Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration

Objectives  To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART). Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment. Results  Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008). Conclusion  Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children.

Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa. Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes. Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0). Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

Prevalence, motivations, and adverse effects of vaginal practices in Africa and Asia: findings from a multicountry household survey

Background: Women worldwide use various vaginal practices to clean or modify their vulva and vagina. Additional population-level information is needed on prevalence and motivations for these practices, characteristics of users, and their adverse effects. Methods: This was a household survey using multistage cluster sampling in Tete, Mozambique; KwaZulu-Natal, South Africa; Yogyakarta, Indonesia; and Chonburi, Thailand. In 2006–2007, vaginal practices and their motivations were examined using structured interviews with women 18–60 years of age (n=3610). Results: Prevalence, frequency, and motivations varied markedly. Two thirds of women in Yogyakarta and Chonburi reported one or more practices. In Yogyakarta, nearly half ingest substances with vaginal effects, and in Chonburi, external washing and application predominate. In Tete, half reported three or four current practices, and a quarter reported five or more practices. Labial elongation was near universal, and 92% of those surveyed cleanse internally. Two third's in KwaZulu-Natal practiced internal cleansing. Insertion of traditional solid products was rare in Chonburi and Yogyakarta, but one tenth of women in KwaZulu-Natal and nearly two thirds of women in Tete do so. Multivariate analysis of the most common practice in each site showed these were more common among less educated women in Africa and young urban women in Asia. Explicit sexual motivations were frequent in KwaZulu-Natal and Tete, intended for pleasure and maintaining partner commitment. Practices in Chonburi and Yogyakarta were largely motivated by femininity and health. Genital irritation was common at African sites. Conclusions: Vaginal practices are not as rare, exotic, or benign as sometimes assumed. Limited evidence of their biomedical consequences remains a concern; further investigation of their safety and sexual health implications is warranted.

Tight junctions in brain barriers during central nervous system inflammation

Homeostasis within the central nervous system (CNS) is a prerequisite to elicit proper neuronal function. The CNS is tightly sealed from the changeable milieu of the blood stream by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the BBB is established by specialized endothelial cells of CNS microvessels, the BCSFB is formed by the epithelial cells of the choroid plexus. Both constitute physical barriers by a complex network of tight junctions (TJs) between adjacent cells. During many CNS inflammatory disorders, such as multiple sclerosis, human immunodeficiency virus infection, or Alzheimer's disease, production of pro-inflammatory cytokines, matrix metalloproteases, and reactive oxygen species are responsible for alterations of CNS barriers. Barrier dysfunction can contribute to neurological disorders in a passive way by vascular leakage of blood-borne molecules into the CNS and in an active way by guiding the migration of inflammatory cells into the CNS. Both ways may directly be linked to alterations in molecular composition, function, and dynamics of the TJ proteins. This review summarizes current knowledge on the cellular and molecular aspects of the functional and dysfunctional TJ complexes at the BBB and the BCSFB, with a particular emphasis on CNS inflammation and the role of reactive oxygen species.

Influence of time point of calibration on accuracy of continuous glucose monitoring in individuals with type 1 diabetes

Abstract Background and Aims: Data on the influence of calibration on accuracy of continuous glucose monitoring (CGM) are scarce. The aim of the present study was to investigate whether the time point of calibration has an influence on sensor accuracy and whether this effect differs according to glycemic level. Subjects and Methods: Two CGM sensors were inserted simultaneously in the abdomen on either side of 20 individuals with type 1 diabetes. One sensor was calibrated predominantly using preprandial glucose (calibration(PRE)). The other sensor was calibrated predominantly using postprandial glucose (calibration(POST)). At minimum three additional glucose values per day were obtained for analysis of accuracy. Sensor readings were divided into four categories according to the glycemic range of the reference values (low, ≤4 mmol/L; euglycemic, 4.1-7 mmol/L; hyperglycemic I, 7.1-14 mmol/L; and hyperglycemic II, >14 mmol/L). Results: The overall mean±SEM absolute relative difference (MARD) between capillary reference values and sensor readings was 18.3±0.8% for calibration(PRE) and 21.9±1.2% for calibration(POST) (P<0.001). MARD according to glycemic range was 47.4±6.5% (low), 17.4±1.3% (euglycemic), 15.0±0.8% (hyperglycemic I), and 17.7±1.9% (hyperglycemic II) for calibration(PRE) and 67.5±9.5% (low), 24.2±1.8% (euglycemic), 15.5±0.9% (hyperglycemic I), and 15.3±1.9% (hyperglycemic II) for calibration(POST). In the low and euglycemic ranges MARD was significantly lower in calibration(PRE) compared with calibration(POST) (P=0.007 and P<0.001, respectively). Conclusions: Sensor calibration predominantly based on preprandial glucose resulted in a significantly higher overall sensor accuracy compared with a predominantly postprandial calibration. The difference was most pronounced in the hypo- and euglycemic reference range, whereas both calibration patterns were comparable in the hyperglycemic range.

