Electron trajectory selection for high harmonic generation inside a short hollow fiber.
The 19th harmonic beam divergences from a Ti:sapphire laser generated using a gas jet and 10-mm-long hollow fibers with bore diameters of 300 and 200 μm were investigated. The beam quality factor M(2) of the harmonic beam generated in a 300-μm hollow fiber was found to be better than the gas jet using the phase match including the atomic dipole phase induced by the short trajectory. On the other hand, a 200-μm hollow fiber was found to generate a more divergent beam with a larger M(2) because of the long trajectory. The electron trajectory contributing to high harmonic generation was selected using the phase-matching process inside a short hollow fiber.


Allergic bronchopulmonary aspergillosis treated successfully for one year with omalizumab.
Current therapy for allergic bronchopulmonary aspergillosis (ABPA) uses oral corticosteroids, exposing patients to the adverse effects of these agents. There are reports of the steroid-sparing effect of anti-IgE therapy with omalizumab for ABPA in patients with cystic fibrosis (CF), but there is little information on its efficacy against ABPA in patients with bronchial asthma without CF. To examine the effects of omalizumab, measured by asthma control, blood eosinophilia, total serum immunoglobulin E (IgE), oral corticosteroid requirements, and forced expiratory volume spirometry in patients with ABPA and bronchial asthma. A retrospective review of charts from 2004-2006 of patients treated with omalizumab at an academic allergy and immunology practice in the Bronx, New York were examined for systemic steroid and rescue inhaler usage, serum immunoglobulin E levels, blood eosinophil counts, and asthma symptoms, as measured by the Asthma Control Test (ACT). A total of 21 charts were screened for the diagnosis of ABPA and bronchial asthma. Four patients with ABPA were identified; two of these patients were male. The median monthly systemic corticosteroid use at 6 months and 12 months decreased from baseline usage. Total serum IgE decreased in all patients at 12 months of therapy. Pre-bronchodilator forced expiratory vital capacity at one second (FEV(1)) was variable at 1 year of treatment. There was an improvement in Asthma Control Test (ACT) symptom scores for both daytime and nighttime symptoms. Treatment with omalizumab creates a steroid-sparing effect, reduces systemic inflammatory markers, and results in improvement in ACT scores in patients with ABPA.


Evaluation of the feasibility of international growth standards for school-aged children and adolescents.
The development of an international growth standard for the screening, surveillance, and monitoring of school-aged children and adolescents has been motivated by 2 contemporaneous events, the global surge in childhood obesity and the release of a new international growth standard for infants and preschool children by the WHO. If a prescriptive approach analogous to that taken by WHO for younger children is to be adopted for school-aged children and adolescents, several issues need to be addressed regarding the universality of growth potential across populations and the definition of optimal growth in children and adolescents. A working group of experts in growth and development and representatives from international organizations concluded that subpopulations exhibit similar patterns of growth when exposed to similar external conditioners of growth. However, based on available data, we cannot rule out that observed differences in linear growth across ethnic groups reflect true differences in genetic potential rather than environmental influences. Therefore, the sampling frame for the development of an international growth standard for children and adolescents must include multiethnic sampling strategies designed to capture the variation in human growth patterns. A single international growth standard for school-aged children and adolescents could be developed with careful consideration of the population and individual selection criteria, study design, sample size, measurements, and statistical modeling of primary growth and secondary ancillary data. The working group agreed that existing growth references for school-aged children and adolescents have shortcomings, particularly for assessing obesity, and that appropriate growth standards for these age groups should be developed for clinical and public health applications.


A cluster randomised controlled trial of advice, exercise or multifactorial assessment to prevent falls and fractures in community-dwelling older adults: protocol for the prevention of falls injury trial (PreFIT).
Falls are the leading cause of accident-related mortality in older adults. Injurious falls are associated with functional decline, disability, healthcare utilisation and significant National Health Service (NHS)-related costs. The evidence base for multifactorial or exercise interventions reducing fractures in the general population is weak. This protocol describes a large-scale UK trial investigating the clinical and cost-effectiveness of alternative falls prevention interventions targeted at community dwelling older adults. A three-arm, pragmatic, cluster randomised controlled trial, conducted within primary care in England, UK. Sixty-three general practices will be randomised to deliver one of three falls prevention interventions: (1) advice only; (2) advice with exercise; or (3) advice with multifactorial falls prevention (MFFP). We aim to recruit over 9000 community-dwelling adults aged 70 and above. Practices randomised to deliver advice will mail out advice booklets. Practices randomised to deliver 'active' interventions, either exercise or MFFP, send all trial participants the advice booklet and a screening survey to identify participants with a history of falling or balance problems. Onward referral to 'active' intervention will be based on falls risk determined from balance screen. The primary outcome is peripheral fracture; secondary outcomes include number with at least one fracture, falls, mortality, quality of life and health service resource use at 18 months, captured using self-report and routine healthcare activity data. The study protocol has approval from the National Research Ethics Service (REC reference 10/H0401/36; Protocol V.3.1, 21/May/2013). User groups and patient representatives were consulted to inform trial design. Results will be reported at conferences and in peer-reviewed publications. A patient-friendly summary of trial findings will be published on the prevention of falls injury trial (PreFIT) website. This protocol adheres to the recommended SPIRIT Checklist. Amendments will be reported to relevant regulatory parties. ISRCTN 71002650; Pre-results.


Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages.
Neurons in the macaque brain arise from progenitors located near the cerebral ventricles in a temporally segregated manner such that lethal doses of ionizing irradiation, if administered over a discrete time interval, can deplete individual nuclei selectively. A previous study showed that neuron number in the dorsal lateral geniculate nucleus is reduced following early gestational exposure to x-irradiation (Algan and Rakic [1997] J. Comp. Neurol. 12:335-352). Here we examine whether similarly timed irradiation decreases neuron number in three associational thalamic nuclei: mediodorsal (MD), anterior, and pulvinar. Ten macaques were exposed to multiple doses of x-rays (total exposure (175-350 cGy) in early gestation (E33-E42) or midgestation (E70-E90); eight nonirradiated macaques were controls. Only the early-irradiated monkeys, not the midgestationally irradiated animals, exhibited deficits in whole-thalamic neuron (-15%) and glia numbers (-21%) compared with controls. Reduction of neuron number (-26%) and volume (-29%) was particularly pronounced in MD. In contrast, cell number and volume were not significantly decreased in the anterior or pulvinar nuclei following early gestational irradiation. Thus, reduced thalamic neuron number was associated specifically with irradiation in early gestation. Persistence of the thalamic neuronal deficit in adult animals indicates that prenatally deleted neurons had not been replenished during maturation or in adulthood. The selective reduction of MD neuron number also supports the protomap hypothesis that neurons of each thalamic nucleus originate sequentially from separate lines of neuronal stem cells (Rakic [1977a] J. Comp. Neurol. 176:23-52). The early gestationally irradiated macaque is discussed as a potentially useful model for studying the neurodevelopmental pathogenesis of schizophrenia.


Substance P selectively activates TNF-alpha gene expression in murine mast cells.
There is increasing evidence that the neurologic system is capable of modulating a wide range of immunologic responses, including certain inflammatory processes in the lung, gastrointestinal tract, and skin. It has been proposed that secreted neuropeptides such as substance P (SP) may mediate these neuroinflammatory interactions by binding to and stimulating immune cells such as mast cells and lymphoid cells. SP is secreted in a variety of tissues by an extensive network of neurosensory C and A5 fibers in response to a wide range of noxious stimuli and injury. Previous studies to examine the effect of SP on mast cells have focused on its role in triggering histamine release and mediating immediate hypersensitivity responses. Recently it was demonstrated that mast cells are also capable of secreting multiple cytokines including TNF-alpha, IL-1, IL-3, IL-4, IL-6, and GM-CSF. In this study we tested the possibility that SP may also influence mast cell-mediated late inflammatory events by modulating the production of one or several of these cytokines. Our results indicate that SP induces TNF-alpha mRNA expression and TNF-alpha secretion in a dose-dependent manner in a murine mast cell line, CFTL12. Likewise, SP stimulates TNF-alpha secretion in freshly isolated murine peritoneal mast cells. The induction of mast cell TNF-alpha is selective, since SP does not stimulate the production of IL-1, IL-3, IL-4, IL-6, or GM-CSF in these cells. The CFTL 12 mast cell line constitutively expresses high levels of SP receptor mRNA which is not modulated by PMA/cycloheximide treatment or SP. These results further support the concept that the neurologic system modulates inflammatory events by neuropeptide-mediated mast cell cytokine release.


High rate of preterm birth in pregnancies complicated by rheumatoid arthritis.
To describe the outcomes of pregnancies complicated by rheumatoid arthritis (RA) and to estimate potential associations between disease characteristics and pregnancy outcomes. We reviewed all pregnancies complicated by RA delivered at our institution from June 2001 through June 2009. Fisher exact tests were used to calculate odds ratios. Univariable regression was performed using STATA 10.1 (StataCorp, College Station, TX). A p value of ≤ 0.05 was considered statistically significant. Forty-six pregnancies in 40 women were reviewed. Sixty percent of pregnancies had evidence of disease flare and 28% delivered prior to 37 weeks. We did not identify associations between preterm birth and active disease at conception or during pregnancy. In univariate analysis, discontinuation of medication because of pregnancy was associated with a significantly earlier gestational age at delivery (362/7 versus 383/7 weeks, p = 0.022). Women with RA may be at higher risk for preterm delivery.


Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: a Joint Statement by International Diabetes Organizations.
Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ≥40 kg/m2) and in those with class II obesity (BMI 35.0-39.9 kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m2 for Asian patients. Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.


Case of Progressive Keratoconus With Newly Diagnosed Pellucid Marginal Degeneration After Corneal Cross-Linking.
The purpose of this study was to document, to our knowledge, the first reported case of keratoconus progression accompanied with newly diagnosed pellucid marginal degeneration after corneal cross-linking (CXL). A novel case of further keratoconus progression plus development of pellucid marginal degeneration in the same eye after CXL was documented with supporting evidence from Scheimpflug and optical coherence tomography imaging. A male patient was diagnosed with progressive keratoconus in the left eye and treated with CXL when aged 25 years. Although strongly cautioned not to rub his eyes, he admitted that he continued eye rubbing in association with atopic disease. At a follow-up examination 3.5 years after CXL, progressive keratoconus was detected and pellucid marginal degeneration was newly diagnosed in the left eye. The eye was retreated with CXL. This case illustrates that progressive keratoconus and pellucid marginal degeneration can occur in the same eye after CXL and demonstrates the deleterious effects that can develop with continued eye rubbing.


Convulsions associated with gastroenteritis in the spectrum of benign focal epilepsies in infancy: 30 cases including four cases with ictal EEG recording.
Benign convulsions associated with gastroenteritis are now recognized as a clinical entity, characterized by an acute cluster of afebrile seizures during an episode of mild diarrhoea with excellent prognosis. We observed 30 children who each experienced at least two seizures associated with mild gastroenteritis. The inclusion criteria were: afebrile seizures during gastroenteritis, dehydration at ≤ 5%, normal neurological findings, normal psychomotor development and no underlying pathology according to laboratory and neuroimaging studies. Mean age was 21 months (range: 6-38). Familial history for epilepsy was positive in 3/30 (10%) and for febrile convulsions in 11/30 (36.6%). Seizure onset was mainly on the third day of gastroenteritis. Seizures were described as generalised by parents in 16/30 patients (53.3%). We directly observed seizures in 14/30 patients (47.7%), and the semiology was partial with secondary generalisation. Focal onset was confirmed in two patients by EEG and in two patients by video-EEG recording. Twenty of 30 patients (66.6%) received antiepileptic drugs during the acute phase. Ten patients (33.3%) received no treatment. During follow-up (mean duration: 53 months), one patient had an isolated afebrile seizure and two others a febrile seizure. At the end of follow-up, antiepileptic treatment was withdrawn for all but two patients. None developed epilepsy. Although the pathogenesis of this clinical entity is unknown, we hypothesize that mild gastroenteritis may provoke a transient brain dysfunction which in turn provokes seizures in children with genetically determined susceptibility.


Evidence of a substantial genetic basis for risk of adult periodontitis.
A few previous studies have suggested that risk for adult periodontitis (AP) has a genetic (heritable) component. We estimated genetic and environmental variances and heritability for gingivitis and adult periodontitis using data from twins reared together. One hundred seventeen (117) pairs of adult twins (64 monozygotic [MZ] and 53 dizygotic [DZ] pairs) were recruited. Probing depth (PD), attachment loss (AL), plaque, and gingivitis (GI) were assessed on all teeth by two examiners. Measurements were averaged over all sites, teeth, and examiners. Extent of disease in subjects was defined at four thresholds: the percentage of teeth with AL > or = 2, AL > or = 3, PD > or = 4, or PD > or = 5 mm. Genetic and environmental variances and heritability were estimated using path models with maximum likelihood estimation techniques. MZ twins were more similar than DZ twins for all clinical measures. Statistically significant genetic variance was found for both the severity and extent of disease. AP was estimated to have approximately 50% heritability, which was unaltered following adjustments for behavioral variables including smoking. In contrast, while MZ twins were also more similar than DZ twins for gingivitis scores, there was no evidence of heritability for gingivitis after behavioral covariates such as utilization of dental care and smoking were incorporated into the analyses. These results confirm previous studies and indicate that approximately half of the variance in disease in the population is attributed to genetic variance. The basis for the heritability of periodontitis appears to be biological and not behavioral in nature.


Developing and testing a cost data collection instrument for noncommunicable disease registry planning.
This article reports on the methods and framework we have developed to guide economic evaluation of noncommunicable disease registries. We developed a cost data collection instrument, the Centers for Disease Control and Prevention's (CDC's) International Registry Costing Tool (IntRegCosting Tool), based on established economics methods We performed in-depth case studies, site visit interviews, and pilot testing in 11 registries from multiple countries including India, Kenya, Uganda, Colombia, and Barbados to assess the overall quality of the data collected from cancer and cardiovascular registries. Overall, the registries were able to use the IntRegCosting Tool to assign operating expenditures to specific activities. We verified that registries were able to provide accurate estimation of labor costs, which is the largest expenditure incurred by registries. We also identified several factors that can influence the cost of registry operations, including size of the geographic area served, data collection approach, local cost of living, presence of rural areas, volume of cases, extent of consolidation of records to cases, and continuity of funding. Internal and external registry factors reveal that a single estimate for the cost of registry operations is not feasible; costs will vary on the basis of factors that may be beyond the control of the registries. Some factors, such as data collection approach, can be modified to improve the efficiency of registry operations. These findings will inform both future economic data collection using a web-based tool and cost and cost-effectiveness analyses of registry operations in low- and middle-income countries (LMICs) and other locations with similar characteristics.


IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes.
IL-10 affects monocytes and T cells by driving the progression of immune responsiveness such that Th2 lymphocyte-mediated effects predominate. In this report, we show that in monocytes and T cells IL-10 stimulates tyrosine phosphorylation of the signal transducers and activators of transcription, STAT1 alpha and STAT3, in a differential manner such that the relative formation of homo- and heterodimers varies between the two cell types. Moreover, monocytes express a novel IL-10-stimulated STAT protein with an M(r) of 70 kDa that is recognized by the anti-STAT3 Ab but is not observed in T cells. IL-10 treatment of both T cells and monocytes results in the ligand-induced tyrosine phosphorylation of tyk2 and Jak1, but not Jak2 or Jak3. Selective modulation of immune responsiveness by IL-10 in cells such as monocytes and T cells may result in part from the differential activation of STAT protein pairs.


Dysregulation of the epigenetic regulator SETDB1 in liver carcinogenesis-more than one way to skin a cat.
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers worldwide. Its development is considered a step-wise process in which genetic and epigenetic alterations lead to the activation of oncogenes and the inactivation of tumor suppressor genes. In contrast to genetic alterations, epigenetic changes that include aberrant methylation, histone modification and RNA interference do not alter the genetic code, but affect the level of mRNA transcripts. In addition, these epigenetic alterations may influence each other. In their elegant study, Wong et al. analyzed the expression of 591 known epigenetic regulators in human HBV-induced HCC by transcriptome sequencing. They identified SETDB1 as the most significantly up-regulated epigenetic regulator in human HCC. In their cohort SETDB1 overexpression was associated with metastasis formation and poorer prognosis of HCC patients. Interestingly, the authors observed several complementary mechanisms contributing to the upregulation of SETDB1 in HCC cells. Besides copy number gains at the SETDB1 gene locus at chromosome 1q21 enhanced SETDB1 transcription mediated by the transcription factor SP1 could be detected. Finally, Wong and colleagues showed that SETDB1 is a target of miR-29, which is frequently downregulated in human HCCs. Taken together, SETDB1 overexpression is mediated by several complementary acting mechanisms suggesting that upregulation of SETDB1 may be a hallmark of HCC progression. This study warrants for independent validation, analyses of a larger series of non-HBV-associated human HCCs, and for further testing of methyltransferase inhibitors as well as molecules targeting SETDB1 in (pre-)clinical studies.


PI3K pathway inhibitors: better not left alone.
The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations.


