Quantitative, Multi-institutional Evaluation of MR Thermometry Accuracy for Deep-Pelvic MR-Hyperthermia Systems Operating in Multi-vendor MR-systems Using a New Anthropomorphic Phantom.
Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique capabilities to non-invasively measure the 3D-temperature. This study investigates MRT accuracy for MR-hyperthermia hybrid systems located at five European institutions while heating a centric or eccentric target in anthropomorphic phantoms with pelvic and spine structures. Scatter plots, root mean square error (RMSE) and Bland-Altman analysis were used to quantify accuracy of MRT compared to high resistance thermistor probe measurements. For all institutions, a linear relation between MRT and thermistor probes measurements was found with R2 (mean ± standard deviation) of 0.97 ± 0.03 and 0.97 ± 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 ± 0.31 °C and 0.30 ± 0.20 °C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 ± 0.20 °C and 0.13 ± 0.08 °C, respectively. This first multi-institutional evaluation of MR-hyperthermia hybrid systems indicates comparable device performance and good agreement between MRT and thermistor probes measurements. This forms the basis to standardize treatments in multi-institution studies of MR-guided hyperthermia and to elucidate thermal dose-effect relations.


Hierarchy of individual calibration levels for heart rate and accelerometry to measure physical activity.
Combining accelerometry with heart rate (HR) monitoring may improve precision of physical activity measurement. Considerable variation exists in the relationships between physical activity intensity (PAI) and HR and accelerometry, which may be reduced by individual calibration. However, individual calibration limits feasibility of these techniques in population studies, and less burdensome, yet valid, methods of calibration are required. We aimed to evaluate the precision of different individual calibration procedures against a reference calibration procedure: a ramped treadmill walking-running test with continuous measurement of PAI by indirect calorimetry in 26 women and 25 men [mean (SD): 35 (9) yr, 1.69 (0.10) m, 70 (14) kg]. Acceleration (along the longitudinal axis of the trunk) and HR were measured simultaneously. Alternative calibration procedures included treadmill testing without calorimetry, submaximal step and walk tests with and without calorimetry, and nonexercise calibration using sleeping HR and gender. Reference accelerometry and HR models explained >95% of the between-individual variance in PAI (P < 0.001). This fraction dropped to 73 and 81%, respectively, for accelerometry and HR models calibrated with treadmill tests without calorimetry. Step-test calibration captured 62-64% (accelerometry) and 68% (HR) of the variance between individuals. Corresponding values were 63-76% and 59-61% for walk-test calibration. There was only little benefit of including calorimetry during step and walk calibration for HR models. Nonexercise calibration procedures explained 54% (accelerometry) and 30% (HR) of the between-individual variance. In conclusion, a substantial proportion of the between-individual variance in relationships between PAI, accelerometry, and HR is captured with simple calibration procedures, feasible for use in epidemiological studies.


"Can I go to Glasgow?" Learnings from patient involvement at the 17th Congress of the International Society for Peritoneal Dialysis (ISPD).
Recognition of the discrepancy between the research priorities of patients and health professionals has prompted efforts to involve patients as active contributors in research activities, including scientific conferences. However, there is limited evidence about the experience, challenges, and impacts of patient involvement to inform best practice. This study aims to describe patient and health professional perspectives on patient involvement at the Congress of the International Society for Peritoneal Dialysis (ISPD). Semi-structured interviews were conducted with 14 patients/caregivers and 15 health professionals from six countries who attended ISPD. Interviews were recorded and transcribed verbatim, and transcripts were analyzed thematically. We identified four themes: protecting and enhancing scientific learning (grounding science in stories, sharing and inspiring new perspectives, distilling the key messages of research presentations, striking a balance between accommodating patients and presenting the science); democratizing access to research (redistributing power, challenging the traditional ownership of knowledge, cultivating self-management through demystifying research); inadequate support for patient/caregiver delegates (lacking purposeful inclusion, challenges in interpreting research findings, soliciting medical advice, difficulty negotiating venue and program, limited financial assistance in attending); and amplifying impact beyond the room (sparking innovation in practice, giving patients and families hope for the future). Patient involvement at the ISPD Congress clarified the applicability of research to patient care and self-management, democratized science, and strengthened the potential impact of research. More structured support for patients to help them purposefully articulate their experience in relation to session objectives may enhance their contribution and their own learning experience.


Surface plasmon resonance in two-dimensional nanobottle arrays.
We report our recent work on surface plasmon polaritons manipulation of two-dimensional arrays of subwavelength bottle-shaped cavities on gold surface. By tuning the geometry of such "nanobottle" it is possible to control the resonant frequencies and near field patterns of different surface plasmon resonances. The plasmonic band structures are not sensitive to the sizes and depths of the nano-bottles, but depend strongly on the polarization. In particular, by using different polarizations, it is observed that different types of plasmonic resonances, whether propagating or localized, can be excited independently. Moreover, we find that the local field and field intensity can by fine-tuned by controlling the topology of the bottleneck of the nanobottle. As a result, we believe these nanobottle arrays are useful for making plasmonic devices.


A mechano-regulation model of fracture repair in vertebral bodies.
In this study a multi-scale mechano-regulation model was developed in order to investigate the mechanobiology of trabecular fracture healing in vertebral bodies. A macro-scale finite element model of the spinal segment L3-L4-L5, including a mild wedge fracture in the body of the L4 vertebra, was used to determine the boundary conditions acting on a micro-scale finite element model simulating a portion of fractured trabecular bone. The micro-scale model, in turn, was utilized to predict the local patterns of tissue differentiation within the fracture gap and then how the equivalent mechanical properties of the macro-scale model change with time. The patterns of tissue differentiation predicted by the model appeared consistent with those observed in vivo. Bone formation occurred primarily through endochondral ossification. New woven bone was predicted to occupy the majority of the space within the fracture site approximately 7-8 weeks after the fracture event. Remodeling of cancellous bone architecture was then predicted, with complete new trabeculae forming due to bridging of the microcallus between the remnant trabeculae.


Injectable self-assembled peptide hydrogels for glucose-mediated insulin delivery.
Closed-loop glucose-responsive insulin delivery with excellent biocompatibility has the potential to improve the health and quality of life of diabetic patients. Herein, we developed an excellent glucose-responsive insulin delivery system using a pH-sensitive peptide hydrogel loaded with insulin and a glucose-specific enzyme. The designed peptide can be used as a carrier that is loaded with insulin and enzyme via a self-assembly process under physiological conditions. When hyperglycemia is encountered, the enzymatic conversion of glucose into gluconic acid leads to a decrease in the local pH, and the hydrogel is disassembled because of the strong inter- and intramolecular electrostatic repulsions between ornithine (Orn) residues; this is followed by the release of insulin. The glucose-responsive hydrogel system was characterized by studying its structure, conformation, rheology, morphology, acid sensitivity and the amounts of consistent release of insulin in vitro and in vivo. In vivo experiments indicated that the closed-loop insulin glucose-responsive system could efficiently regulate blood glucose in streptozocin-induced (STZ-induced) type 1 diabetic rats for 8 days.


Optical implementation of second-order nonlinear Volterra operators with use of triple correlation.
Following the Volterra theorem, every nonlinear operator can be implemented with a sum of integrals applied over the input. The second-order Volterra operator that describes many useful systems can be related to a single integral that is a projection of an operation called the triple correlation. This operation may be easily implemented optically and thus be incorporated into fast real-time nonlinear control systems. We present a theoretical investigation of the relation existing between the Volterra operators and the triple correlation as well as an experimental demonstration that validates the theory.


Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.
Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.


Dependence of regenerated sensory axons on continuous neurotrophin-3 delivery.
Previous studies have shown that injured dorsal column sensory axons extend across a spinal cord lesion site if axons are guided by a gradient of neurotrophin-3 (NT-3) rostral to the lesion. Here we examined whether continuous NT-3 delivery is necessary to sustain regenerated axons in the injured spinal cord. Using tetracycline-regulated (tet-off) lentiviral gene delivery, NT-3 expression was tightly controlled by doxycycline administration. To examine axon growth responses to regulated NT-3 expression, adult rats underwent a C3 dorsal funiculus lesion. The lesion site was filled with bone marrow stromal cells, tet-off-NT-3 virus was injected rostral to the lesion site, and the intrinsic growth capacity of sensory neurons was activated by a conditioning lesion. When NT-3 gene expression was turned on, cholera toxin β-subunit-labeled sensory axons regenerated into and beyond the lesion/graft site. Surprisingly, the number of regenerated axons significantly declined when NT-3 expression was turned off, whereas continued NT-3 expression sustained regenerated axons. Quantification of axon numbers beyond the lesion demonstrated a significant decline of axon growth in animals with transient NT-3 expression, only some axons that had regenerated over longer distance were sustained. Regenerated axons were located in white matter and did not form axodendritic synapses but expressed presynaptic markers when closely associated with NG2-labeled cells. A decline in axon density was also observed within cellular grafts after NT-3 expression was turned off possibly via reduction in L1 and laminin expression in Schwann cells. Thus, multiple mechanisms underlie the inability of transient NT-3 expression to fully sustain regenerated sensory axons.


Fracture prediction from bone mineral density in Japanese men and women.
In a cohort of 2356 Japanese elderly, after adjusting for age and prevalent vertebral fracture, baseline BMD predicted the risk of spine and hip fracture with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age. Low bone mineral density (BMD) is one of the most important predictors of a future fracture. However, we are not aware of any reports among Japanese in Japan. We examined the association of BMD with risk of fracture of the spine or hip among a cohort of 2356 men and women aged 47-95 years, who were followed up by biennial health examinations. Follow-up averaged 4 years after baseline measurements of BMD that were taken with the use of DXA. Vertebral fracture was assessed using semiquantitative methods, and the diagnosis of hip fracture was based on medical records. Poisson and Cox regression analysis were used. The incidence was twice as high in women as in men, after adjusting for age. After adjusting for baseline BMD and prevalent vertebral fracture, however, the gender difference was no longer significant. Age, baseline BMD of spine and femoral neck, and prior vertebral fracture predicted vertebral fracture and hip fracture. Loss of absolute BMD of the femoral neck predicted spine fracture, after adjusting for baseline BMD; rates of change in percent BMD, weight, height, body mass index, and age at menopause did not. The predictive value of baseline BMD for vertebral fracture risk was similar in men and women. The relative risk (RR) for vertebral fracture and hip fracture per SD decrease in BMD declined with age, after adjustment for prevalent vertebral fractures. Baseline BMD, loss of femoral neck BMD, and prior vertebral fracture predict the risk of spine and hip fracture in Japanese with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age, suggesting that factors other than BMD might play a greater role in the elderly.


Frequency-dependent fatigue development during electrical stimulation in the masseter muscle of pigtail monkeys.
Low-frequency fatigue was investigated in nine female and one male adult pigtail monkeys (Macaca nemestrina) with a mean weight of 5.3 kg (range 4.3 to 6.5 kg). After sedation and anesthesia, silver electrodes were inserted into the anterior and posterior parts of the right masseter muscle. The contralateral muscle was used as a control. The masseter muscles were stimulated for 3 minutes (4 Hz, 2 ms, 100 V). After a 5-minute rest period, the stimulation was repeated with the same duration and voltage but at a higher frequency of 8 Hz. Bite forces were measured, and muscle biopsies were obtained from the central part of the right masseter and immediately frozen in liquid nitrogen. After freeze-drying, a fluorometric analysis that used enzymatic methods for measuring levels of glycogen, glucose, lactate, pyruvate, creatine phosphate, nicotinamide-adenine dinucleotide (NAD), and reduced NAD (NADH) was performed. The bite force decreased by 12% after the initial 3 minutes of work. After the second contraction the bite force decreased to 56%. Prominent substrate depletion was observed. The precontraction levels of glycogen, glucose, and phosphocreatine were all reduced. The NADH and the NAD concentrations increased. An accumulation of metabolites was evident. The pyruvate increased by 32% and lactate levels increased by a factor of 3. The male measurements were comparable to the nine female measures for each assessment. The substantial substrate depletion in combination with a prominent accumulation of metabolites may contribute to the development of low-frequency fatigue.


Proliferation, oxidative stress and cell death in cells exposed to 872 MHz radiofrequency radiation and oxidants.
Human SH-SY5Y neuroblastoma and mouse L929 fibroblast cells were exposed to 872 MHz radiofrequency (RF) radiation using continuous waves (CW) or a modulated signal similar to that emitted by GSM mobile phones at a specific absorption rate (SAR) of 5 W/kg in isothermal conditions. To investigate possible combined effects with other agents, menadione was used to induce reactive oxygen species, and tert-butylhydroperoxide (t-BOOH) was used to induce lipid peroxidation. After 1 or 24 h of exposure, reduced cellular glutathione levels, lipid peroxidation, proliferation, caspase 3 activity, DNA fragmentation and viability were measured. Two statistically significant differences related to RF radiation were observed: Lipid peroxidation induced by t-BOOH was increased in SH-SY5Y (but not in L929) cells, and menadione-induced caspase 3 activity was increased in L929 (but not in SH-SY5Y) cells. Both differences were statistically significant only for the GSM-modulated signal. The other end points were not significantly affected in any of the experimental conditions, and no effects were observed from exposure to RF radiation alone. The positive findings may be due to chance, but they may also reflect effects that occur only in cells sensitized by chemical stress. Further studies are required to investigate the reproducibility and dose response of the possible effects.


Molecular Architecture of Early Dissemination and Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area.
We sequenced the genomes of 5,085 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains causing two coronavirus disease 2019 (COVID-19) disease waves in metropolitan Houston, TX, an ethnically diverse region with 7 million residents. The genomes were from viruses recovered in the earliest recognized phase of the pandemic in Houston and from viruses recovered in an ongoing massive second wave of infections. The virus was originally introduced into Houston many times independently. Virtually all strains in the second wave have a Gly614 amino acid replacement in the spike protein, a polymorphism that has been linked to increased transmission and infectivity. Patients infected with the Gly614 variant strains had significantly higher virus loads in the nasopharynx on initial diagnosis. We found little evidence of a significant relationship between virus genotype and altered virulence, stressing the linkage between disease severity, underlying medical conditions, and host genetics. Some regions of the spike protein-the primary target of global vaccine efforts-are replete with amino acid replacements, perhaps indicating the action of selection. We exploited the genomic data to generate defined single amino acid replacements in the receptor binding domain of spike protein that, importantly, produced decreased recognition by the neutralizing monoclonal antibody CR3022. Our report represents the first analysis of the molecular architecture of SARS-CoV-2 in two infection waves in a major metropolitan region. The findings will help us to understand the origin, composition, and trajectory of future infection waves and the potential effect of the host immune response and therapeutic maneuvers on SARS-CoV-2 evolution.IMPORTANCE There is concern about second and subsequent waves of COVID-19 caused by the SARS-CoV-2 coronavirus occurring in communities globally that had an initial disease wave. Metropolitan Houston, TX, with a population of 7 million, is experiencing a massive second disease wave that began in late May 2020. To understand SARS-CoV-2 molecular population genomic architecture and evolution and the relationship between virus genotypes and patient features, we sequenced the genomes of 5,085 SARS-CoV-2 strains from these two waves. Our report provides the first molecular characterization of SARS-CoV-2 strains causing two distinct COVID-19 disease waves.


Functional centrality of amygdala, striatum and hypothalamus in a "small-world" network underlying joy: an fMRI study with music.
Current knowledge about small-world networks underlying emotions is sparse, and confined to functional magnetic resonance imaging (fMRI) studies using resting-state paradigms. This fMRI study applied Eigenvector Centrality Mapping (ECM) and functional connectivity analysis to reveal neural small-world networks underlying joy and fear. Joy and fear were evoked using music, presented in 4-min blocks. Results show that the superficial amygdala (SF), laterobasal amygdala (LB), striatum, and hypothalamus function as computational hubs during joy. Out of these computational hubs, the amygdala nuclei showed the highest centrality values. The SF showed functional connectivity during joy with the mediodorsal thalamus (MD) and nucleus accumbens (Nac), suggesting that SF, MD, and Nac modulate approach behavior in response to positive social signals such as joyful music. The striatum was functionally connected during joy with the LB, as well as with premotor cortex, areas 1 and 7a, hippocampus, insula and cingulate cortex, showing that sensorimotor, attentional, and emotional processes converge in the striatum during music perception. The hypothalamus showed functional connectivity during joy with hippocampus and MD, suggesting that hypothalamic endocrine activity is modulated by hippocampal and thalamic activity during sustained periods of music-evoked emotion. Our study indicates high centrality of the amygdala nuclei groups within a functional network underlying joy, suggesting that these nuclei play a central role for the modulation of emotion-specific activity within this network.


Population dynamics of Neisseria gonorrhoeae in Shanghai, China: a comparative study.
Gonorrhea is a major sexually transmitted disease (STD) in many countries worldwide. The emergence of fluoroquinolone resistance has complicated efforts to control and treat this disease. We report the first study of the evolutionary processes acting on transmission dynamics of a resistant gonococcal population from Shanghai, China. We compare these findings with our previous study of the evolution of a fluoroquinolone sensitive gonococcal population from Baltimore, MD. Ninety six gonococcal samples were collected from male patients in Shanghai, China. All samples were fluoroquinolone resistant. Seven MLST housekeeping genes, two fluoroquinolone resistance genes (gyrA and parC) and the porB gene were sequenced and subjected to population genetic and evolutionary analyses. We estimated genetic diversity, recombination, growth, and selective pressure. The evolutionary history and population dynamics of the Shanghai population were also inferred and compared with that observed in a fluoroquinolone sensitive gonococcal population from Baltimore. For both populations, mutation plays a larger role than recombination in the evolution of the porB gene, whereas the latter seems to be the main force driving the evolution of housekeeping and fluoroquinolone resistance genes. In both populations there was evidence for positively selected sites in all genes analyzed. The phylogenetic analyses showed no temporal clustering in the Shanghai gonococcal population, nor did we detect shared allelic profiles between the Shanghai and the Baltimore populations. Past population dynamics of gonococcal strains from Shanghai showed a rising relative effective population size (Ne) in MLST genes with a declining relative Ne for gyrA and parC, whereas among sensitive strains from Baltimore we previously observed concordance among these genes. In both Shanghai and Baltimore, the past population dynamics of gonococcal strains tracked changes in the prevalence of gonorrhea. Our study illustrates both similarities and differences in the evolutionary processes acting on gonococcal populations in different geographic areas. An explanation of this pattern that may apply in China is the continued use of quinolone antibiotics despite widespread resistance. Population genetic analysis of gonococcal strains in conjunction with epidemiological surveillance may provide insights into the epidemic behavior of antibiotic resistant strains and help to design control measures.


