIV testing interventions in health care settings in the EU/EEA. The grey literature was searched for unpublished studies (2014-2017). Two reviewers independently performed study selection, data extraction and critical appraisal. RESULTS: One hundred and thirty intervention and/or feasibility studies on HIV testing in health care settings were identified. Interventions included testing provision (n = 94), campaigns (n = 14) and education and training for staff and patients (n = 20). HIV test coverage achieved through testing provision varied: 2.9-94% in primary care compared to 3.9-66% in emergency departments. HIV test positivity was lower in emergency departments (0-1.3%) and antenatal services (0-0.05%) than in other hospital departments (e.g. inpatients: 0-5.3%). Indicator condition testing programmes increased HIV test coverage from 3.9-72% before to 12-85% after their implementation, with most studies reporting a 10-20% increase. There were 51 feasibility and/or acceptability studies that demonstrated that HIV testing interventions were generally acceptable to patients and providers in health care settings (e.g. general practitioner testing acceptable: 77-93%). CONCLUSIONS: This review has identified several strategies that could be adopted to achieve high HIV testing coverage across a variety of health care settings and populations in the EU/EEA. Very few studies compared the intervention under investigation to a baseline, but, where this was assessed, data suggested increases in testing.

Key findings on legal and regulatory barriers to HIV testing and access to care across Europe.

OBJECTIVE: The aim of this work within OptTEST by HiE has been to demonstrate the role of legal and regulatory barriers in hindering access to HIV testing, treatment and care across Europe and to produce tools to help dismantle them. METHODS: An online survey to assess country-specific data on legal and regulatory barriers distributed widely across the WHO Europe region. Literature reviews conducted in January-October 2015 in English, in November 2015 in Russian, and updated in April 2017. Semi-structured interviews were conducted with 25 key actors within the HIV field to feed into case studies and tip sheets on how to dismantle legal and regulatory barriers. RESULTS: More than 160 individuals and organisations from 49 countries across the WHO European region provided responses which were analysed and cross checked with other data sources and a searchable database produced (legalbarriers.peoplewithhiveurope.org). The conducted literature reviews yielded 88 papers and reports which identify legal and regulatory barriers to key populations' access to HV testing and care. Based on the interviews with key actors, ranging from PLHIV activists to government officials, on lessons-learned, a series of tip sheets and ten case studies were written-up intended to inform and inspire the HIV community to address and overcome existing barriers (opttest.eu/Tools). CONCLUSION: While some of the barriers identified may require major changes to wider health systems, or long term legal reform, many are open to a simple change in regulations or custom and practice. We have the tools. Why can't we finish the job?

Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.

Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11 C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.

Fast diffusion kurtosis imaging of fibrotic mouse kidneys.

Diffusion kurtosis imaging (DKI) is sensitive to tissue microstructure and may therefore be useful in the diagnosis and monitoring of disease in brain and body organs. Generally, diffusion magnetic resonance imaging (dMRI) in the body is challenging because of the heterogeneous body composition, which can cause image artefacts as a result of chemical shifts and susceptibility differences. In addition, the abdomen possesses physiological factors (e.g. breathing, heartbeat, blood flow) which may severely reduce image quality, especially when echo planar imaging is employed, as is typical in dMRI. Collectively, these challenging measurement conditions impede the use and exploration of DKI in the body. This impediment is further exacerbated by the traditionally large amount of data required for DKI and the low signal-to-noise ratio at the b-values needed to effectively probe the kurtosis regime. Recently introduced fast DKI techniques reduce the challenge of DKI in the body by decreasing the data requirement substantially, so that, for example, triggering and breath-hold techniques may be applied for the entire DKI acquisition without causing unfeasible scan times. One common pathological condition for which body DKI may be of immediate clinical value is kidney fibrosis, which causes progressive changes in organ microstructure. With its sensitivity to microstructure, DKI is an obvious candidate for a non-invasive evaluation method. We present preclinical evidence indicating that the rapidly obtainable tensor-derived mean kurtosis ( W̅) distinguishes moderately fibrotic kidneys from healthy controls. The presence and degree of fibrosis are confirmed by histology, which also indicates fibrosis as the main driver behind the DKI differences observed between groups. We therefore conclude that fast kurtosis is a likely candidate for an MRI-based method for the detection and monitoring of renal fibrosis. We provide protocol recommendations for fast renal DKI in humans based on a b-value optimisation performed using data acquired at 3 T in normal human kidney.

Does a titanium sleeve reduce the frequency of pseudotumors in metal-on-metal total hip arthroplasty at 5-7years follow-up?