Functional organization of ferret auditory cortex.
We characterized the functional organization of different fields within the auditory cortex of anaesthetized ferrets. As previously reported, the primary auditory cortex, A1, and the anterior auditory field, AAF, are located on the middle ectosylvian gyrus. These areas exhibited a similar tonotopic organization, with high frequencies represented at the dorsal tip of the gyrus and low frequencies more ventrally, but differed in that AAF neurons had shorter response latencies than those in A1. On the basis of differences in frequency selectivity, temporal response properties and thresholds, we identified four more, previously undescribed fields. Two of these are located on the posterior ectosylvian gyrus and were tonotopically organized. Neurons in these areas responded robustly to tones, but had longer latencies, more sustained responses and a higher incidence of non-monotonic rate-level functions than those in the primary fields. Two further auditory fields, which were not tonotopically organized, were found on the anterior ectosylvian gyrus. Neurons in the more dorsal anterior area gave short-latency, transient responses to tones and were generally broadly tuned with a preference for high (>8 kHz) frequencies. Neurons in the other anterior area were frequently unresponsive to tones, but often responded vigorously to broadband noise. The presence of both tonotopic and non-tonotopic auditory cortical fields indicates that the organization of ferret auditory cortex is comparable to that seen in other mammals.


Broadening the use of antiretroviral therapy: the case for feline leukemia virus.
Antiretroviral drugs have saved and extended the lives of millions of individuals infected with HIV. The major classes of anti-HIV drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry/fusion inhibitors. While antiretroviral drug regimens are not commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of companion felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. Here, we discuss FeLV biology and current treatment options, and propose that there is a need for antiretroviral treatment options for FeLV infection. The comparative use and analysis of antiretroviral therapy can provide new insights into the mechanism of antiretroviral drug action.


Ocean currents shape the microbiome of Arctic marine sediments.
Prokaryote communities were investigated on the seasonally stratified Alaska Beaufort Shelf (ABS). Water and sediment directly underlying water with origin in the Arctic, Pacific or Atlantic oceans were analyzed by pyrosequencing and length heterogeneity-PCR in conjunction with physicochemical and geographic distance data to determine what features structure ABS microbiomes. Distinct bacterial communities were evident in all water masses. Alphaproteobacteria explained similarity in Arctic surface water and Pacific derived water. Deltaproteobacteria were abundant in Atlantic origin water and drove similarity among samples. Most archaeal sequences in water were related to unclassified marine Euryarchaeota. Sediment communities influenced by Pacific and Atlantic water were distinct from each other and pelagic communities. Firmicutes and Chloroflexi were abundant in sediment, although their distribution varied in Atlantic and Pacific influenced sites. Thermoprotei dominated archaea in Pacific influenced sediments and Methanomicrobia dominated in methane-containing Atlantic influenced sediments. Length heterogeneity-PCR data from this study were analyzed with data from methane-containing sediments in other regions. Pacific influenced ABS sediments clustered with Pacific sites from New Zealand and Chilean coastal margins. Atlantic influenced ABS sediments formed another distinct cluster. Density and salinity were significant structuring features on pelagic communities. Porosity co-varied with benthic community structure across sites and methane did not. This study indicates that the origin of water overlying sediments shapes benthic communities locally and globally and that hydrography exerts greater influence on microbial community structure than the availability of methane.


Development and assessment of an optimized next-generation DNA sequencing approach for the mtgenome using the Illumina MiSeq.
The development of molecular tools to detect and report mitochondrial DNA (mtDNA) heteroplasmy will increase the discrimination potential of the testing method when applied to forensic cases. The inherent limitations of the current state-of-the-art, Sanger-based sequencing, including constrictions in speed, throughput, and resolution, have hindered progress in this area. With the advent of next-generation sequencing (NGS) approaches, it is now possible to clearly identify heteroplasmic variants, and at a much lower level than previously possible. However, in order to bring these approaches into forensic laboratories and subsequently as accepted scientific information in a court of law, validated methods will be required to produce and analyze NGS data. We report here on the development of an optimized approach to NGS analysis for the mtDNA genome (mtgenome) using the Illumina MiSeq instrument. This optimized protocol allows for the production of more than 5 gigabases of mtDNA sequence per run, sufficient for detection and reliable reporting of minor heteroplasmic variants down to approximately 0.5-1.0% when multiplexing twelve samples. Depending on sample throughput needs, sequence coverage rates can be set at various levels, but were optimized here for at least 5000 reads. In addition, analysis parameters are provided for a commercially available software package that identify the highest quality sequencing reads and effectively filter out sequencing-based noise. With this method it will be possible to measure the rates of low-level heteroplasmy across the mtgenome, evaluate the transmission of heteroplasmy between the generations of maternal lineages, and assess the drift of variant sequences between different tissue types within an individual.


Long-Term Determinants of the Seroprevalence of Toxoplasma gondii in a Wild Ungulate Community.
Toxoplasma gondii is an obligate intracellular protozoan which infects warm-blooded vertebrates, including humans, worldwide. In the present study, the epidemiology of T. gondii was studied in the wild ungulate host community (wild boar, red deer, and fallow deer) of Doñana National Park (DNP, south-western Spain) for 13 years (2005-2018). We assessed several variables which potentially operate in the medium and long-term (environmental features, population, and stochastic factors). Overall, the wild ungulate host community of DNP had high seroprevalence values of T. gondii (STG; % ± confidence interval (CI) 95%; wild boar (Sus scrofa) 39 ± 3.3, n = 698; red deer (Cervus elaphus) 30.7 ± 4.4, n = 423; fallow deer (Dama dama) 29.7 ± 4.2, n = 452). The complex interplay of hosts and ecological/epidemiological niches, together with the optimal climatic conditions for the survival of oocysts that converge in this area may favor the spread of the parasite in its host community. The temporal evolution of STG oscillated considerably, mostly in deer species. The relationships shown by statistical models indicated that several factors determined species patterns. Concomitance of effects among species, indicated that relevant drivers of risk operated at the community level. Our focus, addressing factors operating at broad temporal scale, allows showing their impacts on the epidemiology of T. gondii and its trends. This approach is key to understanding the epidemiology and ecology to T. gondii infection in wild host communities in a context where the decline in seroprevalence leads to loss of immunity in humans.