Traumatic Spinal Cord Injury.
This article provides an update on the acute and subacute management and prognostication of patients with traumatic spinal cord injury. Immobilization of the spine and spine clearance should be individualized depending on the ability to perform a reliable neurologic examination, the presence of neck pain, and the imaging findings. Early surgery (within 24 hours) to achieve definitive cord decompression and spine stabilization may be beneficial. Ensuring adequate oxygenation and perfusion and avoiding secondary systemic complications remain the goals of the critical care of these patients. No neuroprotective treatment has been shown to improve outcomes. In fact, the use of high-dose methylprednisolone is now generally discouraged because of its major systemic adverse effects. Survivors of severe cervical traumatic spinal cord injury typically sustain substantial long-term functional impairment. Advances in our understanding of neuroregenerative strategies, especially stem cell transplantation, can offer the future hope of functional improvement to the many patients currently living with the consequences of traumatic spinal cord injury. Yet, at present, these therapies remain strictly investigational. The treatment of traumatic spinal cord injury remains supportive, and prognosis is still poor for patients who are severely affected. While much remains to be learned about how to optimize the acute management of these patients, future efforts would be most useful if focused on injury prevention and the development of effective neuroregenerative therapies.


Outcomes of selected cases from the American Occupational Therapy Foundation's curriculum mentoring project.
This study investigated the outcomes of a yearlong formal curriculum-mentoring project sponsored by the American Occupational Therapy Foundation. Five occupational therapy faculty groups were selected through a competitive application process and paired with mentors to assist in curriculum change. The experiences of each of the teams were studied using multiple methods of data collection, including semistructured interviews conducted in person and via telephone, a mailed questionnaire, and bimonthly electronic journal entries. The process and outcomes of two representative cases are reported in this qualitative, critical case study analysis. Overall, the faculty groups in each of the two teams seemed to benefit from mentoring in differing degrees as a result of their participation in this curriculum mentoring project. An important finding was that a well-focused mentoring plan with clearly outlined expectations needs to be established at the onset of any formal mentoring project. Additionally, a systematic, strategic plan agreed on by both mentors and participants, with a clear outline of responsibilities, will enhance the outcomes of a mentoring relationship.


Early Signaling in Primary T Cells Activated by Antigen Presenting Cells Is Associated with a Deep and Transient Lamellal Actin Network.
Cellular signaling transduction critically depends on molecular interactions that are in turn governed by dynamic subcellular distributions of the signaling system components. Comprehensive insight into signal transduction requires an understanding of such distributions and cellular structures driving them. To investigate the activation of primary murine T cells by antigen presenting cells (APC) we have imaged more than 60 signaling intermediates during T cell stimulation with microscopy across resolution limits. A substantial number of signaling intermediates associated with a transient, wide, and actin-associated lamellum extending from an interdigitated T cell:APC interface several micrometers into the T cell, as characterized in detail here. By mapping the more than 60 signaling intermediates onto the spatiotemporal features of cell biological structures, the lamellum and other ones previously described, we also define distinct spatial and temporal characteristics of T cell signal initiation, amplification, and core signaling in the activation of primary T cells by APCs. These characteristics differ substantially from ones seen when T cells are activated using common reductionist approaches.


Differences in spatial resolution and contrast sensitivity of flight control in the honeybees Apis cerana and Apis mellifera.
Visually guided behaviour is constrained by the capacity of the visual system to resolve detail. This, in turn, is limited by the spatial resolution and contrast sensitivity of the underlying visual system. Because these properties are interdependent and vary non-uniformly, it is only possible to fully understand the limits of a specific visually guided behaviour when they are investigated in combination. To understand the visual limits of flight control in bees, which rely heavily on vision to control flight, and to explore whether they vary between species, we tested how changes in spatial resolution and contrast sensitivity affect the speed and position control of the Asian and European honeybees (Apis cerana and Apis mellifera). Despite the apparent similarity of these species, we found some interesting and surprising differences between their visual limits. While the effect of spatial frequency and contrast on position control is similar between the species, ground speed is differently affected by these variables. A comparison with published data from the bumblebee Bombus terrestris revealed further differences. The visual resolution that limits the detection and use of optic flow for flight control in both species of honeybee is lower than the previously anatomically determined resolution and differs from object detection limits of A. mellifera, providing evidence that the limits of spatial resolution and contrast sensitivity are highly tuned to the particular behavioural task of a species.


Anti-citrullinated protein antibodies are linked to erosive disease in an observational study of patients with psoriatic arthritis.
ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease. As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity. ClinicalTrials.gov, NCT01111240.


Interhemispheric correlation of late pleistocene glacial events.
A radiocarbon chronology shows that piedmont glacier lobes in the Chilean Andes achieved maxima during the last glaciation at 13,900 to 14,890, 21,000, 23,060, 26,940, 29,600, and >/=33,500 carbon-14 years before present ((14)C yr B.P.) in a cold and wet Subantarctic Parkland environment. The last glaciation ended with massive collapse of ice lobes close to 14,000(14)C yr B.P., accompanied by an influx of North Patagonian Rain Forest species. In the Southern Alps of New Zealand, additional glacial maxima are registered at 17,720(14)C yr B.P., and at the beginning of the Younger Dryas at 11,050 (14)C yr B. P. These glacial maxima in mid-latitude mountains rimming the South Pacific were coeval with ice-rafting pulses in the North Atlantic Ocean. Furthermore, the last termination began suddenly and simultaneously in both polar hemispheres before the resumption of the modern mode of deep-water production in the Nordic Seas. Such interhemispheric coupling implies a global atmospheric signal rather than regional climatic changes caused by North Atlantic thermohaline switches or Laurentide ice surges.


The genetic and epigenetic landscapes of the epithelium in asthma.
Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.


Single frequency 1070 nm Nd:GdVO4 laser using a volume Bragg grating.
We demonstrate a single frequency diode-pumped Nd:GdVO(4) laser at 1070 nm using a volume Bragg grating as the output coupler of a short plano-concave cavity. The TEM(00) output had a maximum power of 300 mW and a linewidth less than 23 MHz. The beam propagation parameter M2 and the divergence angle at 200 mW were 1.2 and 0.37°, respectively. The single frequency tuning range was 5.1 GHz at 100 mW. Upon locking the laser frequency to a confocal reference cavity, a relative stability of 7.58 kHz was achieved. If frequency doubled, such as using a periodically-poled lithium niobate (PPLN) crystal, this laser offers an excellent light source for parity non-conservation experiments of atomic thallium.


Ability of Three General-Use Pesticides To Suppress Nymphal Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae).
We evaluated 3 over-the-counter pesticides for their ability to suppress host-seeking Ixodes scapularis and Amblyomma americanum nymphs. We applied liquid concentrate and granular formulations of Bayer Advanced Complete Insect Killer, Spectracide Triazicide Insect Killer, and Ortho Bug-B-Gon to forest plots using equipment available for purchase at retail home improvement outlets. All 3 liquid formulations provided rapid knockdown (≥98% control) of both species 1 day after application. Liquid Ortho Bug-B-Gone provided 100% suppression of I. scapularis throughout the 28-day postapplication period, while the other 2 liquid materials provided >95% control after 28 days. All liquid products also provided ≥95% control of A. americanum nymphs after 28 days. Granular formulations provided less consistent results, including lower 1-day knockdown rates for both species, due to very dry conditions, which prevented adequate release of the active ingredient from the carrier materials. After it rained in the study area, 7 and 14 days after application, we observed ≥99% suppression of both species. At 28 days posttreatment, control ranged between 87.5% and 95.6% for I. scapularis and between 89.3% and 94.4% for A. americanum . We show that these over-the-counter acaricides effectively suppressed 2 medically important tick vectors for at least 4 wk, and they provide a cost-effective tick control option for homeowners. In general, liquid formulations provided more rapid and greater and more consistent suppression than granular formulations, which may have implications for homeowner use of these products.