INTRODUCTION: Little is known about pseudotumor frequency and risk factors for pseudotumor formation among different types of metal-on-metal (MoM) hip arthroplasties. A lower release of chromium and cobalt have been reported in MoM hip arthroplasties with a titanium sleeve compared to MoM designs without a titanium sleeve, but yet it is unknown whether a titanium sleeve reduces the pseudotumor frequency. We conducted a cross-sectional study to investigate: 1) pseudotumor frequency, 2) risk factors of pseudotumor formation 3) and correlations between pseudotumors, serum metal-ions, implant position, and clinical symptoms. HYPOTHESIS: We expected a lower pseudotumor frequency in MoM hip articulation with a titanium sleeve than reported in MoM hip articulation designs using chromium-cobalt sleeve. MATERIALS AND METHOD: A consecutive series of 41 patients/49 hips (31 males), mean age 52 (28-68) years, participated in a 5.5±0.5 (4-6.5) year follow-up study of their M2a_Magnum hip articulation (Biomet Inc., Warsaw, Indiana, USA). Patients were evaluated with magnetic resonance imaging (MRI), measurements of serum metal-ions, plain radiographs, and clinical outcome measures of Harris Hip Score (HHS) and Oxford Hip Score (OHS). RESULTS: Eighteen of 47 hips (38%) had MRI-verified pseudotumors, all cystic, with a mean dimension of 10.6×25.6×41mm. Digital measurements on plain radiographs revealed a higher cup anteversion in patients with a pseudotumor of mean 28.4°±5.05° compared to mean 23.5°±6.5° in patients without a pseudotumor (P=0.009). Serum metal-ion concentrations, acetabular cup inclination and measures of HHS and OHS were similar between patients with and without a pseudotumor (P>0.46). CONCLUSION: At 5.5±0.5years after surgery, MRI-verified cystic pseudotumors were frequently observed in M2a_Magnum hip articulations despite the use of titanium sleeves. The pseudotumors were related to high cup anteversion angles but not related to high serum metal-ions or clinical symptoms. LEVEL OF EVIDENCE: IV: cross-sectional study.

Block-step asymmetry 5 years after large-head metal-on-metal total hip arthroplasty is related to lower muscle mass and leg power on the implant side.

BACKGROUND: Metal-on-metal articulations mimic the human hip anatomy, presumably lower dislocation rates and increase the range-of-motion. This study aims to measure the muscle mass and power of both legs in patients with unilateral metal-on-metal total hip arthroplasty, and to investigate their effect on block-step test, spatio-temporal gait parameters and self-reported function. METHODS: Twenty-eight patients (7 women), mean age 50 (28-68) years, participated in a 5-7 year follow-up. Patients had received one type unilateral large-head metal-on-metal total hip articulation, all of which were well-functioning at follow-up. Mean muscle mass was measured by the total-body Dual energy X-ray Absorption scans, and muscle power was measured in a leg extensor power rig. Block-step test and spatio-temporal gait parameters were measured with an inertial measurement unit. Self-reported function was assessed by the Hip Disability and Osteoarthritis Outcome Score. FINDINGS: We found a significant difference between the mean muscle mass of the implant-side leg and the non-implant-side leg in hip, thigh and calf areas (P<0.008) and in mean muscle power (P=0.025). Correlations between mean muscle mass and mean muscle power were significant for both the implant-side leg (r=0.45, P=0.018) and the non-implant-side leg (r=0.51, P=0.007). The difference in mean muscle power between legs correlated with block-step test asymmetry during ascending (r=0.40, P=0.047) and descending (r=0.53, P=0.006). Correlations between self-reported function and power of the implant-side leg were not significant. INTERPRETATIONS: Young patients have not fully regained muscle mass, muscle power and function 5-7 years after metal-on-metal total hip arthroplasty.

PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice.

