Tuberculosis in antiretroviral treatment programs in lower income countries: availability and use of diagnostics and screening

OBJECTIVES In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. METHODS AND FINDINGS We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient-level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). CONCLUSIONS Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge.

Architektura a ideologie. Výchovné instituce Adolfa Hitlera v protektorátu Čechy a Morava a v Říšské župě Sudety

This article examines the architecture of the Nazi regime in two occupied cities of Czechoslovakia, Praha/Prag and Jihlava/Iglau (the latter being one of the traditionally German-speaking island in the bohemia country), and focuses specifically on the process by which Hitler youth organisations (Hitlerjugend) in case of ‘education’ and indoctrination of youth were or were not successfully established in these cities. As comparison, he takes the political-administrative centres of the Sudeten Reichsgau, Ústí/Aussig, Opava/Troppau, Karlovy Vary/Karlsbad and Liberec/Reichenberg. Drawing on Czech and German archive materials, the extensive body of modern analytical literature, and propagandist literature from the period studied, the author examines the extent to which architecture served as a projection screen for Fascist propaganda in the Occupied Eastern territories. He describes the role played by the Reichsstelle für Raumordnung and shows how the Reich’s propagandist objectives came to be reflected in a high specific typology and stylistic lexicon/configuration for the architecture of Hitler youth hostels and homes He examines the process by which these organisations were powerful implanted into the space of occupied Czechoslovakia (and Sudeten) too, a topic that has not yet been addressed in (art) history too. The building projects developed for the Protectorate (published here for the first time) and managed by the Reich’s Hitler Youth Leadership in Berlin (Kulturamt, Reichsjugendführung, RJF, Abteilung HJ) reveal the ties that existed between the construction authorities in the Reich and the Protectorate, including the Planning Committee for the City of Prague. The author asks how many German and Czech architects participated for their own profit in the Nazi system, and for future research raises the hitherto taboo question of guilt and collaboration with the Nazis and the perception of this phenomenon in art history, i.e. the measure of active cooperation of not just German but also Czech architects who contributed to the planning and implementation of projects and thereby unequivocally had a hand in consolidating the totalitarian regime and de facto in the forced „Germanification” of their own people under occupation.

Architectural Developments in Sungai Tenang, 1902-2013

This paper treats the architectural developments in Sungai Tenang since the occupation by the Netherland's Indies in 1902 until the present. During this time great changes have occurred, among them the virtual disappearance of the traditional houses with carved planks. At the same time, much of the architectural developments can be described as the evolution of a still basically Austronesian house structure. Both these changes and the continuities merit close scrutiny, since they together reflect the persistence of the house as a powerful symbolic form that is capable of expressing changing social structures and cultural values. Up to the present, architecture in Sungai Tenang, in spite of its often modern outward appearance, is still by and large vernacular in the sense that its constructive means, its symbolic forms and its uses are firmly rooted in local traditions.

The Trade Versus Culture Discourse: Tracing its Evolution in Global Law

The intensified flows of goods, services, peoples and ideas across borders intrinsic to globalization have had numerous and multi-faceted effects. Those affecting culture have been perhaps the most controversial, as it is more often than not difficult to identify the spill-overs across economic and non-economic areas and across borders, as it is equally hard to qualify the effects of these spill-overs as positive or negative. The debate also tends to be politically and even emotionally charged, which has so far not proven advantageous to establishing a genuine dialogue, nor to finding solutions. This contention and the divergent interests of major players in the international community have been reflected in the institutions and rules of global law. It is the objective of this chapter to explore this institutional architecture, in particular its main (and opposing) constituent fora of the World Trade Organization (WTO) and the United Nations Educational Social and Cultural Organization (UNESCO). The chapter traces the evolution of these institutions and their interaction over time, as well as the underlying objectives, demands and strategies of the key proponents in the trade versus culture discourse, which ultimately shaped the existent law and policy. The chapter concludes with an appraisal of the present state of affairs situating the discussion into the contemporary global governance landscape.

Limited clinical benefit of minority K103N and Y181C-variant detection in addition to routine genotypic resistance testing in antiretroviral therapy-naive patients

OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the sole implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.

Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes

Modern concepts for the treatment of myocardial diseases focus on novel cell therapeutic strategies involving stem cell-derived cardiomyocytes (SCMs). However, functional integration of SCMs requires similar electrophysiological properties as primary cardiomyocytes (PCMs) and the ability to establish intercellular connections with host myocytes in order to contribute to the electrical and mechanical activity of the heart. The aim of this project was to investigate the properties of cardiac conduction in a co-culture approach using SCMs and PCMs in cultured cell strands. Murine embryonic SCMs were pooled with fetal ventricular cells and seeded in predefined proportions on microelectrode arrays to form patterned strands of mixed cells. Conduction velocity (CV) was measured during steady state pacing. SCM excitability was estimated from action potentials measured in single cells using the patch clamp technique. Experiments were complemented with computer simulations of conduction using a detailed model of cellular architecture in mixed cell strands. CV was significantly lower in strands composed purely of SCMs (5.5 ± 1.5 cm/s, n = 11) as compared to PCMs (34.9 ± 2.9 cm/s, n = 21) at similar refractoriness (100% SCMs: 122 ± 25 ms, n = 9; 100% PCMs: 139 ± 67 ms, n = 14). In mixed strands combining both cell types, CV was higher than in pure SCMs strands, but always lower than in 100% PCM strands. Computer simulations demonstrated that both intercellular coupling and electrical excitability limit CV. These data provide evidence that in cultures of murine ventricular cardiomyocytes, SCMs cannot restore CV to control levels resulting in slow conduction, which may lead to reentry circuits and arrhythmias.