Phantom-Mobility-Based Prosthesis Control in Transhumeral Amputees Without Surgical Reinnervation: A Preliminary Study.
Transhumeral amputees face substantial difficulties in efficiently controlling their prosthetic limb, leading to a high rate of rejection of these devices. Actual myoelectric control approaches make their use slow, sequential and unnatural, especially for these patients with a high level of amputation who need a prosthesis with numerous active degrees of freedom (powered elbow, wrist, and hand). While surgical muscle-reinnervation is becoming a generic solution for amputees to increase their control capabilities over a prosthesis, research is still being conducted on the possibility of using the surface myoelectric patterns specifically associated to voluntary Phantom Limb Mobilization (PLM), appearing naturally in most upper-limb amputees without requiring specific surgery. The objective of this study was to evaluate the possibility for transhumeral amputees to use a PLM-based control approach to perform more realistic functional grasping tasks. Two transhumeral amputated participants were asked to repetitively grasp one out of three different objects with an unworn eight-active-DoF prosthetic arm and release it in a dedicated drawer. The prosthesis control was based on phantom limb mobilization and myoelectric pattern recognition techniques, using only two repetitions of each PLM to train the classification architecture. The results show that the task could be successfully achieved with rather optimal strategies and joint trajectories, even if the completion time was increased in comparison with the performances obtained by a control group using a simple GUI control, and the control strategies required numerous corrections. While numerous limitations related to robustness of pattern recognition techniques and to the perturbations generated by actual wearing of the prosthesis remain to be solved, these preliminary results encourage further exploration and deeper understanding of the phenomenon of natural residual myoelectric activity related to PLM, since it could possibly be a viable option in some transhumeral amputees to extend their control abilities of functional upper limb prosthetics with multiple active joints without undergoing muscular reinnervation surgery.


gamma-Linolenic acid supplementation can affect cancer cell proliferation via modification of fatty acid composition.
We examined the effect of gamma-linolenic acid (GLA) supplementation on the growth and fatty acid composition of three human tumor cell lines (the neuroblastoma CHP-212, the tubal carcinoma TG, and the colon carcinoma SW-620), in order to evaluate the relationship between GLA-induced tumor cell death and the distribution of fatty acids in tumor cells. At the highest GLA concentrations (10 and 20 micrograms/ml), the DNA synthesis was completely abolished; at 5 micrograms/ml GLA only SW-620 cells did not proliferate, while CHP-212 and TG cells showed a residual [3H]-thymidine incorporation. GLA levels were very low in cells grown in control medium; GLA supplementation caused a significant incorporation of GLA itself in all the cell lines at each concentration. In TG and CHP-212 cells, GLA was metabolized, although to a different extent, to dihomo-gamma linolenic acid and arachidonic acid. SW-620 cells neither elongated nor desaturated the incorporated GLA. The highest cytostatic effect was reached when GLA was not transformed into its metabolites, suggesting that the GLA toxicity to tumor cells is not dependent on metabolites but is due to GLA itself.


Adhesive bond dynamics in contacts between T lymphocytes and glass-supported planar bilayers reconstituted with the immunoglobulin-related adhesion molecule CD58.
The interaction of the T cell glycoprotein CD2 and its ligand CD58 is important for T cell interaction with antigen-presenting and target cells. The binding interaction is of low affinity and has a fast off-rate (>5 s-1) in solution. However, solution measurements may not accurately predict the behavior of molecules in an adhesive contact area. Interaction between T cells that express CD2 and glass-supported planar bilayers containing purified and fluorescently labeled CD58 leads to accumulation of CD58 (fluorescence) in the cell/bilayer contact area. CD58 molecules accumulated within the contact area in excess of the CD58 density in the bilayer outside the contact area can be considered as bound by cell surface CD2. Here, this phenomena and fluorescence photobleaching recovery were utilized to determine whether CD2-CD58 bonds are transient in contact areas. Fluorescent CD58 molecules accumulated in the T cell-bilayer interface were completely bleached. The bleached CD58 molecules accumulated in the contact area were rapidly replaced by fluorescent CD58 that diffused into the contact area from adjacent bilayer regions outside the contact area. Rapid recovery of the accumulated fluorescence directly demonstrates that the CD2-CD58 bonds are dissociating and that the dissociation leads to partner exchange, rather than rebinding of the same CD2-CD58 pairs. This suggests that the solution off-rate provides an accurate description of CD2-CD58 interaction in contact areas. Accumulated fluorescent IgG in contacts between K562 cells expressing low affinity Fc receptors and planar bilayers with fluorescent IgG bound to hapten-derivitized phospholipids displayed slower recovery than CD58 by a factor of 10. This suggests that the Fc receptor-IgG interaction has a longer lifetime than the CD2-CD58 interaction. These findings have implications for the mechanism of signaling by CD2 and the mechanism of cell detachment from large numbers of transient interactions.


Dimensions of anxiety sensitivity in the anxiety disorders: evaluation of the ASI-3.
Anxiety sensitivity (AS), the fear of sensations of anxious arousal based on beliefs about their harmful consequences, is increasingly recognized as a multidimensional construct. The recently developed Anxiety Sensitivity Index-3 [ASI-3; Taylor, S., Zvolensky, M., Cox, B., Deacon, B., Heimberg, R., Ledley, D. R., et al. (2007). Robust dimensions of anxiety sensitivity: Development and initial validation of the Anxiety Sensitivity Index-3 (ASI-3). Psychological Assessment, 19, 176-188] measures three dimensions of AS: physical concerns, social concerns, and cognitive concerns. The ASI-3 shows promise, although further evaluation of its psychometric properties and validity in independent samples is needed. We evaluated the ASI-3 in a mixed sample of anxiety disorder patients (N=506) and undergraduate student controls (N=315). The measure demonstrated a stable 3-factor structure and sound psychometric properties, with the three factors showing theoretically consistent patterns of associations with anxiety symptoms and diagnoses. ASI-3 total scores were less discriminative. Implications for conceptual models of anxiety are discussed.


Survival from childhood cancers in Eastern Africa: A population-based registry study.
Cancers occurring in children in Africa are often underdiagnosed, or at best diagnosed late. As a result, survival is poor, even for cancers considered 'curable'. With limited population-level data, understanding the actual burden and survival from childhood cancers in Africa is difficult. In this study, we aimed at providing survival estimates for the most common types of cancers affecting children aged 0-14 years, in three population-based Eastern African registries; Harare, Zimbabwe (Kaposi sarcoma, Wilms tumour (WT), non-Hodgkin lymphoma (NHL), retinoblastoma, and acute lymphocytic leukaemia (ALL)), Kampala, Uganda (Burkitt lymphoma, Kaposi sarcoma, WT, and retinoblastoma), and Nairobi, Kenya (ALL, retinoblastoma, WT, Burkitt lymphoma, and Hodgkin lymphoma). We included cases diagnosed within the years 1998-2009 and followed up till the end of 2011. We estimated the observed and relative survival at 1, 3, and 5 years after diagnosis. We studied 627 individual patient records. Median follow-up ranged from 2.2 months for children with Kaposi sarcoma in Harare to 30.2 months for children with ALL in Nairobi. The proportion of children lost to follow-up was highest in the first year after diagnosis. In Harare and Kampala, the 5-year relative survival was <46% for all cancer types. The 5-year relative survival was best for children in Nairobi, though with wider confidence intervals. Survival from childhood cancers in Africa is still poor, even for cancers with good prognosis and potential for cure. Supporting cancer detection, treatment, and registration activities could help improve survival chances for children with cancers in Africa.


Information-geometric measures as robust estimators of connection strengths and external inputs.
Information geometry has been suggested to provide a powerful tool for analyzing multineuronal spike trains. Among several advantages of this approach, a significant property is the close link between information-geometric measures and neural network architectures. Previous modeling studies established that the first- and second-order information-geometric measures corresponded to the number of external inputs and the connection strengths of the network, respectively. This relationship was, however, limited to a symmetrically connected network, and the number of neurons used in the parameter estimation of the log-linear model needed to be known. Recently, simulation studies of biophysical model neurons have suggested that information geometry can estimate the relative change of connection strengths and external inputs even with asymmetric connections. Inspired by these studies, we analytically investigated the link between the information-geometric measures and the neural network structure with asymmetrically connected networks of N neurons. We focused on the information-geometric measures of orders one and two, which can be derived from the two-neuron log-linear model, because unlike higher-order measures, they can be easily estimated experimentally. Considering the equilibrium state of a network of binary model neurons that obey stochastic dynamics, we analytically showed that the corrected first- and second-order information-geometric measures provided robust and consistent approximation of the external inputs and connection strengths, respectively. These results suggest that information-geometric measures provide useful insights into the neural network architecture and that they will contribute to the study of system-level neuroscience.


Mouse immunoglobulin genes: studies on the reiteration frequency of light-chain genes by hybridisation procedures.
The partially purified immunoglobulin light chain messenger RNA fraction from P3K (MOPC 21) mouse myeloma tissue-culture cells has been employed in hybridisation studies. Fragments of the messenger RNA were generated by alkali hydrolysis. 6-S fragments not containing poly(A) showed the characteristic biphasic hybridisation profile seen with the intact RNA fraction. 12-S and 6-S poly(A)-containing fragments, however, showed single transitions lacking the rapidly hybridising component. Complementary DNA copies of the intact messenger RNA fraction were prepared with RNA-dependent DNA polymerase and the DNA populations fractionated on acrylamide gels. Hybridisation experiments with complementary DNA fractions up to 800 bases in length showed annealing to single (or a few) genes. A rapidly hybridising component (about 200 copies) appears in the cDNA fraction containing the largest transcripts. We conclude that the kappa constant region gene and the MOPC 21 variable region gene are present as one or a few copies in the haploid genome and that the rapidly hybridising component is not due to variable region genes.


