bluuebunny/crossref_metadata_2025 huggingface dataset:
Posterior Cervical lymph Node Metastasis as the Valuable Prognostic Factor for Stage IVA/IVB Nasopharyngeal Carcinoma Treated with Induction Chemotherapy Followed by Concurrent Chemo-Radiotherapy
Authors: Thephamongkhol Kullathorn , Setakornnukul Jiraporn , Rojwatkarnjana Sunanta , Chansilpa Yaowalak
Published: November 2014

Introduction/Aim

To evaluate the prognostic properties of retropharyngeal lymph node (RP), posterior cervical lymph node (PCN), and supraclavicular lymph node (SPC), in stage IVA/IVB nasopharyngeal carcinoma (NPC) patients in setting of induction chemotherapy.

Methods

We performed a retrospective study including 43 patients with stage IVA/IVB NPC (7th AJCC) treated with induction chemotherapy followed by concurrent chemo-radiotherapy. We analyzed prognosis with the multivariate Cox regression model and p-value from the Wald's test, using the backward elimination method (by likelihood ratio test and percent change of coefficient factors).

Result

Overall, 24 patients (55.8%) were in stage IVA and 19 (44.2%) in stage IVB. After a median follow-up time of 30 months, the 2-year overall survival (OS) was 79.1%, while the 2-year progression free survival (PFS) and distant metastasis free survival (DMFS) were 59.8% and 69.1%, respectively. In multivariate analysis for predicting DMFS, SPC involvement was not statistically significant (HR 3.39; 95% CI 0.76-15.07; p=0.1), whereas RP involvement was statistically significant (HR 5.81; 95% CI 1.08-31.16; p=0.04). Moreover, and more importantly, PCN involvement was the only nodal factor to predict all of DMFS, PFS, and OS (respectively HR 5.57, 95% CI 1.12-27.71, p=0.036; HR 16.05, 95% CI 1.93-133.65, p=0.01; and HR 28.02, 95% CI 2.74-286.22, p=0.005).

Discussion

PCN involvement is the only independent prognostic factor of stage IVA/IVB NPC patients treated by induction chemotherapy that predicts DMFS and turns this effect to PFS and OS. PCN involvement is a highly accurate predictor for failure of conventional chemo-radiotherapy. Therefore, patients with PCN involvement should be defined at high-risk, as to be investigated for a new staging system.
Dilution effect of serum CA125 and CA19-9 over a cutoff value, according to obesity
Authors: Kim Jae Heon , Park Bo Ra , Yang Won Jae
Published: November 2014

The dilution effect of high plasma volume contributes to a lower level of specific tumor marker such as prostate-specific antigen. To date, few studies have focused on this effect of other tumor marker levels. Therefore, we evaluated the dilution effects of a higher plasma volume on lowering the serum concentration of various tumor markers such as CA125 and CA19-9. Data from patients (age ≥40 years) visiting our public health center between March 2007 and March 2013 were gathered. A total of 19,439 male and 11,655 female native Koreans were eligible to have a serum CA125 and CA19-9 screening for ovarian and pancreatic cancer, respectively. CA125 levels in 11,234 women were analyzed. There was a statistically significant trend toward a lower likelihood of having a serum CA125 level >35 U/mL with increased body mass index (BMI), with obese men having a 53.1% lower likelihood than those with a normal BMI. After CA19-9 analysis in 29,978 participants, there was also a significant trend toward a lower likelihood of having a serum CA19-9 level >35 U/mL with increased BMI, with obese men having a 27.0% and obese women having a 32.7% lower likelihood than those with a normal BMI. These results might affect tumor screening efficiency for ovarian and pancreatic cancer using serum CA125 and CA19-9, respectively. Further studies are needed to better define these results in clinical practice.
X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism significantly associated with prostate cancer
Authors: Chen Yang , Li Tianyu , Li Jie , Mo Zengnan
Published: November 2014

Prostate cancer (Pca) is one of the noncutaneous cancers occurring worldwide. Its high morbidity and mortality make it a concern. X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism (rs25487) has been reported to be related to Pca. However, the conclusions are controversial. In this study, PubMed, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases were combined with a comprehensive literature search. Four models including dominant (AA + AG vs. GG), recessive (AA vs. AG+GG), codominant (AA vs. AG, AA vs. GG) and per-allele analysis (A vs. G) were applied. Finally, 15 studies with 18 sets of data were included. A positive association was discovered in pooled results for recessive (odds ratio [OR]=1.202, 95% confidence interval [95% CI], 1.060-1.363, I2=46.20%), codominant (AA vs. AG; OR=1.258, 95% CI, 1.099-1.439, I2=38.50%; AA vs. GG; OR=1.283, 95% CI, 1.027-1.602, I2=51.70%) and allele analysis (OR=1.116, 95% CI, 1.001-1.244, I2=58.00%). In ethnicity subgroup analysis, these 4 models were also significant in the Asian subgroup. However, for whites, only 2 models seemed to be significant (AA vs. AG+GG: OR=1.525, 95% CI, 1.111-2.093, I2=52.60%; AA vs. AG: OR=1.678, 95% CI, 1.185-2.375, I2=30.70%). In further analysis, we regrouped the data based on race, in which pooled results and Asian subgroup were again shown to be positive. In the next analysis, expression quantitative trait loci (eQTL), linkage disequilibrium (LD), TagSNP and functional analysis were used. The results showed that the SNP was a tag and functional SNP with LD block in both Asians and whites. In summary, we suggest that XRCC1 Arg399Gln might be significantly associated with development of Pca.
Clinical outcomes model in renal cell cancer patients treated with modified vaccinia Ankara plus tumor-associated antigen 5T4
Authors: Amato Robert J. , Xiong Youxin , Peng Hui , Mohlere Virginia
Published: November 2014

