Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.

BACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.

Hydraulic redistribution of soil water by roots affects whole-stand evapotranspiration and net ecosystem carbon exchange.

*Hydraulic redistribution (HR) of water via roots from moist to drier portions of the soil occurs in many ecosystems, potentially influencing both water use and carbon assimilation. *By measuring soil water content, sap flow and eddy covariance, we investigated the temporal variability of HR in a loblolly pine (Pinus taeda) plantation during months of normal and below-normal precipitation, and examined its effects on tree transpiration, ecosystem water use and carbon exchange. *The occurrence of HR was explained by courses of reverse flow through roots. As the drought progressed, HR maintained soil moisture above 0.15 cm(3) cm(-3) and increased transpiration by 30-50%. HR accounted for 15-25% of measured total site water depletion seasonally, peaking at 1.05 mm d(-1). The understory species depended on water redistributed by the deep-rooted overstory pine trees for their early summer water supply. Modeling carbon flux showed that in the absence of HR, gross ecosystem productivity and net ecosystem exchange could be reduced by 750 and 400 g C m(-2) yr(-1), respectively. *Hydraulic redistribution mitigated the effects of soil drying on understory and stand evapotranspiration and had important implications for net primary productivity by maintaining this whole ecosystem as a carbon sink.

Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch.

Notch signaling is implicated in prostate cancer progression and docetaxel resistance. Cui and colleagues describe the additive efficacy and mechanisms of a γ-secretase inhibitor, PF-03084014, and docetaxel in preclinical models of prostate cancer, suggesting the need for further clinical development of Notch pathway modulators in men with metastatic prostate cancer.

Revising Justice: Punitory Thought and Action in the Work of Atwood, Jordan, and Oates

*Designated as an exemplary master's project for 2015-16*

ERM transactivation is up-regulated by the repression of DNA binding after the PKA phosphorylation of a consensus site at the edge of the ETS domain

The final step of the transduction pathway is the activation of gene transcription, which is driven by kinase cascades leading to changes in the activity of many transcription factors. Among these latter, PEA3/E1AF, ER81/ETV1, and ERM, members of the well conserved PEA3 group from the Ets family are involved in these processes. We show here that protein kinase A (PKA) increases the transcriptional activity of human ERM and human ETV1, through a Ser residue situated at the edge of the ETS DNA-binding domain. PKA phosphorylation does not directly affect the ERM transactivation domains but does affect DNA binding activity. Unphosphorylated wild-type ERM bound DNA avidly, whereas after PKA phosphorylation it did so very weakly. Interestingly, S367A mutation significantly reduced the ERM-mediated transcription in the presence of the kinase, and the DNA binding of this mutant, although similar to that of unphosphorylated wild-type protein, was insensitive to PKA treatment. Mutations, which may mimic a phosphorylated serine, converted ERM from an efficient DNA-binding protein to a poor DNA binding one, with inefficiency of PKA phosphorylation. The present data clearly demonstrate a close correlation between the capacity of PKA to increase the transactivation of ERM and the drastic down-regulation of the binding of the ETS domain to the targeted DNA. What we thus demonstrate here is a relatively rare transcription activation mechanism through a decrease in DNA binding, probably by the shift of a non-active form of an Ets protein to a PKA-phosphorylated active one, which should be in a conformation permitting a transactivation domain to be active.

The prognosis of incurable cachectic cancer patients on home parenteral nutrition: A multi-centre observational study with prospective follow-up of 414 patients

Background: The role of home parenteral nutrition (HPN) in incurable cachectic cancer patients unable to eat is extremely controversial. The aim of this study is to analyse which factors can influence the outcome. Patients and methods: We studied prospectively 414 incurable cachectic (sub)obstructed cancer patients receiving HPN and analysed the association between patient or clinical characteristics and surviving status. Results: Median weight loss, versus pre-disease and last 6-month period, was 24% and 16%, respectively. Median body mass index was 19.5, median KPS was 60, median life expectancy was 3 months. Mean/median survival was 4.7/3.0 months; 50.0% and 22.9% of patients survived 3 and 6 months, respectively. At the multivariable analysis, the variables significantly associated with 3- and 6-month survival were Glasgow Prognostic Score (GPS) and KPS, and GPS, KPS and tumour spread, respectively. By the aggregation of the significant variables, it was possible to dissect several classes of patients with different survival probabilities. Conclusions: The outcome of cachectic incurable cancer patients on HPN is not homogeneous. It is possible to identify groups of patients with a ≥6-month survival (possibly longer than that allowed in starvation). The indications for HPN can be modulated on these clinical/biochemical indices. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Analysis of the utility of QuantiFERON-TB gold in tube and measurement of IFNgamma release by peripheral mononuclear cells in response to different mycobacterium antigen in the work-up of patients with uveitis.

Evaluation Studies

FANTASIO: a versatile experimental set-up to investigate jet-cooled molecules

The design of a new apparatus, named FANTASIO, for studying jet-cooled molecules is described. It includes, around the same supersonic expansion cell, a high resolution Fourier transform spectrometer with single or multipass optics, a tunable diode laser spectrometer with optional cavity ring-down facilities, and a quadrupole mass spectrometer. Performance and operational procedures are illustrated.

Neurology and psychiatry: waking up to opportunities of sleep. State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Modeling of ingot development during the start-up phase of direct chill casting

Direct chill (DC) casting is a core primary process in the production of aluminum ingots. However, its operational optimization is still under investigation with regard to a number of features, one of which is the issue of curvature at the base of the ingot. Analysis of these features requires a computational model of the process that accounts for the fluid flow, heat transfer, solidification phase change, and thermomechanical analysis. This article describes an integrated approach to the modeling of all the preceding phenomena and their interactions.

Identification and doing without it, V: A formal mathematical analysis for a case of mix-up of individuals, and of recovery from failure to attain identification

Identification, when sought, is not necessarily obtained. Operational guidance that is normatively acceptable may be necessary for such cases. We proceed to formalize and illustrate modes of exchanges of individual identity, and provide procedures of recovery strategies in specific prescriptions from an ancient body of law for such situations when, for given types of purposes, individuals of some relevant kind had become intermixed and were undistinguishable. Rules were devised, in a variety of domains, for coping with situations that occur if and when the goal of identification was frustrated. We propose or discuss mathematical representations of such recovery procedures.

Scheduling parallel dedicated machines with the speeding-up resource

We consider a problem of scheduling jobs on m parallel machines. The machines are dedicated, i.e., for each job the processing machine is known in advance. We mainly concentrate on the model in which at any time there is one unit of an additional resource. Any job may be assigned the resource and this reduces its processing time. A job that is given the resource uses it at each time of its processing. No two jobs are allowed to use the resource simultaneously. The objective is to minimize the makespan. We prove that the two-machine problem is NP-hard in the ordinary sense, describe a pseudopolynomial dynamic programming algorithm and convert it into an FPTAS. For the problem with an arbitrary number of machines we present an algorithm with a worst-case ratio close to 3/2, and close to 3, if a job can be given several units of the resource. For the problem with a fixed number of machines we give a PTAS. Virtually all algorithms rely on a certain variant of the linear knapsack problem (maximization, minimization, multiple-choice, bicriteria). © 2008 Wiley Periodicals, Inc. Naval Research Logistics, 2008

Using EMGs and kinematics data to study the take-off technique of experts and novices for a pole vaulting short run-up educational exercise

This study attempts to characterise the electromyographic activity and kinematics exhibited during the performance of take-off for a pole vaulting short run-up educational exercise, for different expertise levels. Two groups (experts and novices) participated in this study. Both groups were asked to execute their take-off technique for that specific exercise. Among the kinematics variables studied, the knee, hip and ankle angles and the hip and knee angular velocities were significantly different. There were also significant differences in the EMG variables, especially in terms of (i) biceps femoris and gastrocnemius lateralis activity at touchdown and (ii) vastus lateralis and gastrocnemius lateralis activity during take-off. During touchdown, the experts tended to increase the stiffness of the take-off leg to decrease braking. Novices exhibited less stiffness in the take-off leg due to their tendency to maintain a tighter knee angle. Novices also transferred less energy forward during take-off due to lack of contraction in the vastus lateralis, which is known to contribute to forward energy transfers. This study highlights the differences in both groups in terms of muscular and angular control according to the studied variables. Such studies of pole vaulting could be useful to help novices to learn expert's technique.