Cocaine dependence modulates the effect of HIV infection on brain activation during intertemporal decision making.
Both HIV infection and chronic cocaine use alter the neural circuitry of decision making, but the interactive effects of these commonly comorbid conditions have not been adequately examined. This study tested how cocaine moderates HIV-related neural activation during an intertemporal decision-making task. The sample included 73 participants who differed on cocaine and HIV status (18 COC+/HIV+, 19 COC+/HIV-, 19 COC-/HIV+, 17 COC-/HIV-). Participants made choices between smaller, sooner and larger, delayed rewards while undergoing functional MRI. Choices varied in difficulty based on subjective value: hard (equivalently valued), easy (disparately valued), and control choices. A mixed-effects model controlling for education and smoking identified main and interactive effects of HIV and COC during hard relative to easy choices (difficulty contrast). COC+ status was associated with lower activation in bilateral frontal gyri and right insular and posterior parietal cortices. HIV+ status was associated with higher activation in the visual cortex, but lower activation in bilateral prefrontal cortices and cerebellum and left posterior parietal cortex. COC moderated the effects of HIV in several clusters centered in the bilateral prefrontal cortices and cerebellum. In post-hoc analyses, there were significant effects of HIV status on activation for COC+, but not COC-, participants; interaction effects remained after controlling for polysubstance use. Cocaine use may diminish the compensatory neural activation often seen among HIV+ samples during decision making. Our results highlight the importance of examining the neuropsychiatric effects of comorbid medical conditions to identify potential neural targets for cognitive remediation interventions.


A Case of Acquired Hemophilia A Diagnosed in Conjunction with Oral Bleeding.
Acquired hemophilia A is a rare disease in which autoantibodies to factor VIII are present. It is often manifested as a sudden onset of a critical bleeding episode, and its incidence is reported to be 1.48 cases per million persons per year. We report herein on a case of acquired hemophilia A associated with a submucosal hematoma of the oral floor, pharynx, and larynx. A 78-year-old male presented with fresh bleeding from his mouth, associated with hematoma of the oral floor, pharynx, and larynx. Laboratory test showed that the activated partial thromboplastin time was prolonged, and the platelet count and prothrombin time were normal. Coagulation tests revealed decreased factor VIII levels, and the presence of factor VIII inhibitor. A diagnosis of acquired hemophilia A was made, and immunotherapy with corticosteroids was initiated. After treatment, the bleeding tendency was controlled. On hospital day 29, the symptoms disappeared. Although acquired hemophilia A is a rare coagulopathic condition, it should be considered as one of the differential diagnoses in a case of sudden onset of severe hemorrhagic tendency of unknown origin.


Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.
This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.


Using a campaign to promote safer medicines practice among healthcare professionals.
The Chesterfield Royal Hospital Foundation Trust has a work plan to improve the safe administration of medicines throughout the hospital. This includes measures to raise nurses' awareness of the risks associated with the administration of medicines, and initiatives to improve safety. Last year, two focus groups were held with qualified nurses from across the hospital to find out how they felt that practice could be made safer and more effective for patients. The nurses suggested that an educational campaign be organised to highlight best practice and to encourage nurses to think differently about medicines administration. This paper summarises the content and outcome of the campaign.


Diet, activity, and overweight among preschool-age children enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC).
Overweight is affecting children at younger ages and in increasing numbers, putting them at risk for a lifetime of chronic disease. Consumption of unhealthy foods and time spent watching television have increased concurrently. Parents of 526 children aged 2 to 4 years old enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) answered questions about their children's food and beverage consumption, television-viewing and computer time, and physical activity. The children's height and weight measurements were collected from administrative records. Crude and adjusted odds ratios were calculated to test for associations between demographic, consumption, and activity variables and overweight or at risk of overweight (body mass index > or =85th percentile for age and sex). Of the participants, 38% of the children were overweight or at risk of overweight. Hispanic and white children were twice as likely as black children to be overweight or at risk of overweight. Fifty-eight percent of the children drank more than one and 30% drank more than two 8-oz servings of fruit juice per day. The children who drank more than one serving of nonjuice fruit drink per day (30%) had increased odds of being overweight or at risk of overweight. On average, the children spent more than twice as much time watching television and using computers as they did engaging in physical activity. In multivariate analyses, race and ethnicity as well as physical activity were associated with being overweight or at risk of overweight. Efforts to improve nutrition and prevent overweight in children should focus on the parents of infants and toddlers and provide them with anticipatory guidance on physical activity for young children and nutrition and food transitions.


Inverse Thermogelation of Aqueous Triblock Copolymer Solutions into Macroporous Shear-Thinning 3D Printable Inks.
Amphiphilic block copolymers that undergo (reversible) physical gelation in aqueous media are of great interest in different areas including drug delivery, tissue engineering, regenerative medicine, and biofabrication. We investigated a small library of ABA-type triblock copolymers comprising poly(2-methyl-2-oxazoline) as the hydrophilic shell A and different aromatic poly(2-oxazoline)s and poly(2-oxazine)s cores B in an aqueous solution at different concentrations and temperatures. Interestingly, aqueous solutions of poly(2-methyl-2-oxazoline)-block-poly(2-phenyl-2-oxazine)-block-poly(2-methyl-2-oxazoline) (PMeOx-b-PPheOzi-b-PMeOx) undergo inverse thermogelation below a critical temperature by forming a reversible nanoscale wormlike network. The viscoelastic properties of the resulting gel can be conveniently tailored by the concentration and the polymer composition. Storage moduli of up to 110 kPa could be obtained while the material retains shear-thinning and rapid self-healing properties. We demonstrate three-dimensional (3D) printing of excellently defined and shape-persistent 24-layered scaffolds at different aqueous concentrations to highlight its application potential, e.g., in the research area of biofabrication. A macroporous microstructure, which is stable throughout the printing process, could be confirmed via cryo-scanning electron microscopy (SEM) analysis. The absence of cytotoxicity even at very high concentrations opens a wide range of different applications for this first-in-class material in the field of biomaterials.


Balancing water resource conservation and food security in China.
China's economic growth is expected to continue into the next decades, accompanied by sustained urbanization and industrialization. The associated increase in demand for land, water resources, and rich foods will deepen the challenge of sustainably feeding the population and balancing agricultural and environmental policies. We combine a hydrologic model with an economic model to project China's future food trade patterns and embedded water resources by 2030 and to analyze the effects of targeted irrigation reductions on this system, notably on national agricultural water consumption and food self-sufficiency. We simulate interprovincial and international food trade with a general equilibrium welfare model and a linear programming optimization, and we obtain province-level estimates of commodities' virtual water content with a hydrologic model. We find that reducing irrigated land in regions highly dependent on scarce river flow and nonrenewable groundwater resources, such as Inner Mongolia and the greater Beijing area, can improve the efficiency of agriculture and trade regarding water resources. It can also avoid significant consumption of irrigation water across China (up to 14.8 km(3)/y, reduction by 14%), while incurring relatively small decreases in national food self-sufficiency (e.g., by 3% for wheat). Other researchers found that a national, rather than local, water policy would have similar effects on food production but would only reduce irrigation water consumption by 5%.


Community-Based Appraisal of the Effects of Parenteral Nutrition Versus Enteral Nutrition on the Quality of Care for Patients With Acute Pancreatitis.
Enteral nutrition (EN) rather than parenteral nutrition (PN) has been advocated in treatment guidelines for acute pancreatitis (AP) as endorsed in randomized studies or meta-analyses. The findings derived from those studies would recognize the criticism of smaller sample sizes or limited patient case-mixes. To determine the generalizability of those findings, community-based appraisal on the advantages of EN over PN is required. Using a Japanese administrative database between 2006 and 2010, we determine whether EN is superior to PN in the real clinical settings. A total of 24,913 patients diagnosed with AP at admission in 1,000 hospitals were identified. Among them, we analyzed 1,803 patients of ≥ 15 years who received EN or PN for AP across 480 hospitals. Among three nutrition categories of PN only, EN only and PN with EN, we examined patient characteristics, comorbidities, complications, AP severity score determined by the Ministry of Health, Labor and Welfare, surgical procedures for the biliary/pancreatic system, use of artificially assisted ventilation and hemodialysis proxy of multiple organ failures and hospital teaching status. To identify the variables associated with PN use, a logistic regression model was used and the propensity score (PS) was calculated to control for the selection bias of patient case-mix preferring PN use. Then, we compared mortality, length of hospital stay (LOS), total charges (TC) and commencement day of oral food intake between EN and PN. A total of 1,191 PN patients, 330 EN patients and 282 mixed EN and PN patients were identified. EN was indicated for patients with mild AP and procedures for the pancreas. PS matching analysis indicated that PN had a higher mortality compared with EN, and PN significantly increased LOS and TC compared with EN. PN deterred the commencement of oral food intake. Community-based study has shown that EN was employed in the less severe case-mixed. Even though considering that selection bias, EN was still superior to PN in AP. Physicians should be aware of the guidelines for the advocacy of EN and need to carefully consider the indications for EN to optimize the quality of AP care.


