Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America

OBJECTIVES: To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource-limited settings. METHODS: We analysed data from 17 ART programmes in 12 countries in sub-Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined. RESULTS: A total of 36,715 patients who started ART 1996-2006 were included in the analysis. Patient numbers increased substantially in sub-Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005-2006. In South America 20 regimes were used in 2005-2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/microl (IQR 53-194) in 2005-2006 in Africa, 134 cells/microl (IQR 72-191) in Asia, and 197 cells/microl (IQR 61-277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/microl in 2005-2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/microl in Africa, 65 cells/microl in Asia and 10 cells/microl in South America. In 2005-2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6-month CD4 cell counts were 74%, 77% and 81%. CONCLUSIONS: The public health approach to providing ART proposed by the World Health Organization has been implemented in sub-Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV-infected men.

Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy

BACKGROUND: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. OBJECTIVE: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. METHODS: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. RESULTS: Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). CONCLUSION: This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

BACKGROUND: Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). METHODS: The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. RESULTS: Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. CONCLUSION: These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Patient Characteristics and Outcomes of Gastrointestinal Stromal Tumor Patients Undergoing Imatinib Plasma Level Testing

Although gastrointestinal stromal tumor (GIST) is effectively treated with imatinib, there are a number of clinical challenges in the optimal treatment of these patients. The plasma steady-state trough level of imatinib has been proposed to correlate with clinical outcome. Plasma imatinib level may be affected by a number of patient characteristics. Additionally, the ideal plasma trough concentration of imatinib is likely to vary based on the KIT genotype (genotype determines imatinib binding affinity) of the individual patient. Patients’ genotype or plasma imatinib level may influence the type and duration of response that is appreciable by clinical evaluation. The objectives of this study were to determine effects of genotype on the type of response appreciable by current imaging criteria, to determine the distribution of plasma imatinib levels in patients with GIST, to determine factors that correlate with plasma imatinib level, to determine the incremental effects of imatinib dose escalation; and to explore the median plasma levels and outcomes of patients with various KIT mutations. We therefore obtained KIT mutation information and analyzed CT response for size and density measurement of GISTs at baseline and within the first four moths of imatinib treatment. In 126 patients with metastatic/unresectable disease, the KIT genotype of patients’ tumor was significantly associated with unique response characteristics measurable by CT. Furthermore, hepatic and peritoneal metastases differed in their response characteristics. A subgroup of patients with KIT exon 9 mutation, who received higher doses of imatinib and experienced higher trough imatinib levels, experienced improved progression-free survival similar to that of KIT exon 11 patients. Therefore, we have found that imatinib plasma levels were higher in patients with elevated Aspartate amino transferase, were women, were older, or were being treated concomitantly with CYP450 substrate drugs. As expected, CYP450 inducers correlated with a lower plasma imatinib levels in GIST patients. Renal metabolism of imatinib accounts for <10%, so it was not included in the analysis but may affect covariates. Interestingly, there was a trend for low imatinib levels and inferior progression-free survival in patients who had undergone complete gastrectomy. Patients with KIT exon 9 mutation in our cohort received higher imatinib doses, experienced higher trough imatinib levels, and experienced a PFS similar to that of KIT exon 11 patients. In conclusion, imatinib plasma levels are influenced by a number of patient characteristics. The optimal imatinib plasma level for individual patients is not known but is an area of intense investigation. Our study confirms patients with KIT exon 9 mutations benefit from high-dose imatinib and higher trough imatinib levels.

Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration

INTRODUCTION HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.

Association Between Baseline Impedance Values and Response Proton Pump Inhibitorsin Patients With Heartburn

BACKGROUND & AIMS: Esophageal impedance measurements have been proposed to indicate the status of the esophageal mucosa, and might be used to study the roles of the impaired mucosal integrity and increased acid sensitivity in patients with heartburn. We compared baseline impedance levels among patients with heartburn who did and did not respond to proton pump inhibitor (PPI) therapy, along with the pathophysiological characteristics of functional heartburn (FH). METHODS: In a case-control study, we collected data from January to December 203 on patients with heartburn and normal findings from endoscopy who were not receiving PPI therapy and underwent impedance pH testing at hospitals in Italy. Patients with negative test results were placed on an 8-week course of PPI therapy (84 patients received esomeprazole and 36 patients received pantoprazole). Patients with more than 50% symptom improvement were classified as FH/PPI responders and patients with less than 50% symptom improvement were classified as FH/PPI nonresponders. Patients with hypersensitive esophagus and healthy volunteers served as controls. In all patients and controls, we measured acid exposure time, number of refluxes, baseline impedance, and swallow-induced peristaltic wave indices. RESULTS: FH/PPI responders had higher acid exposure times, numbers of reflux events, and acid refluxes compared with FH/PPI nonresponders (P < .05). Patients with hypersensitive esophagus had mean acid exposure times and numbers of reflux events similar to those of FH/PPI responders. Baseline impedance levels were lower in FH/PPI responders and patients with hypersensitive esophagus, compared with FH/PPI nonresponders and healthy volunteers (P < .001). Swallow-induced peristaltic wave indices were similar between FH/PPI responders and patients with hypersensitive esophagus. CONCLUSIONS: Patients with FH who respond to PPI therapy have impedance pH features similar to those of patients with hypersensitive esophagus. Baseline impedance measurements might allow for identification of patients who respond to PPIs but would be classified as having FH based on conventional impedance-pH measurements.

