Closing the gaps: Steps towards elimination of mother-to-child transmission of HIV

Background. With significant reductions in the rate of HIV mother-to-child transmission (MTCT) in South Africa, each case of failed prevention of MTCT (PMTCT) should be investigated.  Objective. To establish the cause(s) of MTCT at Khayelitsha’s Community Health Centre (CHC) in order to identify obstacles to MTCT elimination. Methods. Routinely collected data were reviewed for all HIV-infected infants identified at Khayelitsha Site B CHC from January 2012 to April 2013. Results. A total of 926/1 158 (80%) of exposed infants had polymerase chain reaction (PCR) results, with 15/926 (1.6%) PCR-positive. Median (interquartile range (IQR)) values for the maternal indicators were as follows: maternal age, 27 (23 - 31) years; parity, 2 (1 - 3); gestational age at antenatal presentation, 21.5 (17.5 - 30.5) weeks; CD4+, 377(219 - 446) cells/µl. Of the 15 PCR-positive infants, five received ART, five received AZT and five received no prophylaxis. Viral loads were not monitored for any of the women receiving antenatal ART. Nine of the 15 (60%) delivered in hospital, with 6/9 requiring caesarean section. The median (IQR) infant birth weight was 3.0 (2.6 - 3.5) kg. All received prophylactic nevirapine post exposure. Two of the 15 were clinically unwell at birth, and 14 (86.7%) were breastfed, with 10 (66.7%) recorded as exclusively breastfed. Median (IQR) time between delivery and PCR results was 6.6 (6.1 - 7.3) weeks.  Discussion. PMTCT programmes must consider each PCR-positive infant as a sentinel event that can provide valuable insight into correcting ongoing clinical and programmatic reasons for HIV transmission. The main risk factors for MTCT identified in this study were late presentation for antenatal care, inadequate antenatal PMTCT prophylaxis and a lack of viral load monitoring

Clinical mentorship of nurse initiated antiretroviral therapy in Khayelitsha, South Africa: a quality of care assessment.

To combat the AIDS epidemic and increase HIV treatment access, the South African government implemented a nurse-based, doctor-supported model of care that decentralizes administration of antiretroviral treatment (ART) for HIV positive patients through nurse initiated and managed ART. Médecins Sans Frontières (MSF) implemented a mentorship programme to ensure successful task-shifting, subsequently assessing the quality of clinical care provided by nurses

Loss from treatment for drug resistant tuberculosis: risk factors and patient outcomes in a community-based program in Khayelitsha, South Africa

BACKGROUND: A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting. METHODOLOGY: LFT, defined as interruption of treatment for ≥2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013. RESULTS: Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two-year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment. CONCLUSION: LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs

Combined Norepinephrine/Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression, and Oxytocin in the Rat

Background: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB in rodents indicated significant alterations in postpartum maternal care, aggression, and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on MB, aggression, and oxytocin system changes. Methods: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. Results: Amitriptyline and desipramine differentially reduced MB, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in maternal care

K 1-6: an asymmetric planetary nebula with a binary central star

We present new imaging data and archival multiwavelength observations of the little studied emission nebula K 1-6 and its central star. Narrow-band images in H-alpha (+ [NII]) and [OIII] taken with the Faulkes Telescope North reveal a stratified, asymmetric, elliptical nebula surrounding a central star which has the colours of a late G- or early K-type subgiant or giant. GALEX ultraviolet images reveal a very hot subdwarf or white dwarf coincident in position with this star. The cooler, optically dominant star is strongly variable with a period of 21.312 +/- 0.008 days, and is possibly a high amplitude member of the RS CVn class, although an FK Com classification is also possible. Archival ROSAT data provide good evidence that the cool star has an active corona. We conclude that K 1-6 is most likely an old bona fide planetary nebula at a distance of ~1.0 kpc, interacting with the interstellar medium, and containing a binary or ternary central star. The observations and data analyses reported in this paper were conducted in conjunction with Year 11 high school students as part of an Australian Research Council Linkage Grant science education project, denoted Space To Grow, conducted jointly by professional astronomers, educational researchers, teachers, and high-school students.Comment: 13 pages, 5 figures, accepted by the Publications of the Astronomical Society of Australia (PASA

Patient support interventions to improve adherence to drug-resistant tuberculosis treatment: A counselling toolkit