FTIR Spectroscopy for Evaluation and Monitoring of Lipid Extraction Efficiency for Oleaginous Fungi.
To assess whether Fourier Transform Infrared (FTIR) spectroscopy could be used to evaluate and monitor lipid extraction processes, the extraction methods of Folch, Bligh and Lewis were used. Biomass of the oleaginous fungi Mucor circinelloides and Mortierella alpina were employed as lipid-rich material for the lipid extraction. The presence of lipids was determined by recording infrared spectra of all components in the lipid extraction procedure, such as the biomass before and after extraction, the water and extract phases. Infrared spectra revealed the incomplete extraction after all three extraction methods applied to M.circinelloides and it was shown that mechanical disruption using bead beating and HCl treatment were necessary to complete the extraction in this species. FTIR spectroscopy was used to identify components, such as polyphosphates, that may have negatively affected the extraction process and resulted in differences in extraction efficiency between M.circinelloides and M.alpina. Residual lipids could not be detected in the infrared spectra of M.alpina biomass after extraction using the Folch and Lewis methods, indicating their complete lipid extraction in this species. Bligh extraction underestimated the fatty acid content of both M.circinelloides and M.alpina biomass and an increase in the initial solvent-to-sample ratio (from 3:1 to 20:1) was needed to achieve complete extraction and a lipid-free IR spectrum. In accordance with previous studies, the gravimetric lipid yield was shown to overestimate the potential of the SCO producers and FAME quantification in GC-FID was found to be the best-suited method for lipid quantification. We conclude that FTIR spectroscopy can serve as a tool for evaluating the lipid extraction efficiency, in addition to identifying components that may affect lipid extraction processes.


A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis.
Cystic fibrosis is a monogenic disease that deranges multiple systems of ion transport in the airways, culminating in chronic infection and destruction of the lung. The introduction of a normal copy of the cystic fibrosis transmembrane conductance regulator (CFTR) gene into the airway epithelium through gene transfer is an attractive approach to correcting the underlying defects in patients with cystic fibrosis. We tested the feasibility of gene therapy using adenoviral vectors in the nasal epithelium of such patients. An adenoviral vector containing the normal CFTR complementary DNA in four logarithmically increasing doses (estimated multiplicity of infection, 1, 10, 100, and 1000), or vehicle alone, was administered in a randomized, blinded fashion to the nasal epithelium of 12 patients with cystic fibrosis. Gene transfer was quantitated by molecular techniques that detected the expression of CFTR messenger RNA and by functional measurements of transepithelial potential differences (PDs) to assess abnormalities of ion transport specific to cystic fibrosis. The safety of this treatment was monitored by nasal lavage and biopsy to assess inflammation and vector replication. The adenoviral vector was detected in nasal-lavage fluid by culture, the polymerase chain reaction (PCR), or both in a dose-dependent fashion for up to eight days after vector administration. There was molecular evidence of gene transfer by reverse-transcriptase PCR assays or in situ hybridization in five of six patients treated at the two highest doses. However, the percentage of epithelial cells transfected by the vector was very low (< 1 percent), and measurement of PD across the epithelium revealed no significant restoration of chloride transport or normalization of sodium transport. At the lower doses of vector, there were no toxic effects. However, at the highest dose there was mucosal inflammation in two of three patients. In patients with cystic fibrosis, adenoviral-vector-mediated transfer of the CFTR gene did not correct functional defects in nasal epithelium, and local inflammatory responses limited the dose of adenovirus that could be administered to overcome the inefficiency of gene transfer.


Norovirus Epidemiology in Africa: A Review.
Norovirus (NoV) is recognised as a leading cause of gastroenteritis worldwide across all age groups. The prevalence and diversity of NoVs in many African countries is still unknown, although early sero-prevalence studies indicated widespread early infection. Reports on NoVs in Africa vary widely in terms of study duration, population groups and size, inclusion of asymptomatic controls, as well as genotyping information. This review provides an estimate of NoV prevalence and distribution of genotypes of NoVs in Africa. Inclusion criteria for the review were study duration of at least 6 months, population size of >50 and diagnosis by RT-PCR. As regions used for genotyping varied, or genotyping was not always performed, this was not considered as an inclusion criteria. A literature search containing the terms norovirus+Africa yielded 74 publications. Of these 19 studies from 14 out of the 54 countries in Africa met the inclusion criteria. Data from studies not meeting the inclusion criteria, based on sample size or short duration, were included as discussion points. The majority of studies published focused on children, under five years of age, hospitalised with acute gastroenteritis. The mean overall prevalence was 13.5% (range 0.8-25.5%) in children with gastroenteritis and 9.7% (range 7-31%) in asymptomatic controls, where tested. NoV GII.4 was the predominant genotype identified in most of the studies that presented genotyping data. Other prevalent genotypes detected included GII.3 and GII.6. In conclusion, NoV is a common pathogen in children with diarrhoea in Africa, with considerable carriage in asymptomatic children. There is however, a paucity of data on NoV infection in adults.


Challenges facing the anesthesiologist in the emergency department.
This review focuses on developments in airway management and concious sedation/analgesic techniques employed by anesthesiologists in the emergency department. Emergency medicine physicians routinely employ airway devices and techniques that were previously reserved for anesthesiologists. An understanding of the uses and limitations of these devices are essential for successful outcomes. Anesthesiologists responding to the emergency department may be faced with soiled or traumatized airways. The use of newer devices in cervical trauma and the difficult airway is reviewed. Consious sedation in the emergency department is also reviewed. There are no published recommendations demonstrating the advantage of specific agents for sedation in the emergency department. A wide variety of medications and techniques are currently being employed. Studies indicate that the incidence of adverse effects from these agents range from less than 1% to almost 30%. Various organizations have published guidelines detailing the appropriate protocols and equipment that must be present in the emergency department to monitor patients undergoing conscious sedation. These recommendations have not been universally implemented, and several recent studies suggest that a substantial number of emergency departments may have major deficiencies. The consultant anesthesiologist responding to a critical airway may face a variety of challenges, including traumatized or soiled airways, patients with cervical spine fractures, and patients who have undergone sedation techniques that may have progressed to deep and general anesthesia. Anesthesiologists may also face the challenge of responding to these emergent situations without all the equipment or adequately trained support staff necessary to handle those emergencies safely.


Pressurized intraperitoneal chemotherapy (PIPAC) in women with gynecologic malignancies: a review.
The objective of this study was to provide an overview of published and ongoing trials of pressurized intraperitoneal chemotherapy (PIPAC) in ovarian cancer. The study comprised a systematic literature review. We identified 10 studies, including 2 ex vivo and in vitro studies, 6 clinical studies, and 2 ongoing clinical trials using PIPAC in women with recurrent ovarian cancer and pseudomyxoma peritonei. Experimental evidence and clinical study data demonstrate that PIPAC increases peritoneal cavity coverage and depth of peritoneal infiltration, and is technically feasible. Occupational safety has been established. PIPAC has demonstrated antitumor activity based on histological, radiological, and clinical evidence. The toxicity of PIPAC is manageable and restricted to Common Terminology Criteria for Adverse Events grade 2-3 events when used without concomitant cytoreductive surgery. Further clinical trials assessing efficacy and dose escalation are ongoing. PIPAC is technically feasible, has a safe local and systemic safety profile, and has antitumor activity in women with peritoneal carcinomatosis from recurrent ovarian cancer.


Serological evidence of hantavirus infection in rural and urban regions in the state of Amazonas, Brazil.
Hantavirus disease is caused by the hantavirus, which is an RNA virus belonging to the family Bunyaviridae. Hantavirus disease is an anthropozoonotic infection transmitted through the inhalation of aerosols from the excreta of hantavirus-infected rodents. In the county of Itacoatiara in the state of Amazonas (AM), Brazil, the first human cases of hantavirus pulmonary and cardiovascular syndrome were described in July 2004. These first cases were followed by two fatal cases, one in the municipality of Maués in 2005 and another in Itacoatiara in 2007. In this study, we investigated the antibody levels to hantavirus in a population of 1,731 individuals from four different counties of AM. Sera were tested by IgG/IgM- enzyme-linked immune-sorbent assay using a recombinant nucleocapsid protein of the Araraquara hantavirus as an antigen. Ten sera were IgG positive to hantavirus (0.6%). Among the positive sera, 0.8% (1/122), 0.4% (1/256), 0.2% (1/556) and 0.9% (7/797) were from Atalaia do Norte, Careiro Castanho, Itacoatiara and Lábrea, respectively. None of the sera in this survey were IgM-positive. Because these counties are distributed in different areas of AM, we can assume that infected individuals are found throughout the entire state, which suggests that hantavirus disease could be a local emerging health problem.