Aims

We developed an outcomes model to select patients for renal cell cancer vaccine immunotherapy.

Materials and methods

We examined clinical data from 2 phase II studies of modified vaccinia Ankara as vector to express 5T4 (MVA-5T4), calculated progression-free survival (PFS) and overall survival (OS), and created risk groups based on the number of factors involved.

Results

Median OS was 12.4 months; median PFS was 3.6 months. Significant factors (p<0.05) included neutrophils (both), bone metastases (OS), ECOG performance status (OS), lactate dehydrogenase levels (both), prior therapy with tyrosine kinase inhibitors plus immunotherapy (OS), Fuhrman grade (OS), and 5T4-specific ELISPOT response (PFS). By group, median OS was not reached in patients with favorable risk (censored at cutoff), was 13.7 months in those with intermediate risk and 4.0 months in those with poor risk.

Conclusions

Further validation of this model will identify the patients most likely to respond to MVA-5T4 and provide a framework for outcomes models for other vaccine therapies.
Investigation of BK virus, Epstein-Barr virus and human papillomavirus sequences in postoperative thyroid gland specimens
Authors: Stamatiou Dimitris , Derdas Stavros P. , Symvoulakis Emmanouil K. , Sakorafas Georgios H. , Zoras Odysseas , Spandidos Demetrios A.
Published: November 2014

Background

Although recent evidence has implicated viruses in the regulation of epithelial-to-mesenchymal transition and tumor progression, little is known regarding viral infections in thyroid malignancies. Thus the aim of this study was to detect sequences of 3 potentially oncogenic viruses – BK virus (BKV), Epstein-Barr virus (EBV) and human papillomavirus (HPV) – in a series of postoperative thyroid gland specimens.

Methods

Thirty patients with thyroid nodules who underwent surgery for thyroid disease within a 3-year period were enrolled. Both nodular and adjacent normal thyroid tissue was surgically excised from each patient. Viral gene sequences of BKV (VP1), EBV (LMP1, EBNA2 and EBER1) and HPV were amplified by PCR. The PCR results were confirmed by direct sequencing analysis.

Results

VP1 gene sequences were detected in 60% (18/30) of thyroid cancer or multinodular hyperplasia lesions compared with in 43.3% (13/30) of adjacent normal thyroid tissue specimens. Fifteen of thirty (50%) of thyroid cancer or multinodular hyperplasia samples revealed LMP1 sequences compared with 46.7% (14/30) of corresponding normal thyroid tissues. EBNA2 gene sequences were detected in 90% (27/30) of thyroid cancer or multinodular hyperplasia samples, compared with 90% (27/30) of adjacent normal thyroid tissue specimens. All samples were negative for EBER1 sequences, while HPV DNA was not detected in either nodular or normal thyroid tissue.

Conclusions

This study suggests that BKV and EBV “infection” is an early event, occurring within normal tissue. Our findings do not show a clear role for the viruses examined, instead they suggest an “endemicity” pattern rather than a causal effect.
Biased Paternal Transmission of TRH Variant to Female down Syndrome Probands: Possible Correlation with Low Breast Cancer Frequency
Authors: Dey Arpita , Chatterjee Arpita , Maiti Atanu , Mukherjee Nupur , Sinha Swagata , Panda Chinmay K. , Mukhopadhyay Kanchan
Published: November 2014

Thyroid malfunction is more common in individuals with Down syndrome (DS) than in the general population. It has been hypothesized that thyroid may influence cancer risk. Individuals with DS are at greater risk of developing leukemia than the general population, while solid tumors especially breast cancer (BC) are rare. BC patients have higher levels of circulating thyroid-stimulating hormone (TSH) and prolactin (PRL), both regulated by the thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide. This study was aimed at investigating the status of TRH functional polymorphisms in subjects with DS and BC. Unrelated families with DS probands (n=180), individuals with BC (n=99) and ethnically matched controls (n=216) were recruited. Genomic DNA isolated from peripheral blood was subjected to PCR amplification followed by DNA sequence analysis. Data obtained were analyzed by population- and family-based statistical analysis. Among 30 studied sites, only 2 (rs7645772 and rs13097335) were polymorphic. Case-control analysis showed a lack of any significant association with DS, while the rs13097335 GG and GT genotype frequency was significantly different in the BC samples. A paternal-biased transmission of the G allele was observed in female DS probands. It may be concluded that rs13097335 may have a protective role toward the development of BC.
Temporal Regulation of venous Extracellular Matrix Components during Arteriovenous Fistula Maturation
Authors: Hall Michael R. , Yamamoto Kota , Protack Clinton D. , Tsuneki Masayuki , Kuwahara Go , Assi Roland , Brownson Kirstyn E. , Bai Hualong , Madri Joseph A. , Dardik Alan
Published: November 2014