AcSDKP regulates cell proliferation through the PI3KCA/Akt signaling pathway.
The natural tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) is generated from the N-terminus of thymosin-β4 through enzymatic cleavage by prolyl oligopeptidase (POP). AcSDKP regulation of proliferation of different cells is implicated in hematopoiesis and angiogenesis. This tetrapeptide present in almost all cells was recently detected at elevated concentrations in neoplastic diseases. However, previously reported in vitro and in vivo studies indicate that AcSDKP does not contribute to the pathogenesis of cancers. Here we show that exogenous AcSDKP exerts no effect on the proliferation of actively dividing malignant cells. Using S17092, a specific POP inhibitor (POPi), to suppress the biosynthesis of AcSDKP in U87-MG glioblastoma cells characterized by high intracellular levels of this peptide, we found that all tested doses of POPi resulted in an equally effective depletion of AcSDKP, which was not correlated with the dose-dependent decreases in the proliferation rate of treated cells. Interestingly, addition of exogenous AcSDKP markedly reversed the reduction in the proliferation of U87-MG cells treated with the highest dose of POPi, and this effect was associated with activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. However, extracellular-regulated protein kinase (ERK) activation was unaltered by S17092 and AcSDKP co-treatment. Knockdown of individual PI3K catalytic subunits revealed that p110α and p110β contributed differently to AcSDKP regulation of U87-MG cell proliferation. Disruption of p110α expression by small interfering RNA (siRNA) abrogated AcSDKP-stimulated Akt phosphorylation, whereas knockdown of p110β expression exhibited no such effect. Our findings indicate for the first time that the PI3KCA/Akt pathway mediates AcSDKP regulation of cell proliferation and suggest a role for this ubiquitous intracellular peptide in cell survival.


Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury.
Numerous red blood cells are generated every second from proliferative progenitor cells under a homeostatic state. Increased erythropoietic activity is required after myelo-suppression as a result of chemo-radio therapies. Our previous study revealed that the endothelial cell-selective adhesion molecule (ESAM), an authentic hematopoietic stem cell marker, plays essential roles in stress-induced hematopoiesis. To determine the physiological importance of ESAM in erythroid recovery, ESAM-knockout (KO) mice were treated with the anti-cancer drug, 5-fluorouracil (5-FU). ESAM-KO mice experienced severe and prolonged anemia after 5-FU treatment compared to wild-type (WT) mice. Eight days after the 5-FU injection, compared to WT mice, ESAM-KO mice showed reduced numbers of erythroid progenitors in bone marrow (BM) and spleen, and reticulocytes in peripheral blood. Megakaryocyte-erythrocyte progenitors (MEPs) from the BM of 5-FU-treated ESAM-KO mice showed reduced burst forming unit-erythrocyte (BFU-E) capacities than those from WT mice. BM transplantation revealed that hematopoietic stem/progenitor cells from ESAM-KO donors were more sensitive to 5-FU treatment than that from WT donors in the WT host mice. However, hematopoietic cells from WT donors transplanted into ESAM-KO host mice could normally reconstitute the erythroid lineage after a BM injury. These results suggested that ESAM expression in hematopoietic cells, but not environmental cells, is critical for hematopoietic recovery. We also found that 5-FU treatment induces the up-regulation of ESAM in primitive erythroid progenitors and macrophages that do not express ESAM under homeostatic conditions. The phenotypic change seen in macrophages might be functionally involved in the interaction between erythroid progenitors and their niche components during stress-induced acute erythropoiesis. Microarray analyses of primitive erythroid progenitors from 5-FU-treated WT and ESAM-KO mice revealed that various signaling pathways, including the GATA1 system, were impaired in ESAM-KO mice. Thus, our data demonstrate that ESAM expression in hematopoietic progenitors is essential for erythroid recovery after a BM injury.


Effects of hypertonic saline, HAES and dimethylsulphoxide on free oxygen radicals in haemorrhagic shock oxygen radicals in haemorrhagic shock.
The aim of this study was to investigate the effects of antioxidant and resuscitation fluids which were used during haemorrhagic shock on tissue ischemia. Forty New Zealand type rabbits were divided into four groups as C (control), I (hypertonic saline), H (HAES) and D (Dimethylsulphoxide-DMSO). Haemorrhagic shock was induced by bleeding from carotid artery. Thirty minutes after shock, Group C was not resuscitated while Group I was resuscitated with Hypertonic saline 7.2, Group H with 10 % HAES and Group D with HAES 10 % and DMSO. Thiobarbituric acid reactive substances (TBARS) and lactate levels in blood, liver and small bowel samples were measured. There were no significant differences among the groups tissue and plasma TBARS and lactate levels. Resuscitation fluids and addition of antioxidants to the resuscitation fluids do not have any superiorities over each other to prevent tissue ischemic insult in haemorrhagic shock.


A broken heart in a broken car.
Takotsubo syndrome (TTS) is still a relatively understudied and often undetected disease. It is usually preceded by emotional or physical triggers. We here report a case of TTS following a car accident. Typical apical ballooning with moderate reduction of left ventricular ejection fraction (LVEF) and increased level of pro-B-type natriuretic peptide (BNP) as well as slightly increased creatine kinase and troponin T values were found in this 76-year-old female patient, 6 h after a car accident. At 10 weeks follow-up, we observed a normalization of regional wall motion, LVEF, electrocardiogram and pro-BNP. TTS is an acute heart failure syndrome and an important differential diagnosis of acute coronary syndrome.


Living with schizophrenia: Health-related quality of life among primary family caregivers.
To examine influencing factors of health-related quality of life in primary family caregivers of people with schizophrenia receiving inpatient psychiatric rehabilitation services. Families, particularly primary family caregivers, have become more important than ever in mental health care. Yet, research on health-related quality of life among primarily family caregivers is limited. A correlational study design was used. A convenience sample of 122 primary family caregivers participated in the study. Data were analysed with descriptive statistics, Pearson's product-moment correlation, t test, one-way analysis of variance and a hierarchical multiple regression analysis. Primary family caregivers who were parents, older, less educated, and had a lower monthly household income, increased affiliate stigma and decreased quality of family-centred care experienced poor health-related quality of life. Particularly, monthly household income, affiliate stigma and quality of family-centred care appeared to be the most critical determinants of health-related quality of life. Efforts to enhance satisfaction of life should focus on reducing affiliate stigma as well as increasing monthly household income and strengthening the quality of family-centred care. Findings may assist in the development of culturally integrated rehabilitation programmes to decrease affiliate stigma and increase family engagement as a means of promoting quality of life for primary family caregivers living with people who have schizophrenia.