PURPOSE: Tumour hypoxia is linked to treatment resistance. Positron emission tomography (PET) using hypoxia tracers such as fluoroazomycin arabinoside (FAZA) may allow identification of patients with hypoxic tumours and the monitoring of the efficacy of hypoxia-targeting treatment. Since hypoxia PET is characterized by poor image contrast, and tumour hypoxia undergoes spontaneous changes and is affected by therapy, it remains unclear to what extent PET scans are reproducible. Tumour-bearing mice are valuable in the validation of hypoxia PET, but identification of a reliable reference tissue value (blood sample or image-derived muscle value) for repeated scans may be difficult due to the small size of the animal or absence of anatomical information (pure PET). Here tumour hypoxia was monitored over time using repeated PET scans in individual tumour-bearing mice before and during fractionated radiotherapy. METHODS: Mice bearing human SiHa cervix tumour xenografts underwent a PET scan 3 h following injection of FAZA on two consecutive days before initiation of treatment (baseline) and again following irradiation with four and ten fractions of 2.5 Gy. On the last scan day, mice were given an intraperitoneal injection of pimonidazole (hypoxia marker), tumours were collected and the intratumoral distribution of FAZA (autoradiography) and hypoxia (pimonidazole immunohistology) were determined in cryosections. RESULTS: Tissue section analysis revealed that the intratumoral distribution of FAZA was strongly correlated with the regional density of hypoxic (pimonidazole-positive) cells, even when necrosis was present, suggesting that FAZA PET provides a reliable measure of tumour hypoxia at the time of the scan. PET-based quantification of tumour tracer uptake relative to injected dose showed excellent reproducibility at baseline, whereas normalization using an image-derived nonhypoxic reference tissue (muscle) proved highly unreliable since a valid and reliable reference value could not be determined. The intratumoral distribution of tracer was stable at baseline as shown by a voxel-by-voxel comparison of the two scans (R = 0.82, range 0.72-0.90). During treatment, overall tracer retention changed in individual mice, but there was no evidence of general reoxygenation. CONCLUSION: Hypoxia PET scans are quantitatively correct and highly reproducible in tumour-bearing mice. Preclinical hypoxia PET is therefore a valuable and reliable tool for the development of strategies that target or modify hypoxia.

The Danish vaccination register.

Immunisation information systems (IIS) are valuable tools for monitoring vaccination coverage and for estimating vaccine effectiveness and safety. Since 2009, an advanced IIS has been developed in Denmark and will be implemented during 2012­14. This IIS is based on a database existing since 2000. The reporting of all administered vaccinations including vaccinations outside the national programme will become mandatory. Citizens will get access to data about their own vaccinations and healthcare personnel will get access to information on the vaccinations of their patients. A national concept of identification, a national solution combining a personal code and a card with codes, ensures easy and secure access to the register. From the outset, the IIS will include data on childhood vaccinations administered from 1996 and onwards. All Danish citizens have a unique identifier, a so called civil registration number, which allows the linking of information on vaccinations coming from different electronic data sources. The main challenge will be to integrate the IIS with the different electronic patient record systems currently existing at general practitioner, vaccination clinic and hospital level thereby avoiding double-entry. A need has been identified for an updated international classification of vaccine products on the market. Such a classification would also be useful for the future exchange of data on immunisations from IIS between countries.

PET imaging of patients with non-small cell lung cancer employing an EGF receptor targeting drug as tracer.

BACKGROUND: We have previously developed (11)C-erlotinib as a new positron emission tomography (PET) tracer and shown that it accumulates in epidermal growth factor receptor (EGFR)-positive lung cancer xenografts in mice. Here, we present a study in patients with non-small cell lung cancer (NSCLC) investigating the feasibility of (11)C-erlotinib PET as a potential method for the identification of lung tumours accumulating erlotinib. METHODS: Thirteen patients with NSCLC destined for erlotinib treatment were examined by contrast-enhanced computed tomography (CT), (11)C-erlotinib PET/low-dose CT and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/low-dose CT before start of the erlotinib treatment. After 12 weeks treatment, they were examined by (18)F-FDG PET/contrast-enhanced CT for the assessment of clinical response. RESULTS: Of the 13 patients included, 4 accumulated (11)C-erlotinib in one or more of their lung tumours or lymph-node metastases. Moreover, (11)C-erlotinib PET/CT identified lesions that were not visible on (18)F-FDG PET/CT. Of the four patients with accumulation of (11)C-erlotinib, one died before follow-up, whereas the other three showed a positive response to erlotinib treatment. Three of the nine patients with no accumulation died before follow-up, four showed progressive disease while two had stable disease after 12 weeks of treatment. CONCLUSION: Our data show a potential for (11)C-erlotinib PET/CT for visualizing NSCLC lung tumours, including lymph nodes not identified by (18)F-FDG PET/CT. Large clinical studies are now needed to explore to which extent pre-treatment (11)C-erlotinib PET/CT can predict erlotinib treatment response.

Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography.

The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [(11)C]methyl iodide or [(11)C]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [(11)C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [(11)C]GSK931145 was reduced to homogeneous levels. Although [(11)C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [(11)C]GSK931145. In contrast, [(11)C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [(11)C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [(11)C]GSK931145 is now being progressed into higher species.

Norwegian population data for the 10 autosomal STR loci in the AMPFlSTR SGM Plus system.

Allele frequencies of the STR loci included in the AmpFlSTR SGM Plus kit were determined in 1000 unrelated individuals from all regions of Norway. For the 10 autosomal STR loci the observed heterozygosity frequencies ranged from 0.766 (D16S539) to 0.885 (D2S1338). No significant deviation from Hardy-Weinberg equilibrium was observed. The exact test disequilibrium analysis revealed one departure from independence out of 45 pairwise comparisons. Calculations of theta coefficients for all 10 loci in two additional subpopulations of different geographical origin revealed an overall value of theta=0.002.