Statistical testing against baseline was common in dental research

OBJECTIVES To assess the presence of within-group comparisons with baseline in a subset of leading dental journals and to explore possible associations with a range of study characteristics including journal and study design. STUDY DESIGN AND SETTING Thirty consecutive issues of five leading dental journals were electronically searched. The conduct and reporting of statistical analysis in respect of comparisons against baseline or otherwise along with the manner of interpretation of the results were assessed. Descriptive statistics were obtained, and chi-square test and Fisher's exact were undertaken to test the association between trial characteristics and overall study interpretation. RESULTS A total of 184 studies were included with the highest proportion published in Journal of Endodontics (n = 84, 46%) and most involving a single center (n = 157, 85%). Overall, 43 studies (23%) presented interpretation of their outcomes based solely on comparisons against baseline. Inappropriate use of baseline testing was found to be less likely in interventional studies (P < 0.001). CONCLUSION Use of comparisons with baseline appears to be common among both observational and interventional research studies in dentistry. Enhanced conduct and reporting of statistical tests are required to ensure that inferences from research studies are appropriate and informative.

Bone metabolic and hormonal characteristics of Australian Antarctic expeditioners

Summary: Serum 25(OH)D levels decline without sunlight exposure. We studied 120 expeditioners to Antarctica to determine the skeletal and hormonal responses to sunlight deprivation. With emerging vitamin D insufficiency, serum calcium decreased, PTH increased, and bone loss at the proximal femur was observed. Baseline serum 25(OH)D levels >100 nmol/L prevented vitamin D insufficiency. Introduction: Vitamin D stores deplete without adequate sunlight exposure unless supplementation is provided. We studied 120 healthy adults who spent a year in Antarctica as a model for sunlight deprivation to define the timing and magnitude of the skeletal and hormonal responses to emerging vitamin D insufficiency. Methods: Fasting blood samples were assessed at baseline, 6 and 12 months for serum 25-hydroxyvitamin D (25(OH)D), osteocalcin (OC), bone formation (P1NP) and resorption (CTx), PTH and calcium. Lumbar spine and proximal femur BMD was measured using DXA. Differences over time were determined using repeated measures ANOVA. Percent changes were expressed as (Delta value/(value A +value B)/2)x100. Relationships between outcome measures were determined using Spearman's correlations. Results: Vitamin D insufficiency (<50 nmol/L) was observed in 85% of expeditioners by 6 months when serum calcium decreased and PTH increased (p<0.01). By 12 months, OC increased by 7.4±3.0% (p<0.05), and BMD decreased by 1.0±2.0% at the total proximal femur (p<0.05). For those with vitamin D sufficiency at baseline (>50 nmol/L), sunlight deprivation produced vitamin D insufficiency within 4 months unless baseline values were >100 nmol/L. Conclusion: Supplementation may be necessary for expeditioners with limited access to UV light.

(Tables 1, 2) Permafrost borehole characteristics in the Nordic Area during the IPY 2007-2009

This paper provides a snapshot of the permafrost thermal state in the Nordic area obtained during the International Polar Year (IPY) 2007-2009. Several intensive research campaigns were undertaken within a variety of projects in the Nordic countries to obtain this snapshot. We demonstrate for Scandinavia that both lowland permafrost in palsas and peat plateaus, and large areas of permafrost in the mountains are at temperatures close to 0°C, which makes them sensitive to climatic changes. In Svalbard and northeast Greenland, and also in the highest parts of the mountains in the rest of the Nordic area, the permafrost is somewhat colder, but still only a few degrees below the freezing point. The observations presented from the network of boreholes, more than half of which were established during the IPY, provide an important baseline to assess how future predicted climatic changes may affect the permafrost thermal state in the Nordic area. Time series of active-layer thickness and permafrost temperature conditions in the Nordic area, which are generally only 10 years in length, show generally increasing active-layer depths and rising permafrost temperatures.