Vitreal Cytokine Profile Differences Between Eyes With Epiretinal Membranes or Macular Holes.
Cytokines play an important role in cell signaling in inflammatory and repair processes, also within the posterior segment of the eye. These molecules are thus implicated in the pathophysiology of several vitreoretinal diseases. In the present study, we compared vitreal cytokine profiles in patients with idiopathic epiretinal membranes (ERMs) and idiopathic full-thickness macular holes (MHs) without epiretinal membranes. Native vitreal humor was collected during elective pars plana vitrectomy for the treatment of macular pathologies (group 1: ERM; group 2: MH) from patients without any other ocular or systemic disease. The concentrations of 43 chemokines and cytokines were measured in parallel by multiplex beads analysis. Intergroup comparisons were conducted using the Mann-Whitney U test and Bonferroni's correction, at a level of significance of P < 0.0012. Vitreal samples from 31 patients with ERMs (group 1) and from 30 with MHs (group 2) were analyzed. For 12 of the tested cytokines (GM-CSF, MCP-1, MIF, CCL15, CCL20, CCL17, CX3CL1, CXCL10, CXCL16, and TGF-β-1, -2, and -3), no intergroup differences were revealed; for the other 31, the concentrations were higher in the ERM than in the MH group (P < 0.0012 in each case). The vitreal levels of 72% of the tested cytokines were higher in ERM than in MH. This indicates that even in the absence of clinical markers, activation of inflammatory and profibrotic mechanisms is implicated in the progression of ERMs. Although frequently used as such in the past, eyes with ERMs should be considered with caution as a healthy control group.


Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood.
Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high-, and low-impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome-wide association study (GWAS)-implicated BMD variants. We used dual-energy X-ray absorptiometry to estimate femoral neck, total hip, and spine areal-BMD and total body less head (TBLH) bone mineral content (BMC) Z-scores. The BMD genetic score was negatively associated with each bone Z-score (eg, TBLH-BMC: estimate = -0.03, p = 1.3 × 10(-6) ). Total PA was positively associated with bone Z-scores; these associations were driven by time spent in high-impact PA (eg, TBLH-BMC: estimate = 0.05, p = 4.0 × 10(-10) ) and were observed even for children with lower than average bone Z-scores. We found no evidence of PA-adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA-genetic score-Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH-BMC in males (p interaction = 7.1 × 10(-5) ), where PA was associated with higher TBLH-BMC Z-score among the BMD-lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10(-9) ). In conclusion, the beneficial effect of PA on bone, especially high-impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS-implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.


Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres.
The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.


Symptom distress, catastrophic thinking, and hope in nasopharyngeal carcinoma patients.
The purposes of this study were to explore symptom distress, catastrophic thinking (catastrophizing) and hope, and factors predicting hope in Taiwanese nasopharyngeal carcinoma (NPC) patients within 3 years of receiving radiation therapy (RT). Instruments used were the modified Symptom Distress Scale, disease catastrophizing scale (modified from Coping Strategies Questionnaire), and Herth's Hope Index. Adult NPC patients (N = 115; 33 undergoing RT, 44 who completed RT within 1 year, and 38 who completed RT more than 1 year but less than 3 years) were recruited from an outpatient RT center in Northern Taiwan. Although participants' overall symptom distress was mild to moderate, they scored moderate level for several distressful symptoms: dry mouth, fatigue, hearing difficulty, loss of appetite, insomnia, and pain. Patients undergoing RT had greater symptom distress than subjects in the other 2 groups. Regression analysis revealed that catastrophizing was the only predictor of hope. Patients who engaged in catastrophizing reported much lower levels of hope. Particular care and attention are recommended to help NPC patients deal with the top distressful symptoms listed. Nursing interventions to reduce catastrophic thinking and enhance hope are discussed.


Tele-dietetics with food images as dietary intake record in nutrition assessment.
Tele-dietetic is not common in current practice. To promote this, food images as dietary intake records should be validated before application. Two-dimensional (2D) digital images are reliable and have been validated in previous studies. However, the depth is virtual with a 2D image. And ingredient types, sauce types, cooking methods, and amount of oil added have not been researched for accurate food analysis. This study was designed to compare the reliability and accuracy of these parameters estimated using 2D and three-dimensional (3D) food images. Ten nutritionists evaluated 10 selected food items between January 2008 and June 2008. Ten 2D food images and ten 3D images of the same food items were captured for the observers' evaluation. The actual weightings or volume of the food items were measured as the gold standard for comparisons. Intraclass correlations (ICCs), percentage agreement, and one-sample t-tests were analyzed to compare the reliability and accuracy of each type of images. Both images showed high reliability among observers with 3D images giving less variance (2D: ICC=0.916, F=17.001, p<0.001; 3D: ICC=0.846, F=6.501, p<0.001). Both images resulted in good ingredient and cooking method identification, but 3D was better in identifying sauce type. 2D images provided better volume and oil estimation when compared with 3D images. The research findings confirmed the application of 2D and 3D food images as reliable and accurate dietary records for nutritionists to evaluate clients' dietary habits. This implied the feasibility of tele-dietetics that one's nutrition status could be assessed over the Internet.


Hydra, a niche for cell and developmental plasticity.
The silencing of genes whose expression is restricted to specific cell types and/or specific regeneration stages opens avenues to decipher the molecular control of the cellular plasticity underlying head regeneration in hydra. In this review, we highlight recent studies that identified genes involved in the immediate cytoprotective function played by gland cells after amputation; the early dedifferentiation of digestive cells into blastema-like cells during head regeneration, and the early late proliferation of neuronal progenitors required for head patterning. Hence, developmental plasticity in hydra relies on spatially restricted and timely orchestrated cellular modifications, where the functions played by stem cells remain to be characterized.