Mobile autopsy teams in the investigation of war crimes in Kosovo 1999.

On request of the International Criminal Tribunal for the former Yugoslavia (ICTY), the Danish-Swedish forensic teams worked in Kosovo during the summer and the fall of 1999. The teams worked mainly as "mobile teams" at sites with few graves. Only two larger sites were examined. Most of the bodies were buried separately. A few "multiple burial" graves were examined, but no mass graves were encountered. The main purpose of the autopsies was to establish the cause and manner of death. Identification was of less importance, but a majority of the bodies had been identified prior to the autopsy. A total of 308 bodies, mainly males, were examined. The age varied greatly with a mean age of 47 years. The most common cause of death was gun shot wounds and the most common manner of death was homicide.

5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside.

Exercise is known to increase insulin sensitivity and is an effective form of treatment for the hyperglycemia observed in type 2 diabetes. Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling.

Dissociative cycloelimination, a new selenium based pericyclic reaction.

The stereospecific oxidation of hydrazine into cis-diimide and the catalytic disproportionation of hydrogen peroxide effected by selenoxides are suggested to involve a dissociative cycloelimination from an intermediary selenurane.

Region-selective effects of long-term lithium and carbamazepine administration on cyclic AMP levels in rat brain.

The effect of lithium and carbamazepine in the treatment of bipolar affective disorder is well established. Although a number of biochemical effects have been found, the exact molecular mechanisms underlying their therapeutic actions have not been elucidated nor are the target regions in the brain identified. Taken into account the important role of the cyclic AMP second messenger system in the regulation of neuronal exitability and the indications of its involvement in the patophysiology of bipolar affective disorder, we have focused on the drug effects on cyclic AMP levels. The objectives of this investigation were to measure the effects on basal cyclic AMP levels, and to locate target regions within the rat brain after long-term administration of lithium and carbamazepine. Drug treatments were carried out for a period of 28 days. After either drug treatment the cyclic AMP level was increased 3-4 times in frontal cortex but unchanged in hippocampus, hypothalamus, thalamus, amygdala and in cerebellum. In neostriatum the cyclic AMP level was decreased to about 30% after treatment with lithium. We suggest the common region-selective effect, observed for both drugs in frontal cortex, to be essential for the therapeutic actions of lithium and carbamazepine.

[Carpal tunnel syndrome and hand edema in temporal arteritis]. / Karpaltunnelsyndrom og håndødem ved arteritis temporalis.

An 89 year-old male was admitted to hospital presenting oedema, reduced sensibility, paraesthesia and reduced mobility of both hands. EMG was in accordance with bilateral carpal tunnel syndrome. An elevated sedimentation rate was found and biopsy from the temporal artery showed arteritis. During glucocorticoid treatment the symptoms disappeared and the EMG and sedimentation rate returned to normal.

Selective effects of long-term lithium and carbamazepine administration on G-protein subunit expression in rat brain.

The efficacy of lithium and carbamazepine in treatment of bipolar affective disorder is well established. Although a number of biochemical effects have been found the exact molecular mechanisms underlying their therapeutic actions have not been elucidated. Nor have the target regions in the brain been located. The objectives of the present investigation were to identify the selective effects and target regions of long-term treatment, with either lithium or carbamazepine, on G-protein subunit expression in rat brain. Effects were measured in hippocampus, hypothalamus, amygdala, frontal cortex, neostriatum, thalamus, raphe nuclei and cerebellum. At the protein level amounts of Galphao decreased significantly (P < 0.01) in neostriatum and Gbeta increased in frontal cortex in response to both drug treatments. At the mRNA level amounts of Galphai1 increased significantly (P < 0.01) in neostriatum. Galphas messenger amounts decreased in frontal cortex and increased in thalamus. These effects were common for both drugs, however, in addition also some differential effects, specific for either of the two drugs, were observed. We conclude frontal cortex and neostriatum are important target regions of long-term treatment with either lithium or carbamazepine and suggest Galphao, Galphas, Galphai1 and Gbeta to be selective target molecules.

The weight of the normal spleen.

The aim of the present study was to determine the weight of the normal spleen based upon a retrospective material of 539 medico-legal autopsies. Only cases above 20 years of age without indication of disease or conditions known to influence the spleen weight were included. It is found that the spleen weight is positively correlated to height, body weight and degree of acute congestion but not to sex or age. A table in which the spleen weight is correlated to height and weight is presented. The table can be used for comparison with the actual findings at an autopsy.