Purpose

The venous limb of arteriovenous fistulae (AVF) adapts to the arterial environment by dilation and wall thickening; however, the temporal regulation of the expression of extracellular matrix (ECM) components in the venous limb of the maturing AVF has not been well characterized. We used a murine model of AVF maturation that recapitulates human AVF maturation to determine the temporal pattern of expression of these ECM components.

Methods

Aortocaval fistulae were created in C57BL/6J mice and the venous limb was analyzed on postoperative days 1, 3, 7, 21, and 42. A gene microarray analysis was performed on day 7; results were confirmed by qPCR, histology, and immunohistochemistry. Proteases, protease inhibitors, collagens, glycoproteins, and other non-collagenous proteins were characterized.

Results

The maturing AVF has increased expression of many ECM components, including increased collagen and elastin. Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP1) showed increased mRNA and protein expression during the first 7 days of maturation. Increased collagen and elastin expression was also significant at day 7. Expression of structural proteins was increased later during AVF maturation. Osteopontin (OPN) expression was increased at day 1 and sustained during AVF maturation.

Conclusions

During AVF maturation, there is significantly increased expression of ECM components, each of which shows distinct temporal patterns during AVF maturation. Increased expression of regulatory proteins such as MMP and TIMP precedes increased expression of structural proteins such as collagen and elastin, potentially mediating a controlled pattern of ECM degradation and vessel remodeling without structural failure.
Effectiveness of Skin Perfusion Pressure Monitoring during Surgery for an Ischemic Steal Syndrome Associated Refractory Ulcer
Authors: Okubo Kentaro , Sato Takashi , Matsubara Chieko , Tsuboi Masato , Ishii Yasuo , Tojimbara Tamotsu
Published: November 2014

We describe an 80-year-old man with end-stage renal disease due to type 2 diabetes who had been maintained on hemodialysis for 9 years. He developed refractory ulcers from an abraded wound in the right hand of his access arm. The arteriovenous fistula (AVF) was located between the right brachial artery and the median antecubital vein draining into the cephalic vein and the deep veins close to the elbow. The blood flow of the right brachial artery measured by using Doppler ultrasonography was 920 ml/min. On the contrary, the radial and ulnar arteries were poorly palpable near the wrist, and ultrasonography could not be performed accurately because of a high degree of calcification. The skin perfusion pressure (SPP) of the first finger on the affected side decreased to 22 mmHg. However, the SPP improved to approximately 40 mmHg upon blocking an inflow into the deep vein. According to SPP data, only a communicating branch of the deep vein was ligated, and the AVF itself was preserved. One month after surgery, the skin ulcer healed, and maintenance hemodialysis was performed by using the preserved cephalic vein for blood access.

In conclusion, we successfully treated a refractory wound associated with steal syndrome, without terminating the AVF. SPP-guided surgery may be safe and effective to adjust the blood flow in patients with AVF having steal syndrome.
Ultrasound-Guided Subclavian Venipuncture is More Rapidly Learned than the Anatomic Landmark Technique in Simulation Training
Authors: Tokumine Joho , Matsushima Hisao , Lefor Alan Kawarai , Igarashi Hiroshi , Ono Kazuyuki
Published: November 2014

Purpose

Both ultrasound-guided subclavian venipuncture (US-SV) and landmark-guided subclavian venipuncture (LM-SV) are important in critical care, because the clinical utility of ultrasound guidance is still debated. Education of residents and medical students should include both techniques. The aim of this study is to compare learning these two techniques in a simulation environment.

Methods

This study was approved by the research ethics review committee. Trainees included residents and medical students who were instructed using the “Videos in Clinical Medicine” for LM-SV, or a dedicated slide series for US-SV, using the long-axis in-plane with needle-guide technique. After the lecture, trainees attempted to perform venipuncture in a simulator. All participants performed both techniques. The procedure time from initial skin puncture to detecting back-flow of fluid from the simulated vein was measured. A procedure time over 3 min, arterial puncture, or pneumothorax was counted as a failure. The end-point for each trainee was three successive successful venipunctures without a failure. A trainee who reached the end-point was considered as having acquired adequate skill. Statistical analysis of the procedure time comparing the techniques was done using the Mann-Whitney U test.

Results

Twenty trainees participated in this training. Adequate skill to perform US-SV was achieved within three tries, but up to nine attempts were needed for LM-SV. One arterial puncture occurred during LM-SV. No pneumothoraxes occurred during the simulation training.