Antioxidants improve vascular function in children conceived by assisted reproductive technologies: A randomized double-blind placebo-controlled trial.

AIMS Children conceived by assisted reproductive technology (ART) display vascular dysfunction. Its underlying mechanism, potential reversibility and long-term consequences for cardiovascular risk are unknown. In mice, ART induces arterial hypertension and shortens the life span. These problems are related to decreased vascular endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. The aim of this study was to determine whether ART-induced vascular dysfunction in humans is related to a similar mechanism and potentially reversible. To this end we tested whether antioxidants improve endothelial function by scavenging free radicals and increasing NO bioavailability. METHODS AND RESULTS In this prospective double-blind placebo controlled study in 21 ART and 21 control children we assessed the effects of a four-week oral supplementation with antioxidant vitamins C (1 g) and E (400 IU) or placebo (allocation ratio 2:1) on flow-mediated vasodilation (FMD) of the brachial artery and pulmonary artery pressure (echocardiography) during high-altitude exposure (3454 m), a manoeuver known to facilitate the detection of pulmonary vascular dysfunction and to decrease NO bioavailability by stimulating oxidative stress. Antioxidant supplementation significantly increased plasma NO measured by ozone-based chemiluminescence (from 21.7 ± 7.9 to 26.9 ± 7.6 µM, p = 0.04) and FMD (from 7.0 ± 2.1 to 8.7 ± 2.0%, p = 0.004) and attenuated altitude-induced pulmonary hypertension (from 33 ± 8 to 28 ± 6 mm Hg, p = 0.028) in ART children, whereas it had no detectable effect in control children. CONCLUSIONS Antioxidant administration to ART children improved NO bioavailability and vascular responsiveness in the systemic and pulmonary circulation. Collectively, these findings indicate that in young individuals ART-induced vascular dysfunction is subject to redox regulation and reversible.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study.

BACKGROUND As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the effect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the effect of age on mortality of patients on ART in South Africa and whether this effect is mediated by baseline immunological status. METHODS In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the first time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. FINDINGS Between Jan 1, 2004, and Dec 31, 2013, 84,078 eligible adults started ART. Of these, we followed up 83,566 patients for 174,640 patient-years. 8% (1817 of 23,258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2·52 (95% CI 2·01-3·17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per μL, the adjusted mortality hazard ratio was 2·52 (2·04-3·11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per μL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44,909 patients still alive and in care were aged 50 years or older. INTERPRETATION Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. FUNDING National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis.

Printed Narrative: The Festival Books for Archduke Ernest of Austria from Brussels and Antwerp 1594

Workshop „The Narrative in Eastern and Western Art“, Graduate School of Letters, Kyoto, 2-5 December 2013 Abstract by Ivo Raband, University of Berne Printed Narrative: The Festival Books for Ernest of Austria from Brussels and Antwerp 1594 During the early modern period the medium of the festival book became increasingly more important as an object of ‘political narration’ throughout Europe. Focusing on Netherlandish examples from the sixteenth and seventeenth centuries, my talk will focus on the festival books printed for the Joyous Entries of Archduke Ernest of Austria (1553–1595). Ernest was appointed Governor General of the Netherlands by King Philipp II in 1593, being the first Habsburg Prince to reside in Brussels since 30 years. In Brussels and Antwerp, the Archduke was greeted with the traditional Blijde Imkomst, Joyous Entry, which dates back to the fourteenth century and was a necessity to actually become the sovereign of Brabant and Antwerp and to uphold the privileges of the cities. Decorated with ephemeral triumphal arches, stages, and tableaux vivants, both cities welcomed Ernest and, at the same time, demonstrated their civic self-assurance and negotiated their statuses. In honor of these events of civic power, the city magistrates commissioned festival books. These books combine a Latin text with a description of the events and the ephemeral structures, including circa 30 engravings and etchings. Being the only visual manifestation of the Joyous Entries, the books became important representational objects. The prints featured in festival books will be my point of departure for discussing the importance of narrative political prints and the concept of the early modern festival book as a ‘political object’. By comparing the prints from Ernest’s entries with others from the period between 1549 and 1635, I will show how the prints became as important as the event itself. Thus, I want to pose the question of whether it would have been possible to substitute a printed version of the event for the actual ceremony.

A unified approach to architecture conformance checking

Architectural decisions can be interpreted as structural and behavioral constraints that must be enforced in order to guarantee overarching qualities in a system. Enforcing those constraints in a fully automated way is often challenging and not well supported by current tools. Current approaches for checking architecture conformance either lack in usability or offer poor options for adaptation. To overcome this problem we analyze the current state of practice and propose an approach based on an extensible, declarative and empirically-grounded specification language. This solution aims at reducing the overall cost of setting up and maintaining an architectural conformance monitoring environment by decoupling the conceptual representation of a user-defined rule from its technical specification prescribed by the underlying analysis tools. By using a declarative language, we are able to write tool-agnostic rules that are simple enough to be understood by untrained stakeholders and, at the same time, can be can be automatically processed by a conformance checking validator. Besides addressing the issue of cost, we also investigate opportunities for increasing the value of conformance checking results by assisting the user towards the full alignment of the implementation with respect to its architecture. In particular, we show the benefits of providing actionable results by introducing a technique which automatically selects the optimal repairing solutions by means of simulation and profit-based quantification. We perform various case studies to show how our approach can be successfully adopted to support truly diverse industrial projects. We also investigate the dynamics involved in choosing and adopting a new automated conformance checking solution within an industrial context. Our approach reduces the cost of conformance checking by avoiding the need for an explicit management of the involved validation tools. The user can define rules using a convenient high-level DSL which automatically adapts to emerging analysis requirements. Increased usability and modular customization ensure lower costs and a shorter feedback loop.