Complications and failure after total ankle arthroplasty.
Second-generation total ankle arthroplasty has been reported to have good intermediate-term results. The purpose of the present study was to report on the cause and frequency of reoperation and failure after total ankle arthroplasty and to determine demographic and clinical predictors of reoperation and failure. Three hundred and six consecutive primary total ankle arthroplasties were performed with use of the DePuy Agility Total Ankle System between 1995 and 2001. At a mean of thirty-three months after the arthroplasty, we retrospectively reviewed the records with regard to patient age, gender, the indications for the index procedure, adjuvant procedures, the timing and frequency of reoperation, and the indications for and the type of reoperations performed. Kaplan-Meier analysis was performed to determine the rate of prosthetic survival, and Cox regression analysis was performed to determine predictors of reoperation and failure. Eighty-five patients (28%) underwent 127 reoperations (involving 168 procedures) after primary total ankle arthroplasty. The most common procedures at the time of reoperation were débridement of heterotopic bone (fifty-eight), correction of axial malalignment (forty), and component replacement (thirty-one). Eight patients underwent below-the-knee amputation. Age was found to be the only significant predictor of reoperation and failure after total ankle arthroplasty. The five-year survival rate with reoperation as the end point was 54%. The five-year survival rate with failure as the end point was 80% for all patients and 89% for patients who were more than fifty-four years of age. The prosthesis could not be salvaged in nine ankles (2.9%); the inability to salvage the prosthesis was most often due to loosening or infection. We noted a relatively high rate of reoperation after total ankle arthroplasty with this second-generation device. Younger age was found to have a negative effect on the rates of reoperation and failure. Most prostheses could be salvaged; however, the functional outcome of this procedure is uncertain.


13C NMR characterization of an exchange reaction between CO and CO2 catalyzed by carbon monoxide dehydrogenase.
Carbon monoxide dehydrogenase (CODH) catalyzes the reversible oxidation of CO to CO2 at a nickel-iron-sulfur cluster (the C-cluster). CO oxidation follows a ping-pong mechanism involving two-electron reduction of the C-cluster followed by electron transfer through an internal electron transfer chain to external electron acceptors. We describe 13C NMR studies demonstrating a CODH-catalyzed steady-state exchange reaction between CO and CO2 in the absence of external electron acceptors. This reaction is characterized by a CODH-dependent broadening of the 13CO NMR resonance; however, the chemical shift of the 13CO resonance is unchanged, indicating that the broadening is in the slow exchange limit of the NMR experiment. The 13CO line broadening occurs with a rate constant (1080 s-1 at 20 degrees C) that is approximately equal to that of CO oxidation. It is concluded that the observed exchange reaction is between 13CO and CODH-bound 13CO2 because 13CO line broadening is pH-independent (unlike steady-state CO oxidation), because it requires a functional C-cluster (but not a functional B-cluster) and because the 13CO2 line width does not broaden. Furthermore, a steady-state isotopic exchange reaction between 12CO and 13CO2 in solution was shown to occur at the same rate as that of CO2 reduction, which is approximately 750-fold slower than the rate of 13CO exchange broadening. The interaction between CODH and the inhibitor cyanide (CN-) was also probed by 13C NMR. A functional C-cluster is not required for 13CN- broadening (unlike for 13CO), and its exchange rate constant is 30-fold faster than that for 13CO. The combined results indicate that the 13CO exchange includes migration of CO to the C-cluster, and CO oxidation to CO2, but not release of CO2 or protons into the solvent. They also provide strong evidence of a CO2 binding site and of an internal proton transfer network in CODH. 13CN- exchange appears to monitor only movement of CN- between solution and its binding to and release from CODH.


Long-term transmission of measles virus in Central and continental Western Europe.
The World Health Organization (WHO) has adopted an elimination goal for measles and rubella, which is supposed to be met in the WHO European Region (EUR) by 2015. For verification of elimination, it is required that the genotyping data of detected measles viruses provide evidence for the interruption of endemic transmission. In order to record and assess the extent of endemic measles virus (MV) circulation in a part of the EUR, we analyzed transmission chains of the epidemiologically most relevant MV variants identified in Central and continental Western Europe (CCWE) from 2006 to 2013. Based on MV sequence data deposited in the WHO global database for molecular surveillance of measles (MeaNS), the circulation period was calculated for each MV variant at the country-level and for the entire region of CCWE. The MV variants "D5-Okinawa," "D4-Hamburg," "D4-Manchester," and "D8-Frankfurt-Main" spread widely in CCWE; they caused large and long-lasting outbreaks with secondary spread that resulted in additional outbreaks. Nation-wide outbreaks (epidemics) with thousands of measles cases occurred in four countries (Switzerland, France, Bulgaria, and Romania) and were characterized by continuous detection of the same MV variant for more than 12 months suggesting endemic transmission. In the entire region of CCWE, the circulation period of the four predominant MV variants ranged from 18 to 44 months. The long-lasting MV transmission which affected predominantly unvaccinated individuals in different hard-to-reach groups and in the general population is not consistent with the measles elimination goal. Additional efforts are necessary to meet the elimination target in the EUR.


Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats.
Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.


Pollutant particles enhanced H2O2 production from NAD(P)H oxidase and mitochondria in human pulmonary artery endothelial cells.
Particulate matter (PM) induces oxidative stress and cardiovascular adverse health effects, but the mechanistic link between the two is unclear. We hypothesized that PM enhanced oxidative stress in vascular endothelial cells and investigated the enzymatic sources of reactive oxygen species and their effects on mitogen-activated protein kinase (MAPK) activation and vasoconstriction. We measured the production of extracellular H2O2, activation of extracellular signal-regulated kinases1/2 (ERK1/2) and p38 MAPKs in human pulmonary artery endothelial cells (HPAEC) treated with urban particles (UP; SRM1648), and assessed the effects of H2O2 on vasoconstriction in pulmonary artery ring and isolated perfused lung. Within minutes after UP treatment, HPAEC increased H2O2 production that could be inhibited by diphenyleneiodonium (DPI), apocynin (APO), and sodium azide (NaN3). The water-soluble fraction of UP as well as its two transition metal components, Cu and V, also stimulated H2O2 production. NaN3 inhibited H2O2 production stimulated by Cu and V, whereas DPI and APO inhibited only Cu-stimulated H2O2 production. Inhibitors of other H2O2-producing enzymes, including Nomega-methyl-L-argnine, indomethacin, allopurinol, cimetidine, rotenone, and antimycin, had no effects. DPI but not NaN3 attenuated UP-induced pulmonary vasoconstriction and phosphorylation of ERK1/2 and p38 MAPKs. Knockdown of p47phox gene expression by small interfering RNA attenuated UP-induced H2O2 production and phosphorylation of ERK1/2 and p38 MAPKs. Intravascular administration of H2O2 generated by glucose oxidase increased pulmonary artery pressure. We conclude that UP induce oxidative stress in vascular endothelial cells by activating NAD(P)H oxidase and the mitochondria. The endothelial oxidative stress may be an important mechanism for PM-induced acute cardiovascular health effects.


Wild bird mortality and West Nile virus surveillance: biases associated with detection, reporting, and carcass persistence.
Surveillance targeting dead wild birds, in particular American crows (Corvus brachyrhynchos), plays a critical role in West Nile virus (WNV) surveillance in the United States. Using crow decoy surrogates, detection and reporting of crow carcasses within urban and rural environments of DeKalb County, Georgia were assessed for potential biases that might occur in the county's WNV surveillance program. In each of two replicated trials, during July and September 2003, 400 decoys were labeled with reporting instructions and distributed along randomly chosen routes throughout designated urban and rural areas within DeKalb County. Information-theoretic methods were used to compare alternative models incorporating the effects of area and trial on probabilities of detection and reporting. The model with the best empirical support included the effects of area on both detection and reporting of decoys. The proportion of decoys detected in the urban area (0.605, SE=0.024) was approximately twice that of the rural area (0.293, SE=0.023), and the proportion of decoys reported in the urban area (0.273, SE=0.023) was approximately three times that of the rural area (0.103, SE=0.028). These results suggest that human density and associated factors can substantially influence dead crow detection and reporting and, thus, the perceived distribution of WNV. In a second and separate study, the persistence and fate of American crow and house sparrow (Passer domesticus) carcasses were assessed in urban and rural environments in Athens-Clarke, Madison, and Oconee counties, Georgia. Two replicated trials using 96 carcasses of each species were conducted during July and September 2004. For a portion of the carcasses, motion sensitive cameras were used to monitor scavenging species visits. Most carcasses (82%) disappeared or were decayed by the end of the 6-day study. Carcass persistence averaged 1.6 days in rural areas and 2.1 days in urban areas. We analyzed carcass persistence rates using a known-fate model framework in program MARK. Model selection based on Akaike's Information Criteria (AIC) indicated that the best model explaining carcass persistence rates included species and number of days of exposure; however, the model including area and number of days of exposure received approximately equal support. Model-averaged carcass persistence rates were higher for urban areas and for crow carcasses. Six mammalian and one avian species were documented scavenging upon carcasses. Dead wild birds could represent potential sources of oral WNV exposure to these scavenging species. Species composition of the scavenger assemblage was similar in urban and rural areas but "scavenging pressure" was greater in rural areas.


Chiral protein scissors activated by light: recognition and protein photocleavage by a new pyrenyl probe.
Strong chiral discrimination and site-selective photocleavage of two model proteins, lysozyme and bovine serum albumin (BSA), by new pyrenyl probes are reported here. The enantiomeric pyrenyl probes D-phenylalanine-1(1-pyrene)methylamide (PMA- D-Phe) and L-phenylalanine-1(1-pyrene)methylamide (PMA- l-Phe) were synthesized by coupling the carboxyl function of D-phenylalanine or L-phenylalanine with the amino group of 1(1-pyrene)methylamine. Binding affinities of the two enantiomers with the proteins were quantitated in absorption titrations. BSA indicated 10-fold selectivity for PMA- D-Phe, and the binding constants for the L- and D-enantiomers were 3.8 x 10(5) and 4.0 x 10(6) M(-1), respectively. Lysozyme, similarly, indicated a 6-fold preference for PMA- D-Phe with binding constants of 3.3 x 10 (5) and 2.0 x 10(6) M(-1) for the L- and D-isomers, respectively. Such strong chiral discrimination illustrates the key role of the chiral center of the probe (Phe) in the binding interactions. The enantiomers were tested to examine how the chiral discrimination for their binding influences reactivity toward protein photocleavage. Irradiation of the probe-protein complexes, at 342 nm in the presence of hexammine cobalt(III) chloride, resulted in the cleavage of the protein backbone. Photocleavage did not proceed in the dark or in the absence of the pyrenyl probes. Both enantiomers indicated low reactivity with BSA (<5% yield), while large photocleavage yields ( approximately 57%) have been noted with lysozyme. This lysozyme photocleavage yield is a significant improvement over previous reports. However, both enantiomers cleaved lysozyme at the same location between Trp108-Val109, despite the strong chiral selectivity for binding. H-atom abstraction from Trp 108, accessible from the active site cleft, could initiate the observed peptide bond cleavage.


Cognitive stimulation for Portuguese older adults with cognitive impairment: a randomized controlled trial of efficacy, comparative duration, feasibility, and experiential relevance.
Although some studies point to cognitive stimulation as a beneficial therapy for older adults with cognitive impairments, this area of research and practice is still lacking dissemination and is underrepresented in many countries. Moreover, the comparative effects of different intervention durations remain to be established and, besides cognitive effects, pragmatic parameters, such as cost-effectiveness and experiential relevance to participants, are seldom explored. In this work, we present a randomized controlled wait-list trial evaluating 2 different intervention durations (standard = 17 vs brief = 11 sessions) of a cognitive stimulation program developed for older adults with cognitive impairments with or without dementia. 20 participants were randomly assigned to the standard duration intervention program (17 sessions, 1.5 months) or to a wait-list group. At postintervention of the standard intervention group, the wait-list group crossed over to receive the brief intervention program (11 sessions, 1 month). Changes in neuropsychological, functionality, quality of life, and caregiver outcomes were evaluated. Experience during intervention and costs and feasibility were also evaluated. The current cognitive stimulation programs (ie, standard and brief) showed high values of experiential relevance for both intervention durations. High adherence, completion rates, and reasonable costs were found for both formats. Further studies are needed to definitively establish the potential efficacy, optimal duration, cost-effectiveness, and experiential relevance for participants of cognitive intervention approaches.


Measuring the health systems impact of disease control programmes: a critical reflection on the WHO building blocks framework.
The WHO health systems Building Blocks framework has become ubiquitous in health systems research. However, it was not developed as a research instrument, but rather to facilitate investments of resources in health systems. In this paper, we reflect on the advantages and limitations of using the framework in applied research, as experienced in three empirical vaccine studies we have undertaken. We argue that while the Building Blocks framework is valuable because of its simplicity and ability to provide a common language for researchers, it is not suitable for analysing dynamic, complex and inter-linked systems impacts. In our three studies, we found that the mechanical segmentation of effects by the WHO building blocks, without recognition of their interactions, hindered the understanding of impacts on systems as a whole. Other important limitations were the artificial equal weight given to each building block and the challenge in capturing longer term effects and opportunity costs. Another criticism is not of the framework per se, but rather how it is typically used, with a focus on the six building blocks to the neglect of the dynamic process and outcome aspects of health systems.We believe the framework would be improved by making three amendments: integrating the missing "demand" component; incorporating an overarching, holistic health systems viewpoint and including scope for interactions between components. If researchers choose to use the Building Blocks framework, we recommend that it be adapted to the specific study question and context, with formative research and piloting conducted in order to inform this adaptation. As with frameworks in general, the WHO Building Blocks framework is valuable because it creates a common language and shared understanding. However, for applied research, it falls short of what is needed to holistically evaluate the impact of specific interventions on health systems. We propose that if researchers use the framework, it should be adapted and made context-specific.


A role for the medial temporal lobe in feedback-driven learning: evidence from amnesia.
The ability to learn from feedback is a key component of adaptive behavior. This type of learning is traditionally thought to depend on neural substrates in the striatum and not on the medial temporal lobe (MTL). Here we show that in humans the MTL becomes necessary for feedback-based learning when feedback is delayed. Specifically, amnesic patients with MTL damage were impaired at probabilistic learning of cue-outcome associations when response-contingent feedback was delayed by a few seconds, but not when feedback was immediate. By contrast, patients with striatal dysfunction due to Parkinson's disease demonstrated the opposite pattern: impaired learning when trial-by-trial feedback was immediate but not when feedback was delayed, indicating that the striatum is necessary for learning only when feedback is immediate. Together, these results reveal that multiple complementary learning processes support what appears to be identical behavior in healthy individuals and point to an important role for the MTL in feedback-driven learning.


Heavy drinking and problem drinking among youth in Uganda: A structural equation model of alcohol marketing, advertisement perceptions and social norms.
To determine the role of alcohol marketing, perceptions of marketing and social norms on heavy alcohol use and problem drinking among vulnerable youth in Uganda. The Kampala Youth Survey is a cross-sectional study conducted in 2014 with service-seeking youth (ages 12-18 years) living in the slums of Kampala (n = 1134) who were participating in Uganda Youth Development Link drop-in centres. Survey measures assessed perceptions of alcohol advertisements, social norms regarding alcohol use, heavy alcohol use and problem drinking. Factor analyses and structural equation models were computed to determine the predictors (e.g. social norms and alcohol marketing exposure) for drinking amounts, heavy drinking and problem drinking. Alcohol marketing allure, perceptions of adults' alcohol attitudes and respondent's male gender were significantly predictive of heavy drinking. Similarly, in addition to drinking amount and heaviness, only alcohol marketing exposure and friends' alcohol attitudes, as well as respondent's own attitudes about alcohol, significantly predicted variation in problem drinking. Alcohol marketing exposure and allure are significant predictors of heavy drinking and problem drinking among youth in Uganda. Prevention programs that reduce exposure to and allure of alcohol marketing may prove promising for reducing alcohol use and related problems among these vulnerable youth in a low-resource setting.


Hyperspectral environmental illumination maps: characterizing directional spectral variation in natural environments.
Objects placed in real-world scenes receive incident light from every direction, and the spectral content of this light may vary from one direction to another. In computer graphics, environmental illumination is approximated using maps that specify illumination at a point as a function of incident angle. However, to-date, existing public databases of environmental illumination specify only three colour channels (RGB). We have captured a new set of 12 environmental illumination maps (eight outdoor scenes; four indoor scenes) using a hyperspectral imaging system with 33 spectral channels. The data reveal a striking directional variation of spectral distribution of lighting in natural environments. We discuss limitations of using daylight models to describe natural environmental illumination.


The outcome of brittle type 1 diabetes--a 20 year study.
To determine the long-term (20 years from presentation) outcome of brittle type 1 diabetes characterized by recurrent episodes of ketoacidosis (DKA). The cohort studied was a group of brittle diabetic patients from various parts of UK originally identified between 1979 and 1985. Patients were traced, where possible, via their diabetic clinics and/or general practitioners. Data on survival or otherwise were obtained from hospital case notes and information from diabetes care team members. For survivors, clinical and demographic information obtained included complication status and whether they still had brittle characteristics. They were also compared with a matched case-control group of type 1 patients with no history of brittle behaviour. The original cohort comprised 33 patients- all female and mean ± SD, aged 18 ± 5 years and diabetes duration 8 ± 4 years. Thirteen were not traceable and 10 of the remaining 20 (50%) had died during the mean 22 years of follow-up. Deaths occurred evenly throughout the period, and causes were chronic renal failure (3), DKA (3), hypoglycaemia (2), subarachnoid haemorrhage (1) and uncertain (1). Age at death ranged from 27 to 45 years. Of the 10 survivors, none remained brittle, but they had a substantial burden of complications. Compared with the non-brittle control group, there was a significant excess of nephropathy and autonomic neuropathy. We conclude that brittle diabetes characterized by recurrent DKA has high long-term outcome mortality. These deaths were premature and almost all diabetes related. Those who survived had resolution of brittleness, but suffered a significant complication burden.