Real-time adaptive models for the personalized prediction of glycemic profile in type 1 diabetes patients

Prediction of glycemic profile is an important task for both early recognition of hypoglycemia and enhancement of the control algorithms for optimization of insulin infusion rate. Adaptive models for glucose prediction and recognition of hypoglycemia based on statistical and artificial intelligence techniques are presented.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels

Vascular endothelial growth factor (VEGF) can induce normal angiogenesis or the growth of angioma-like vascular tumors depending on the amount secreted by each producing cell because it remains localized in the microenvironment. In order to control the distribution of VEGF expression levels in vivo, we recently developed a high-throughput fluorescence-activated cell sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a specific VEGF dose from a heterogeneous primary population. Here we tested the hypothesis that cell-based delivery of a controlled VEGF level could induce normal angiogenesis in the heart, while preventing the development of angiomas. Freshly isolated human adipose tissue-derived stem cells (ASC) were transduced with retroviral vectors expressing either rat VEGF linked to a FACS-quantifiable cell-surface marker (a truncated form of CD8) or CD8 alone as control (CTR). VEGF-expressing cells were FACS-purified to generate populations producing either a specific VEGF level (SPEC) or uncontrolled heterogeneous levels (ALL). Fifteen nude rats underwent intramyocardial injection of 10(7) cells. Histology was performed after 4 weeks. Both the SPEC and ALL cells produced a similar total amount of VEGF, and both cell types induced a 50%-60% increase in both total and perfused vessel density compared to CTR cells, despite very limited stable engraftment. However, homogeneous VEGF expression by SPEC cells induced only normal and stable angiogenesis. Conversely, heterogeneous expression of a similar total amount by the ALL cells caused the growth of numerous angioma-like structures. These results suggest that controlled VEGF delivery by FACS-purified ASC may be a promising strategy to achieve safe therapeutic angiogenesis in the heart.

Evolution of multidrug-resistant Staphylococcus aureus infections in horses and colonized personnel in an equine clinic between 2005 and 2010

A total of 70 Staphylococcus aureus isolates from postoperative infections in hospitalized horses were isolated between January 2005 and January 2011. Among them, 12 isolates were methicillin-susceptible S. aureus (MSSA), 18 were borderline-oxacillin-resistant S. aureus (BORSA), and 40 were methicillin-resistant S. aureus (MRSA). During the same period, the equine clinic personnel were screened for nasal carriage of BORSA and MRSA. Genotyping revealed that BORSA ST1(MLST)-t2863(spa) isolates were responsible for most equine infections and were the main isolates found in colonized members of the personnel between 2005 and 2007, and that in 2007, MRSA ST398-t011-IVa(SCCmec) emerged in infection sites and personnel, replacing BORSA. Besides decreased susceptibility to oxacillin, all MRSA and BORSA of these two major clonal lineages displayed resistance to gentamicin and kanamycin conferred by the aac(6')-Ie-aph(2')-Ia gene and to trimethoprim conferred by dfr(K) in MRSA and dfr(A) in BORSA. All MRSA had additional resistance to tetracycline conferred by tet(M), whereas BORSA generally also display resistance to streptomycin conferred by str. The number of hospital-acquired MRSA infections in horses could be limited after the introduction of basic hygiene measures and personnel decolonization. Two MRSA carriers could not be decolonized using mupirocin, and a year after decolonization, additional members were recolonized with MRSA. Hygiene measures should, therefore, be maintained to limit the transmission of S. aureus between personnel and horses.

Missed opportunities to prevent mother-to-child-transmission: systematic review and meta-analysis

To determine magnitude and reasons of loss to program and poor antiretroviral prophylaxis coverage in prevention of mother-to-child transmission (PMTCT) programs in sub-Saharan Africa.

Variability of growth in children starting antiretroviral treatment in southern Africa

Poor growth is an indication for antiretroviral therapy (ART) and a criterion for treatment failure. We examined variability in growth response to ART in 12 programs in Malawi, Zambia, Zimbabwe, Mozambique, and South Africa.

The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure

Objectives  To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. Results  Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. Conclusion  The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.