Physiological and biochemical characteristics of polar cod (Boreogadus saida) from Kongsfjorden

Seasonality of biomarker baseline levels were studied in polar cod (Boreogadus saida), caught in Kongsfjorden, Svalbard, in April, July, September and December, 2006-2007. Physiological parameters (condition factor, gonado- and hepato-somatic indexes, energy reserves, potential metabolic activity and antifreeze activity) in polar cod were used to interpret the seasonality of potential biomarkers. The highest levels of ethoxyresorufin-O-deethylase (EROD) activity occurred concomitantly with the highest potential metabolic activity in July due to e.g. intense feeding. During pre-spawning, EROD showed significant inhibition and gender differences. Hence, its potential use in environmental monitoring should imply gender differentiation at least during this period. Glutathione S-transferase and catalase activities were stable from April to September, but changed in December suggesting a link to low biological activity. Knowledge of the biomarker baseline levels and their seasonal trends in polar cod is essential for a trustworthy interpretation of forthcoming toxicity data and environmental monitoring in the Arctic.

Lesion, and haematologic and serum characteristics of Weddell seals (Leptonychotes weddellii) sampled in McMurdo Sound, Antarctica

We examined and collected biomedical samples from Weddell seals (Leptonychotes weddellii) during studies of post-breeding-season foraging behaviour of adults and movements of weaned pups as a complement to ongoing studies on the ecology and population dynamics of the McMurdo seals (Stewart et al. 2000, 2003). Here we report on Weddell seal health assessments conducted during the 1996/97, 1997/98 and 1998/99 breeding seasons at the Delbridge Islands (77.68°S, 166.50°E), McMurdo Sound, Antarctica. Our objectives were to compile baseline biomedical data for Weddell seals in McMurdo Sound, and to identify infectious and non-infectious diseases affecting the population. Development of such a database, including information on normal background morbidity and mortality, is an important first step in evaluating natural versus anthropogenic impacts on population health (Geraci et al. 1999; Reddy et al. 2001). These data will be integral to international studies of southern ocean pinnipeds that seek to evaluate the influence of biotic and abiotic factors on the ecology of these apex predators.

Table 1: Main characteristics of the BIOTA observatories included in this study & Table 3: Occurrence of termite taxa at the observatories

Termites are the most important soil ecosystem engineers of semi-arid and arid habitats. They enhance decomposition processes as well as the subsequent mineralisation of nutrients by bacteria and fungi. Through their construction of galleries, nests and mounds, they promote soil turnover and influence the distribution of nutrients and also alter texture and hydrological properties of soils, thereby affecting the heterogeneity of their ecosystem. The main aim of the present thesis was to define the impact of termites on ecosys-tem functioning in a semi-arid ecosystem. In a baseline study, I assessed the diversity of termite taxa in relation to the amount of precipitation, the vegetation patterns and the land use systems at several sites in Namibia. Subsequently, I focussed on a species that is highly abundant in many African savannas, the fungus growing and mound building species Macro-termes michaelseni (Sjöstedt, 1914). I asked how this species influences the spatial hetero-geneity of soil and vegetation patterns. From repeated samplings at 13 sites in Namibia, I obtained 17 termite taxa of 15 genera. While the type of land use seems to have a minor effect on the termite fauna, the mean annual precipitation explained 96% and the Simpson index of vascular plant diversity 81% of the variation in taxa diversity. The number of termite taxa increased with both of these explanation variables. In contrast to former studies on Macrotermes mounds in several regions of Africa that I reviewed, soil analyses from M. michaelseni mounds in the central Namibian savanna revealed that they contain much higher nitrogen contents when compared to their parent material. Further analyses revealed that nitrate forms a major component of the nitrogen content in termite mounds. As nitrate solves easily in water, evaporation processes are most probably responsible for the transport of solved nitrates to the mound surface and their accumulation there. The analysed mounds in central Namibia contained higher sand propor-tions compared to the mounds of the former studies. Through the higher percentage of coarse and middle sized pores, water moves more easily in sandy soils compared to more clayey soils. In consequence, evaporation-driven nitrate accumulation can occur in the studied mounds at high rates. ff...

Pedestrian impact: baseline and preliminary concepts evaluation, volume II - technical discussion. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Pedestrian impact: baseline and preliminary concepts evaluation, volume I - summary. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Baseline report of environmental conditions in deepwater dumpsite 106

"NOAA--S/T 77-2822."