Conclusions

US-SV was learned more quickly than LM-SV in a simulation model.
Hematuria following Kidney Tumorectomy: Can it Hide an Arteriovenous Fistula?
Authors: Pavan Nicola , Liguori Giovanni , Vedovo Francesca , Bucci Stefano , Bertolotto Michele , Trombetta Carlo
Published: November 2014

We present the case and radiologic images of a 64-year-old man who presented with gross hematuria and fever 2 months after undergoing retroperitoneal partial nephrectomy for a 4.7 × 4.6 cm papillary renal cell carcinoma. Angio-TC demonstrated an aneurysmatic dilatation of the anterior inferior segmental artery of the right kidney with an art-riovenous fistula; the patient was treated with angiography and selective cannulation by deploying 4 platinum coils. At follow-up, we used contrast-enhanced ultrasound to monitor coil embolization of the renal artery pseudoaneurysm.
Effect of Application of Liquid Swine Manure on Soil Organic Carbon and Enzyme Activities in Two Contrasting Saskatchewan Soils
Authors: King Tom , Schoenau Jeff J. , Malhi Sukhdev S.
Published: November 2014

Repeated application of animal manure to agricultural fields as a source of plant nutrients has led to questions concerning the impact of this practice on soil organic carbon (C) and biochemical properties, specifically the activity of soil enzymes. There are also some environmental concerns of using livestock manure. The objectives of this study were to determine the effects of repeated applications of liquid swine manure (LSM) on total organic C (TOC), light fraction organic C (LFOC) and on the activity of the soil enzymes (arylsulfatase, alkaline phosphatase and urease) in two contrasting soil-climatic zones and cropping systems in Saskatchewan. Liquid hog manure was applied annually at 37,000 L ha-1 and 74,000 L ha-1rates for three years at Melfort (Mollic Cryoboralf) and for four years at Plenty (Typic Boroll) in Saskatchewan, Canada. Soil samples were collected to a depth of 0-15 cm in the spring of 2003 and analyzed for TOC, LFOC and enzyme activities. Annual application (37,000 L ha-1) and larger application made every two years (74,000 L ha-1) of LSM at Melfort increased LFOC, which was attributed to stimulation of plant growth and thus residue inputs, from the nutrients contained within the manure. Applications of LSM at 37,000 L ha-1 and 74,000 L ha-1 at the Plenty site increased both TOC and LFOC concentration when compared to the control. Soil at the Plenty site is a Typic Boroll of heavy clay texture, which aids in protecting soil organic matter (SOM) from decomposition by soil microorganisms. Melfort was the only site that responded to LSM applications in terms of increased enzyme activity, which may be a result of a shorter application history. The Melfort site also had significantly higher LFOC in the manure treatments compared to the other site and LFOC has been linked to enzyme activity. The results of this study indicate that it may take a long period of time for addition of LSM to produce measurable changes in TOC and LFOC, as the effect from LSM is mainly from the stimulation of plant growth rather than from direct additions of C, and the nutrients contained in the LSM may potentially enhance microbial decomposition. In soils that receive repeated applications of LSM, nutrient loading may contribute to reduced enzyme activity after a period of time.
Hoe Europa zijn zigeuners uitvond
Authors: Bogdal K.M.
Published: November 2014

How Europe invented its gypsies. On the dark side of modernity

Europe is commonly depicted as the cradle of modernity. But this image usually has a blind eye for marginal communities and cultures existing seemingly apart of the big developments. An example of this is the neglect of the Roma people who settled here early, on the threshold of the Middle Ages and the modern era. The attitude of the European people towards this mobile ethnic group can be described as moving between contempt and fascination. Referring to images of gypsies in literature and other cultural expressions the author shows how during the Romantic era the gypsies were serving as a projection object for desires and fantasies about socially deviant lifestyles. The subsequent process of ‘de-Europeanization’ together with the creation of exotic images through ethnology is described as well as the racial theories and their political consequences for the Roma people in the twentieth century. Instead of contributing to the creation of borderlines and fuelling destruction fantasies, art and sciences should give more attention to the undividedness of humankind and to human dignity.
De taal van de Roma en Sinti
Authors: Bakker P.
Published: November 2014

The language of the Roma and Sinti

The Roma and Sinti (formerly called gypsies) have a language of their own called Romani or Romanes. The language has been present in the Netherlands since 1420, and the first documentation from our country dates from the 1500s. Linguists have established that the language is a continuation of Indian languages. The dialects of Romani from all corners of Europe also show the clear unity of the language. It is not – as sometimes supposed – a secret jargon. After centuries of neglect or downright oppression of the people and their language, Romani is now recognized at the national and European levels. This also led to an increasing use of a written language, used for all genres, from literature to cookbooks and political texts. Despite having been spoken beside other languages for over a millennium, its vitality is higher than for all of the more recent immigrant languages in the Netherlands.
Tussen eigenheid en aanpassing
Authors: Jorna P.
Published: November 2014

Between authenticity and adjustment. On the culture and integration of Dutch Roma and Sinti

This article focuses on ‘culture’ as a concept currently dominating the approach towards Roma and Sinti, in policies and public opinion in the Netherlands and probably in Europe too. The author argues that a culture-sensitive approach is useful indeed, but a fixation on culture leads into a dead end street – especially in the static way in which it is (implicitly) conceptualised. Explaining some traditional Roma habits and values, the author describes examples of everyday life in Roman communities, as well as some lively debates among Roma and Sinti insiders. It is important that the complexity and dynamics of Roma culture are recognised and that outsiders stop defining what Roma culture ‘is’. Instead, recognising the differences between communities as well as the reality of changing norms and values will provide a breeding ground for finding a healthy balance between authenticity and adjustment.
MiFID II, een complex product
Authors: Schreuder Erwin
Published: November 2014

MiFID II, een complex product

Op 12 juni 2014 zijn de herziene Richtlijn voor Markten in Financiële Instrumenten (MiFID II) en de Verordening voor Markten in Financiële Instrumenten (MiFIR) gepubliceerd. MiFID II en MiFIR zijn de gezamenlijke opvolger van MiFID I. De regelgeving is relevant voor beleggingsondernemingen (zoals effectenbemiddelaars en vermogensbeheerders) en exploitanten van handelsplatformen voor financiële instrumenten. Vergeleken met MiFID I gelden er veel nieuwe regels, waaronder transparantievereisten bij beurshandel en nieuwe gedragsregels voor beleggingsondernemingen. Tevens worden voorheen ongereguleerde activiteiten onder toezicht geplaatst. De uitdaging voor marktpartijen om per uiterlijk januari 2017 te voldoen aan de nieuwe regels is groot, mede vanwege vele rule-based normen.

Richtlijn 2014/65/EU van het Europees Parlement en de Raad van 15 mei 2014 betreffende markten voor financiële instrumenten en tot wijziging van Richtlijn 2002/92/EG en Richtlijn 2011/61/EU, Pb. EU 2014, L 173/34.
De modernisering voorbij: de mededingingsbeperking in het kartelverbod en in het staatssteunverbod
Authors: Parret Laura
Published: November 2014

De modernisering voorbij: de mededingingsbeperking in het kartelverbod en in het staatssteunverbod: Een aanzet voor een vergelijkende studie

Zowel de mededingingsregels als de staatssteunregels hebben de afgelopen jaren een zogenoemde modernisering ondergaan. De meest recente modernisering, die van de staatssteunregels, vond inspiratie in de eerdere modernisering van de mededingingsregels. Beide hebben minstens één gemeenschappelijk kenmerk: de invoering van een meer economische benadering. Aanleiding genoeg om stil te staan bij het verband tussen beide onderdelen van het brede mededingingsrecht. Deze bijdrage doet dat aan de hand van het aan de artikelen 101 en 107 VWEU gemeenschappelijke begrip ‘mededingingsbeperking’ en de impact van de modernisering daarop. Zullen de respectievelijke moderniseringen het kartelverbod en het staatssteunverbod dichter bij elkaar brengen of juist niet?

Artikel 101 en 107 VWEU
Simulatie onder slachtoffers van schokkende gebeurtenissen
Authors: Kunst Maarten
Published: November 2014

Malingering psychological symptoms among victims of critical incidents: A plea for independent assessment of psychological symptoms in compensation procedures

High-impact incidents, such as (natural) disasters, severe (traffic) accidents, and exposure to (war) violence, may have severe psychological consequences, both for direct and indirect victims. Such consequences may qualify for financial compensation. However, some victims malinger their psychological status to get compensated for damages they have not suffered. This type of fraudulent behavior costs insurance companies and publicly funded compensation services enormous amounts of money and may eventually make compensation unaffordable. To prevent this from occurring, it is argued that lawyers who need to decide upon victims’ claims for compensation should call in independent experts to evaluate the genuineness of victims’ reported psychological symptoms by administrating a malingering detection test. To enable correct interpretation of the outcome of such a test, the base rate problem is extensively discussed. In short, this problem means that correct test interpretation in individual cases depends on the prevalence of malingering in the population to which a victim belongs. Finally, several counter arguments for the standard assessment of malingering by independent experts are discussed.
Mathematical Lies We Tell Students
Authors: Graybeal Christy Danko
Published: November 2014

This department publishes brief news articles, announcements, and guest editorials on current mathematics education issues that stimulate the interest of TCM readers and cause them to think about an issue or consider a specific viewpoint about some aspect of mathematics education.
Bidirectional links between HIV and intimate partner violence in pregnancy: implications for prevention of mother‐to‐child transmission
Authors: Hatcher Abigail M , Woollett Nataly , Pallitto Christina C , Mokoatle Keneuoe , Stöckl Heidi , MacPhail Catherine , Delany‐Moretlwe Sinead , García‐Moreno Claudia
Published: November 2014

Introduction

Prevention of mother‐to‐child transmission (PMTCT) has the potential to eliminate new HIV infections among infants. Yet in many parts of sub‐Saharan Africa, PMTCT coverage remains low, leading to unacceptably high rates of morbidity among mothers and new infections among infants. Intimate partner violence (IPV) may be a structural driver of poor PMTCT uptake, but has received little attention in the literature to date.

Methods

We conducted qualitative research in three Johannesburg antenatal clinics to understand the links between IPV and HIV‐related health of pregnant women. We held focus group discussions with pregnant women (n=13) alongside qualitative interviews with health care providers (n=10), district health managers (n=10) and pregnant abused women (n=5). Data were analysed in Nvivo10 using a team‐based approach to thematic coding.

Findings

We found qualitative evidence of strong bidirectional links between IPV and HIV among pregnant women. HIV diagnosis during pregnancy, and subsequent partner disclosure, were noted as a common trigger of IPV. Disclosure leads to violence because it causes relationship conflict, usually related to perceived infidelity and the notion that women are “bringing” the disease into the relationship. IPV worsened HIV‐related health through poor PMTCT adherence, since taking medication or accessing health services might unintentionally alert male partners of the women's HIV status. IPV also impacted on HIV‐related health via mental health, as women described feeling depressed and anxious due to the violence. IPV led to secondary HIV risk as women experienced forced sex, often with little power to negotiate condom use. Pregnant women described staying silent about condom negotiation in order to stay physically safe during pregnancy.

Conclusions

IPV is a crucial issue in the lives of pregnant women and has bidirectional links with HIV‐related health. IPV may worsen access to PMTCT and secondary prevention behaviours, thereby posing a risk of secondary transmission. IPV should be urgently addressed in antenatal care settings to improve uptake of PMTCT and ensure that goals of maternal and child health are met in sub‐Saharan African settings.
Choice of initial therapy
Authors: Battegay Manuel
Published: November 2014

Current international and national treatment guidelines such as EACS, BHIVA, DHHS or IAS update regularly recommendations on the choice of initial combination antiretroviral treatment (cART) regimens. Preferred cART regimens include a backbone with two nucleoside (nucleotide) reverse transcriptase inhibitors combined either with one non‐nucleoside reverse transcriptase inhibitor or one ritonavir boosted protease inhibitor or more recently one integrase inhibitor. Response rates according to viral load measurements increased in recent years, in particular due to better tolerability. The choice of initial therapy is flexible and influenced by several factors such as height of viral load, genotypic resistance testing, CD4 cell count, co‐morbidities, interactions, potential adverse events, (potential for) pregnancy, convenience, adherence, costs as well as physician's and patient's preferences. Diverse highly potent initial cART regimens exist. Following the many possibilities, the choice of a regimen is based on a mixture of evidence‐informed data and individualized concepts, some of the latter only partly supported by strong evidence. For example, different perceptions and personal experiences exist about boosted protease inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or integrase inhibitors and vice versa which may influence the initial choice. This lecture will discuss choices of initial cART in view of international guidelines and the evidence for individualization of initial HIV therapy.
Large disparities in HIV treatment cascades between eight European and high‐income countries – analysis of break points
Authors: Raymond Alice , Hill Andrew , Pozniak Anton
Published: November 2014

Introduction

Patients on antiretroviral treatment with undetectable HIV RNA levels have a significantly lower risk of clinical disease progression and onward HIV transmission. This study aimed to estimate and compare the percentage of all HIV‐positive people who are diagnosed, are linked to care, are taking antiretroviral treatment and have undetectable HIV RNA, in eight European and high‐income countries: the United States, the United Kingdom, France, the Netherlands, Denmark, Australia, British Columbia (Canada) and Georgia.

Materials and Methods

For each country, the number of people in five key stages of the HIV treatment cascade was collected: 1. HIV infected, 2. Known to be HIV positive, 3. Linked to care, 4. Taking antiretroviral treatment, and 5. Having undetectable HIV RNA. Estimates were extracted from national reports [1–3], the UNAIDS database, conference proceedings [4] and peer‐reviewed articles [5–7]. The quality of the estimates and reporting methods were assessed individually for each country, with selection criteria such as availability of nationwide database and routinely collected data. Treatment cascades were constructed using estimates from 2010 to 2012.

Results

As shown in Table 1, the percentage of all infected people with undetectable HIV RNA ranged from 20% in Georgia to 59% in Denmark. Of the high‐income countries, the United States has the lowest percentage of individuals with undetectable viral load (25% to median 52%), associated with the highest HIV incidence rate (15.30 per 100,000 to median 6.07 per 100,000). The pattern of the cascades differed between countries: in the United States, there is a fall from 66% to 33% (−33%) between linkage to care and start of antiretroviral treatment. However, in Georgia, the greatest loss in continuum was zat diagnosis, with 48% of undiagnosed HIV‐positive individuals.

Conclusions

There are great disparities among European and high‐income countries in the percentage of HIV‐positive individual with undetectable HIV RNA. Furthermore, the treatment cascades show different key break points, underlying inequalities in HIV care between countries.
Predictive value of prostate‐specific antigen for prostate cancer: a nested case‐control study in EuroSIDA
Authors: Shepherd Leah , Borges Álvaro Humberto , Ravn Lene , Harvey Richard , Viard Jean‐Paul , Bower Mark , Grulich Andrew , Silverberg Michael , De Wit Stephane , Kirk Ole , Lundgren Jens , Mocroft Amanda ,   on behalf of EuroSIDA in Eurocoord
Published: November 2014

Introduction

Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV− men, the usefulness of prostate‐specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV− men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men.

Methods

Men with PCa (n=21) and up to two matched controls (n=40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics.

Results

Sixty‐one men were included with a median six (IQR 2–9) years follow‐up. Time between last sample and PCa was seven (4–11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48–57) and CD4 of 437 (243–610) cells/mm3. Median tPSA [2.8 (IQR: 1.6–4.6) and 0.8 (0.5–1.2) µg/L] and fPSA [0.4 (0.2–0.8) and 0.3 (0.2–0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7–9.5) and 0.9 (0.6–1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5–1.4) and 0.2 (0.2–0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2‐fold higher 4.7 (CI: 1.7–12.9) and 5.4 (1.7–17.4)]. Elevated tPSA values in cases were detectable ≥5 years before PCa (p<0.01). Testosterone [overall median 19.4 (IQR 15.3–23.9) nmol/L at first sample) and SHBG [50.0 (34.0–66.0) nmol/L] levels were similar in cases and controls at first and last sample (all p>0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC = 0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%).

Conclusions

PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age‐related cut‐offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa.
Adverse events: ART and the kidney: alterations in renal function and renal toxicity
Authors: Post Frank
Published: November 2014

Renal dysfunction is common in HIV‐positive patients who receive antiretroviral therapy (ART). Several antiretrovirals have been associated with kidney disease progression, inhibition of renal tubular transporters that mediate creatinine secretion or impaired reabsorption of phosphate and low‐molecular weight proteins. These aberrations of renal function are typically non‐treatment limiting and of unclear clinical significance. By contrast, severe renal toxicity is infrequent in well‐managed patents. Tenofovir‐DF and atazanavir may cause acute tubular injury, tubule‐interstitial nephritis or nephrolithiasis. Discontinuation of the offending drug is required to mitigate the adverse effects on kidney or bone. This presentation will discuss ART‐associated changes in renal function and treatment‐limiting renal toxicity in terms of incidence, risk factors, putative mechanism and provide recommendations for clinical practice.
Gender differences in HIV‐positive persons in use of cardiovascular disease‐related interventions: D:A:D study
Authors: Hatleberg Camilla Ingrid , Ryom Lene , El‐Sadr Wafaa , Mocroft Amanda , Reiss Peter , de Wit Stephan , Dabis Francois , Pradier Christian , d'Arminio Monforte Antonella , Rickenbach Martin , Law Matthew , Lundgren Jens , Sabin Caroline
Published: November 2014

Introduction

There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV‐positive individuals. We investigated whether such differences exist in the D:A:D study.

Materials and Methods

Follow‐up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid‐lowering drugs (LLDs), angiotensin‐converting enzyme inhibitors (ACEIs), anti‐hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10‐year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors.

Results

At enrolment, women (n=13,039; median (interquartile range) 34 (29–40) years) were younger than men (n=36,664, 39 (33–46) years, p=0.001), and were less likely to be current smokers (29% vs. 39%, p=0.0001), to have diabetes (2% vs. 3%, p=0.0001) or to have hypertension (7% vs. 11%, p=0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person‐years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti‐hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high‐risk group, initiation rates of most interventions (with the exception of anti‐hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1).

Conclusion

Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions.
HIV treatment 2020: what will it look like?
Authors: Gulick Roy
Published: November 2014

Currently there are 28 approved antiretroviral drugs in six mechanistic classes, and recommended first‐line regimens are highly potent, well tolerated, and as convenient as one pill, once‐a‐day. How will HIV treatment change by 2020? Over the next few years, we are likely to see potent 2‐drug regimens tested head‐to‐head with standard three‐drug regimens, and some of these will likely become standard‐of‐care. Newer agents with novel drug resistance profiles (e.g. doravirine, an NNRTI) or new mechanisms of action (e.g. BMS 663068, a CD4 attachment inhibitor) will provide virologic activity in patients with drug‐resistant viral strains. Comparative studies of current and newer agents such as the investigational prodrug of tenofovir (TAF) will help define less toxic regimens. We will see additional convenient co‐formulations developed; with them, we are likely to have second‐ and even third‐line regimens administered one pill, once‐daily. Long‐acting injectable investigational formulations currently in clinical trials such as rilpivirine LA (administered monthly) and cabotegravir (administered quarterly), and others (including combinations of these agents) could provide additional convenient treatment options. Other novel formulations (e.g. patches, implants, rings) and combinations of antiretrovirals with other kinds of medications (e.g. contraceptives) may be developed and tested. In the developing world, we will see increasing numbers of patients taking potent, well‐tolerated convenient first‐line and subsequent regimens with the goal of “20 by 20” – 20 million treated people by 2020. Generic formulations of antiretroviral drugs, including combinations, will be increasingly available and used worldwide. With the current appreciation that inflammation and immune activation play an important role in the natural history of treated HIV infection, anti‐inflammatory agents will be tested and may supplement (or even be co‐formulated with) standard antiretroviral regimens. Recognizing our progress to date, these and other innovations will further improve HIV therapy by 2020.
Forty‐eight‐week efficacy and safety and early CNS tolerability of doravirine (MK‐1439), a novel NNRTI, with TDF/FTC in ART‐naive HIV‐positive patients
Authors: Gatell Josep M , Morales‐Ramirez Javier O , Hagins Debbie P , Thompson Melanie , Keikawus Arasteh , Hoffmann Christian , Rugina Sorin , Osiyemi Olayemi , Escoriu Simona , Dretler Robin , Harvey Charlotte , Xu Xia , Teppler Hedy
Published: November 2014

Introduction

Doravirine (DOR) is an investigational NNRTI (aka MK‐1439) that retains activity against common NNRTI‐resistant mutants. We have previously reported the Part 1 results from a two‐part, randomized, double‐blind, Phase IIb study in ART‐naïve HIV‐1‐positive patients [1]. At doses of 25, 50, 100 and 200 mg qd, DOR plus open‐label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2.

Methods

Patients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre‐specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined).

Results

Part 1 week 48 efficacy and safety results are shown below.

The most common DR clinical AEs in the DOR and EFV groups, respectively, were abnormal dreams (10.2%; 9.5%), nausea (7.8%; 2.4%), fatigue (7.2%; 4.8%), diarrhoea (4.8%; 9.5%) and dizziness (3.0%; 23.8%), and were generally mild to moderate.

Part 1 + 2 Week 8 CNS Event Analysis: One hundred thirty‐two patients were randomized in Part 2, 66 to DOR 100 mg and 66 to EFV. Combining Part 1 and 2, a total of 108 patients received DOR 100 mg and 108 received EFV. By week 8, at least one CNS AE was reported in 22.2% of the DOR group and 43.5% of the EFV group (p<0.001). The most common CNS AEs were dizziness (DOR 9.3%; EFV 27.8%), insomnia (6.5%; 2.8%), abnormal dreams (5.6%; 16.7%) and nightmares (5.6%; 8.3%).

Conclusions

In ART‐naïve, HIV‐1‐positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment‐emergent CNS AEs by week 8 than those who received EFV.
HIV/AIDS mortality in a south east European country versus a west European country
Authors: Dragovic Gordana , Smith Colette , Jevtovic Djordje , Kusic Jovana , Salemovic Dubravka , Ranin Jovan
Published: November 2014

Introduction

Antiretroviral (ARV) treatment available in low‐middle income countries differs as suggested in international HIV‐treatment guidelines. Thus, we compared ARV regimens introduced as a first‐line therapy, time of initiation, frequency of making combination antiretroviral therapy (cART) switches, frequency of viral and immunological monitoring and treatment outcome in south east European (SEE) country (i.e. HIV Centre in Belgrade, Serbia, (HCB)) and west European country (i.e. Royal Free Centre for HIV Medicine at the Royal Free Hospital London, UK (RFH)).

Materials and Methods

ARV naïve patients starting cART from 2003 to 2012 were included. Comparisons of the two cohorts were made using a chi‐square test or Fisher's exact test for categorical variables and a Mann‐Witney U test for continuous variables. Kaplan Meier survival curves were compared using the log rank test.

Results

Of 597 patients from HCB, 361 (61%) initiated cART with prior AIDS diagnosed, while 337 (19%) of 1763 patients from RFH. Average baseline CD4+ T cell counts were significantly lower in Serbia than in UK (177 cells/mm3 vs 238 cells/mm3). The total (mediana, IQR) CD4+ T cell count measurements in the first year of cART was 2 (1, 2) at the HCB, while it was statistically significant higher at the RFH 5 (3, 7), respectively (p<0.0001). At the RFH, it appeared that the cART switching is due to patient's preference or toxicity (46%), while the lack of supply and toxicity (37%) were the most important reasons for treatment change in HCB, within the same period of time (p<0.05). Mortality rates were higher at the HCB versus RFH (p<0.0001). After 12, 24 and 36 months of cART, 3%, 5% and 8% of patients died in HCB, whereas 2%, 3% and 4% of patients died in RFH, respectively (Figure 1).

Conclusions

In south European countries, as a consequence of low testing rate, ARV treatment is introduced at an advanced stage of disease, having a high mortality rate as a consequence. Switching within ARV drugs appears often due to lack of drug supplies and frequently drug‐related toxicity in south east Europe, while in the east European country due to patient's preferences and rarely due to drug‐related toxicity.