In response to the growing burden of drug-resistant tuberculosis (DR-TB) in South Africa (SA), Médecins Sans Frontières (MSF), with local government health departments, piloted a decentralised model of DR-TB care in Khayelitsha, Western Cape Province, in 2007. The model takes a patient-centred approach to DR-TB treatment that is integrated into existing TB and HIV primary care programmes. One essential component of the model is individual and family counselling to support adherence to and completion of treatment. The structured and standardised adherence support sessions have been compiled into a DR-TB counselling toolkit. This is a comprehensive guide that focuses on DR-TB treatment literacy, adherence strategies to encourage retention in care, and provision of support throughout the patient’s long treatment journey. Along with other strategies to promote completion of treatment, implementation of a strong patient support component of DR-TB treatment is considered essential to reduce rates of loss from treatment among DR-TB patients. We describe our experience from the implementation of this counselling model in a high DR-TB burden setting in Khayelitsha, Cape Town, SA

Time to ART initiation among patients treated for rifampicin-resistant tuberculosis in Khayelitsha, South Africa: impact on mortality and treatment success

Setting Khayelitsha, South Africa, with high burdens of rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection. Objective To describe time to antiretroviral treatment (ART) initiation among HIV-infected RR-TB patients initiating RR-TB treatment and to assess the association between time to ART initiation and treatment outcomes. Design A retrospective cohort study of patients with RR-TB and HIV co-infection not on ART at RR-TB treatment initiation. RESULTS: Of the 696 RR-TB and HIV-infected patients initiated on RR-TB treatment between 2009 and 2013, 303 (44%) were not on ART when RR-TB treatment was initiated. The median CD4 cell count was 126 cells/mm 3 . Overall 257 (85%) patients started ART during RR-TB treatment, 33 (11%) within 2 weeks, 152 (50%) between 2-8 weeks and 72 (24%) after 8 weeks. Of the 46 (15%) who never started ART, 10 (21%) died or stopped RR-TB treatment within 4 weeks and 16 (37%) had at least 4 months of RR-TB treatment. Treatment success and mortality during treatment did not vary by time to ART initiation: treatment success was 41%, 43%, and 50% among patients who started ART within 2 weeks, between 2-8 weeks, and after 8 weeks (p = 0.62), while mortality was 21%, 13% and 15% respectively (p = 0.57). Mortality was associated with never receiving ART (adjusted hazard ratio (aHR) 6.0, CI 2.1-18.1), CD4 count ≤100 (aHR 2.1, CI 1.0-4.5), and multidrug-resistant tuberculosis (MDR-TB) with second-line resistance (aHR 2.5, CI 1.1-5.4). CONCLUSIONS: Despite wide variation in time to ART initiation among RR-TB patients, no differences in mortality or treatment success were observed. However, a significant proportion of patients did not initiate ART despite receiving >4 months of RR-TB treatment. Programmatic priorities should focus on ensuring all patients with RR-TB/HIV co-infection initiate ART regardless of CD4 count, with special attention for patients with CD4 counts ≤ 100 to initiate ART as soon as possible after RR-TB treatment initiation

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Can Orthopedic Oncologists Predict Functional Outcome in Patients with Sarcoma after Limb Salvage Surgery in the Lower Limb? A Nationwide Study

Accurate predictions of functional outcome after limb salvage surgery (LSS) in the lower limb are important for several reasons, including informing the patient preoperatively and, in some cases, deciding between amputation and LSS. This study aimed to elucidate the correlation between surgeon-predicted and patient-reported functional outcome of LSS in the Netherlands. Twentythree patients (between six months and ten years after surgery) and five independent orthopedic oncologists completed the Toronto Extremity Salvage Score (TESS) and the RAND-36 physical functioning subscale (RAND-36 PFS). The orthopedic oncologists made their predictions based on case descriptions (including MRI scans) that reflected the preoperative status. The correlation between patient-reported and surgeon-predicted functional outcome was "very poor" to "poor" on both scores ( 2 values ranged from 0.014 to 0.354). Patient-reported functional outcome was generally underestimated, by 8.7% on the TESS and 8.3% on the RAND-36 PFS. The most difficult and least difficult tasks on the RAND-36 PFS were also the most difficult and least difficult to predict, respectively. Most questions had a "poor" intersurgeon agreement. It was difficult to accurately predict the patient-reported functional outcome of LSS. Surgeons' ability to predict functional scores can be improved the most by focusing on accurately predicting more demanding tasks

Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C

The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition