Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis

BACKGROUND: The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are in patients who are lost to programmes. METHODS AND FINDINGS: We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness. CONCLUSIONS: In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring

BACKGROUND: In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. DESIGN AND METHODS: Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. RESULTS: A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1-26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0-21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/microl (IQR 77-265) in programmes with viral load monitoring and 102 cells/microl (44-181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7-18 after starting ART (aHR 1.38; 95% CI 0.97-1.98), similar during months 19-30 (aHR 0.97; 95% CI 0.58-1.60) and less common during months 31-42 (aHR 0.29; 95% CI 0.11-0.79). CONCLUSION: In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Spanish Supreme Court Rules in Favour of Google Search Engine... and a Flexible Reading of Copyright Statutes?

On 3 April 2012, the Spanish Supreme Court issued a major ruling in favour of the Google search engine, including its ‘cache copy’ service: Sentencia n.172/2012, of 3 April 2012, Supreme Court, Civil Chamber.* The importance of this ruling lies not so much in the circumstances of the case (the Supreme Court was clearly disgusted by the claimant’s ‘maximalist’ petitum to shut down the whole operation of the search engine), but rather on the court going beyond the text of the Copyright Act into the general principles of the law and case law, and especially on the reading of the three-step test (in Art. 40bis TRLPI) in a positive sense so as to include all these principles. After accepting that none of the limitations listed in the Spanish Copyright statute (TRLPI) exempted the unauthorized use of fragments of the contents of a personal website through the Google search engine and cache copy service, the Supreme Court concluded against infringement, based on the grounds that the three-step test (in Art. 40bis TRLPI) is to be read not only in a negative manner but also in a positive sense so as to take into account that intellectual property – as any other kind of property – is limited in nature and must endure any ius usus inocui (harmless uses by third parties) and must abide to the general principles of the law, such as good faith and prohibition of an abusive exercise of rights (Art. 7 Spanish Civil Code).The ruling is a major success in favour of a flexible interpretation and application of the copyright statutes, especially in the scenarios raised by new technologies and market agents, and in favour of using the three-step test as a key tool to allow for it.

The EU’s Trouble with Mashups: From Disabling to Enabling a Digital Art Form

New tools for editing of digital images, music and films have opened up new possibilities to enable wider circles of society to engage in ’artistic’ activities of different qualities. User-generated content has produced a plethora of new forms of artistic expression. One type of user-generated content is the mashup. Mashups are compositions that combine existing works (often) protected by copyright and transform them into new original creations. The European legislative framework has not yet reacted to the copyright problems provoked by mashups. Neither under the US fair use doctrine, nor under the strict corset of limitations and exceptions in Art 5 (2)-(3) of the Copyright Directive (2001/29/EC) have mashups found room to develop in a safe legal environment. The contribution analyzes the current European legal framework and identifies its insufficiencies with regard to enabling a legal mashup culture. By comparison with the US fair use approach, in particular the parody defense, a recent CJEU judgment serves as a comparative example. Finally, an attempt is made to suggest solutions for the European legislator, based on the policy proposals of the EU Commission’s “Digital Agenda” and more recent policy documents (e.g. “On Content in the Digital Market”, “Licenses for Europe”). In this context, a distinction is made between non-commercial mashup artists and the emerging commercial mashup scene.

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.