A Retrospective Analysis of Prevalence of Gastrointestinal Parasites among School Children in the Palajunoj Valley of Guatemala

This study retrospectively analyzed demographic factors that may affect the prevalence of intestinal parasites among Guatemalan school children. The findings of the study showed that young age, wet season, female gender, and severe malnutrition all correlated positively with increased rates of infection. Clinical visits were performed on 10,586 school children aged 5-15 years over a four-year period (2004-2007) in the Palajunoj Valley of Guatemala, during which 5,705 viable stool samples were screened for infection with the following parasites: Ascaris lumbricoides, Giardia lamblia, Entamoeba histolytica, Hymenolepis nana, and Blastocystis hominis. The average overall prevalences of infection for specific parasites were A. lumbricoides 17.7%, E. histolytica 16.1%, G. lamblia 10.9%, H. nana 5.4%, and B. hominis 2.8%. Statistical analysis showed significantly higher rates of infection among younger children with G. lamblia (odds ratio [OR]=0.905, 95% confidence interval [CI] 0.871-0.941, p<0.0001) and E. histolytica (p=0.0006), greater prevalence of H. nana among females (OR=1.275, CI 1.010-1.609, p=0.0412), higher infection rates during the wet season for E. histolytica (p=0.0003) and H. nana (OR=0.734, CI 0.557-0.966, p=0.0275), and greater rates of infection with G. lamblia among malnourished children (for moderately malnourished children OR=1.498, CI 1.143-1.963, p<0.0001) and E. histolytica (for mildly malnourished children OR=1.243, CI 1.062-1.455, p=0.0313). The results suggest that the prevalence of gastrointestinal parasites among young Guatemalan children is highly dependent on the specific species of the parasite

Regulation of locomotor activity by metabotropic glutamate receptors in the nucleus accumbens and ventral tegmental

ABSTRACT Glutamatergic innervation of the ventral tegmental area (VTA) and the nucleus accumbens (NA) regulates locomotor activity. The present study was designed to evaluate the involvement of metabotropic glutamate receptors (mGluRs) in motor activity. Agonists selective for each of the three subgroups of mGluRs were microinjected into the VTA or NA, and motor activity was monitored. The group I agonist (S)-3,5-dihydroxyphenylglycine elicited a dose-dependent elevation in motor activity after microinjection into either the VTA or NA. The effect in the NA was blocked by the mGluR1-specific antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The group II agonist (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine also elicited a short-duration motor activation after microinjection into either structure. The dose response in the VTA was biphasic, and the coadministration of the group II/III-specific antagonist (RS)-␣-methyl-4-phosphonophenylglycine partially blocked motor activation in both the NA and VTA. Although the group III agonist L-(ϩ)-2-amino-4-phosphonobutyric acid produced a relatively modest behavioral stimulation after microinjection into the NA, it was without effect in the VTA. These data indicate a role for mGluR subgroups in the regulation of motor activity in the VTA and NA

Origin and Neuronal Function of in Vivo Nonsynaptic Glutamate

Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine–glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na and Ca2 channels produced relatively minimal changes (0– 30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine–glutamate antiporter. By measuring [ 35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine–glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5- phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4- aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporterderived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine–glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission. Key words: microdialysis;glutamate;cystine;striatum;nonvesicular;cystine–glutamate antiporter;system xc

Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins

Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production

Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease

AbstractIntroductionRecent failures in phase 3 clinical trials in Alzheimer's disease (AD) suggest that novel approaches to drug development are urgently needed. Phase 3 risk can be mitigated by ensuring that clinical efficacy is established before initiating confirmatory trials, but traditional phase 2 trials in AD can be lengthy and costly.MethodsWe designed a Bayesian adaptive phase 2, proof-of-concept trial with a clinical endpoint to evaluate BAN2401, a monoclonal antibody targeting amyloid protofibrils. The study design used dose response and longitudinal modeling. Simulations were used to refine study design features to achieve optimal operating characteristics.ResultsThe study design includes five active treatment arms plus placebo, a clinical outcome, 12-month primary endpoint, and a maximum sample size of 800. The average overall probability of success is ≥80% when at least one dose shows a treatment effect that would be considered clinically meaningful. Using frequent interim analyses, the randomization ratios are adapted based on the clinical endpoint, and the trial can be stopped for success or futility before full enrollment.DiscussionBayesian statistics can enhance the efficiency of analyzing the study data. The adaptive randomization generates more data on doses that appear to be more efficacious, which can improve dose selection for phase 3. The interim analyses permit stopping as soon as a predefined signal is detected, which can accelerate decision making. Both features can reduce the size and duration of the trial. This study design can mitigate some of the risks associated with advancing to phase 3 in the absence of data demonstrating clinical efficacy. Limitations to the approach are discussed

Thinking about complexity in health: A systematic review of the key systems thinking and complexity ideas in health

Rationale, aims, and objectivesAs the Sustainable Development Goals are rolled out worldwide, development leaders will be looking to the experiences of the past to improve implementation in the future. Systems thinking and complexity science (ST/CS) propose that health and the health system are composed of dynamic actors constantly evolving in response to each other and their context. While offering practical guidance for steering the next development agenda, there is no consensus as to how these important ideas are discussed in relation to health. This systematic review sought to identify and describe some of the key terms, concepts, and methods in recent ST/CS literature.MethodUsing the search terms “systems thinkin * AND health OR complexity theor* AND health OR complex adaptive system* AND health,” we identified 516 relevant full texts out of 3982 titles across the search period (2002-2015).ResultsThe peak number of articles were published in 2014 (83) with journals specifically focused on medicine/healthcare (265) and particularly the Journal of Evaluation in Clinical Practice (37) representing the largest number by volume. Dynamic/dynamical systems (n = 332), emergence (n = 294), complex adaptive system(s) (n = 270), and interdependent/interconnected (n = 263) were the most common terms with systems dynamic modelling (58) and agent-based modelling (43) as the most common methods.ConclusionsThe review offered several important conclusions. First, while there was no core ST/CS “canon,” certain terms appeared frequently across the reviewed texts. Second, even as these ideas are gaining traction in academic and practitioner communities, most are concentrated in a few journals. Finally, articles on ST/CS remain largely theoretical illustrating the need for further study and practical application. Given the challenge posed by the next phase of development, gaining a better understanding of ST/CS ideas and their use may lead to improvements in the implementation and practice of the Sustainable Development Goals

Investigating the influence of LiDAR ground surface errors on the utility of derived forest inventories

Light detection and ranging, or LiDAR, effectively produces products spatially characterizing both terrain and vegetation structure; however, development and use of those products has outpaced our understanding of the errors within them. LiDAR’s ability to capture three-dimensional structure has led to interest in conducting or augmenting forest inventories with LiDAR data. Prior to applying LiDAR in operational management, it is necessary to understand the errors in Li- DAR-derived estimates of forest inventory metrics (i.e., tree height). Most LiDAR-based forest inventory metrics require creation of digital elevation models (DEM), and because metrics are calculated relative to the DEM surface, errors within the DEMs propagate into delivered metrics. This study combines LiDAR DEMs and 54 ground survey plots to investigate how surface morphology and vegetation structure influence DEM errors. The study further compared two LiDAR classification algorithms and found no significant difference in their performance. Vegetation structure was found to have no influence, whereas increased variability in the vertical error was observed on slopes exceeding 30°, illustrating that these algorithms are not limited by high-biomass western coniferous forests, but that slope and sensor accuracy both play important roles. The observed vertical DEM error translated into ±1%–3% error range in derived timber volumes, highlighting the potential of LiDAR-derived inventories in forest management

Lecanemab in patients with early Alzheimer\u27s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). RESULTS: At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181. CONCLUSIONS: Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01767311