Infectious complications in OIF/OEF veterans with traumatic brain injury.
Of veterans from the U.S. Global War on Terrorism who have sought care in the Department of Veterans Affairs, approximately 12% have an infectious disease diagnosis. Infections in those veterans with traumatic brain injury (TBI) include infections associated with blast injuries and burns, such as skin and soft tissue infections; infections as a result of retained bullet or shrapnel fragments; pulmonary infections resulting from lung injury, intubation, or resultant tracheostomy; hospital-acquired infections, such as those associated with methicillin-resistant Staphylococcus aureus and other antimicrobial resistant organisms such as Acinetobacter baumannii; and infections from implanted prosthetic devices, such as metal hardware or skull flaps. Longer-term cognitive impairment may result in behaviors that place veterans with TBI at risk for human immunodeficiency virus or hepatitis C virus infections. Finally, chronic infections acquired abroad, such as cutaneous leishmaniasis or Q-fever, may be diagnosed after veterans return to the United States. These infections present challenges in terms of added morbidity and costs associated with complex antimicrobial management; isolation requirements; and surgical procedures, such as those to remove infected retained fragments or prosthetic devices. In this review, providers will become more familiar with the scope and complexity of infectious disease management in veterans with TBI.


Students' intelligence test results after six and sixteen months of irregular schooling due to the COVID-19 pandemic.
The COVID-19 pandemic has affected schooling worldwide. In many places, schools closed for weeks or months, only part of the student body could be educated at any one time, or students were taught online. Previous research discloses the relevance of schooling for the development of cognitive abilities. We therefore compared the intelligence test performance of 424 German secondary school students in Grades 7 to 9 (42% female) tested after the first six months of the COVID-19 pandemic (i.e., 2020 sample) to the results of two highly comparable student samples tested in 2002 (n = 1506) and 2012 (n = 197). The results revealed substantially and significantly lower intelligence test scores in the 2020 sample than in both the 2002 and 2012 samples. We retested the 2020 sample after another full school year of COVID-19-affected schooling in 2021. We found mean-level changes of typical magnitude, with no signs of catching up to previous cohorts or further declines in cognitive performance. Perceived stress during the pandemic did not affect changes in intelligence test results between the two measurements.


Carrier-mediated processes in blood--brain barrier penetration and neural uptake of paraquat.
Due to the structural similarity to N-methyl-4-phenyl pyridinium (MPP(+)), paraquat might induce dopaminergic toxicity in the brain. However, its blood--brain barrier (BBB) penetration has not been well documented. We studied the manner of BBB penetration and neural cell uptake of paraquat using a brain microdialysis technique with HPLC/UV detection in rats. After subcutaneous administration, paraquat appeared dose-dependently in the dialysate. In contrast, MPP(+) could not penetrate the BBB in either control or paraquat pre-treated rats. These data indicated that the penetration of paraquat into the brain would be mediated by a specific carrier process, not resulting from the destruction of BBB function by paraquat itself or a paraquat radical. To examine whether paraquat was carried across the BBB by a certain amino acid transporter, L-valine or L-lysine was pre-administered as a co-substrate. The pre-treatment of L-valine, which is a high affinity substrate for the neutral amino acid transporter, markedly reduced the BBB penetration of paraquat. When paraquat was administered to the striatum through a microdialysis probe, a significant amount of paraquat was detected in the striatal cells after a sequential 180-min washout with Ringer's solution. This uptake was significantly inhibited by a low Na(+) condition, but not by treatment with putrescine, a potent uptake inhibitor of paraquat into lung tissue. These findings indicated that paraquat is possibly taken up into the brain by the neutral amino acid transport system, then transported into striatal, possibly neuronal, cells in a Na(+)-dependent manner.


External Validity in Policy Evaluations that Choose Sites Purposively.
Evaluations of the impact of social programs are often carried out in multiple "sites," such as school districts, housing authorities, local TANF offices, or One-Stop Career Centers. Most evaluations select sites purposively following a process that is nonrandom. Unfortunately, purposive site selection can produce a sample of sites that is not representative of the population of interest for the program. In this paper, we propose a conceptual model of purposive site selection. We begin with the proposition that a purposive sample of sites can usefully be conceptualized as a random sample of sites from some well-defined population, for which the sampling probabilities are unknown and vary across sites. This proposition allows us to derive a formal, yet intuitive, mathematical expression for the bias in the pooled impact estimate when sites are selected purposively. This formula helps us to better understand the consequences of selecting sites purposively, and the factors that contribute to the bias. Additional research is needed to obtain evidence on how large the bias tends to be in actual studies that select sites purposively, and to develop methods to increase the external validity of these studies.


Macular hole surgery with triamcinolone acetonide-assisted internal limiting membrane peeling: one-year results.
To report the 1-year results of macular hole surgery with triamcinolone acetonide (TA)-assisted internal limiting membrane (ILM) peeling and to compare those with results of indocyanine green (ICG)-assisted ILM peeling. In a nonrandomized, retrospective, interventional case series, 40 eyes of 39 consecutive patients with idiopathic full-thickness macular holes underwent macular hole surgery with TA-assisted ILM peeling. Surgical results 1 year after surgery, including changes in best-corrected visual acuity (BCVA) and macular hole closure, were evaluated. Moreover, we compared the results for these 40 eyes (TA group) with those for 27 eyes of 27 consecutive patients who had undergone macular hole surgery with 0.25% ICG-assisted ILM peeling (ICG group). In the TA group, macular holes were closed in 39 (98%) of 40 eyes. Mean BCVA +/- SD significantly improved from 0.78 +/- 0.31 logarithm of the minimal angle of resolution (logMAR) preoperatively to 0.20 +/- 0.30 logMAR (P < 0.001). BCVA improved by > or =0.2 logMAR in 37 eyes (93%). BCVA was 20/40 or better in 33 (83%) of 30 eyes. In the ICG group, macular holes were closed in all 27 eyes (100%), and mean BCVA +/- SD significantly improved from 0.81 +/- 0.4 logMAR preoperatively to 0.34 +/- 0.2 logMAR 1 year postoperatively (P < 0.001). BCVA improved by > or =0.2 logMAR in 22 eyes (81%). BCVA was 20/40 or better in 16 (59%) of 27 eyes. Significant differences between groups were seen in mean BCVA 1 year after surgery (P = 0.049) but not in BCVA of 20/40 or better (P = 0.17) or change in BCVA by > or =0.2 logMAR (P = 0.05). TA is useful as an adjuvant for ILM peeling in macular hole surgery, and BCVA 1 year after surgery might be more favorable when compared with ICG-assisted ILM peeling.


Effects of environmental temperature change on mercury absorption in aquatic organisms with respect to climate warming.
Because of global warming, the quantity of naturally generated mercury (Hg) will increase, subsequently methylation of Hg existing in seawater may be enhanced, and the content of metal in marine products rise which consequently results in harm to human health. Studies of the effects of temperatures on Hg absorption have not been adequate. In this study, in order to observe the effects of temperature changes on Hg absorption, inorganic Hg or methylmercury (MeHg) was added to water tanks containing loaches. Loach survival rates decreased with rising temperatures, duration, and exposure concentrations in individuals exposed to inorganic Hg and MeHg. The MeHg-treated group died sooner than the inorganic Hg-exposed group. The total Hg and MeHg content significantly increased with temperature and time in both metal-exposed groups. The MeHg-treated group had higher metal absorption rates than inorganic Hg-treated loaches. The correlation coefficients for temperature elevation and absorption were significant in both groups. The results of this study may be used as basic data for assessing in vivo hazards from environmental changes such as climate warming.


Finding the way forward for forensic science in the US-A commentary on the PCAST report.
A recent report by the US President's Council of Advisors on Science and Technology (PCAST), (2016) has made a number of recommendations for the future development of forensic science. Whereas we all agree that there is much need for change, we find that the PCAST report recommendations are founded on serious misunderstandings. We explain the traditional forensic paradigms of match and identification and the more recent foundation of the logical approach to evidence evaluation. This forms the groundwork for exposing many sources of confusion in the PCAST report. We explain how the notion of treating the scientist as a black box and the assignment of evidential weight through error rates is overly restrictive and misconceived. Our own view sees inferential logic, the development of calibrated knowledge and understanding of scientists as the core of the advance of the profession.


Modulation of the trigeminofacial pathway during syllabic speech.
The human orofacial system is richly endowed with low-threshold, slowly adapting mechanoreceptors that respond to self-generated movements and external loads. The functional linkage between these afferents and the recruitment of motor units in the lower face during the dynamics of speech is unknown. Mechanically evoked activity in the orbicularis oris muscles was studied in young human female adults (N=10) during a lip force recruitment task associated with the repetition of the nonsense speech utterance "ah-wah." This speech task involved the recruitment of perioral motor units against an elastic load. A skin contactor probe coupled to a servo-controlled linear motor delivered punctate ipsilateral mechanical inputs (25 ms duration, 1800 mum displacement) to the glabrous surface of the upper lip in order to index the modulation and specificity of the compound trigeminofacial response as a function of speech force recruitment threshold (Ft). Modulation of the early (Ft=0.2 N) and later (Ft=1.0 N) components of the evoked perioral response was found at the two force thresholds. Beginning at approximately 60 ms post-stimulus, a significant suppression response was found among lower lip EMG recording sites and its magnitude was greatest when the mechanical perturbation occurred during the early phase of lip force recruitment. Variation in the lip force trajectories was manifest by a greater difference in net interangle force associated with lip perturbations indexed to the early Ft. This was interpreted to reflect the operation of a feedforward mechanism which may play a more significant role during an evolving speech action. Thus, the application of servo-controlled mechanosensory inputs effectively indexed the excitability of the facial motor nucleus during production of a simple speech phrase. Future studies are needed to explore mechanisms of short-term adaptation and trigeminofacial modulation during propositional speech in health and disease.


Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.
Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.


Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.
Screening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions. One hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information. PCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients. While our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics.


Comorbidities and medications of patients with chronic hepatitis C under specialist care in the UK.
Designing services with the capacity and expertise to meet the needs of the chronic hepatitis C (CHC) population in the era of direct acting antivirals (DAAs), and widening access to such treatments, requires detailed understanding of the characteristics and healthcare needs of the existing patient population. In this retrospective analysis of data from the National HCV Research UK Biobank between March 2012 and October 2014, the characteristics of the CHC population currently under specialist care in the UK were evaluated-with specific focus upon use of medications, adverse lifestyle choices, and comorbidities. Demographic data, risk factors for CHC acquisition, HCV genotype, liver disease status, lifestyle factors, comorbidities, and medication classes were collected. Data were analyzed by history of injecting drug use (IDU), age, and severity of liver disease. A total of 6278 patients (70.5% white; median age, 52 years) from 59 UK specialist centres were included; 59.1% of patients had acquired HCV through IDU. The prevalence of adverse lifestyle factors was significantly lower in non-IDU compared with previous IDU or recent IDU patients. Depression was common in the previous (50.8%) and recent IDU (68.1%) groups, compared with 27.6% in non-IDU patients. Cirrhosis was common (23.6%), and prevalence increased with age. We describe a heterogeneous, polymorbid, and aging population of CHC patients in secondary care, and demonstrate underrepresentation of injecting drug users within the current system. The implications of this present significant challenges to physicians and healthcare commissioners in designing services which are fit for purpose inthe DAA era.


Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.
Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.


Robotic assisted VATS lobectomy for loco-regionally advanced non-small cell lung cancer.
Despite lung cancer screening programs and efforts at early detection, patients with non-small cell lung cancer continue to present with loco-regionally advanced disease. In particular, patients with positive mediastinal lymph nodes (N1/2, stage II/IIIA) present a challenge to the thoracic surgeon. The thorough lymphadenectomy required by these patients can be difficult to perform with standard VATS approaches. In addition, hilar fibrosis may result from the neoadjuvant therapy these patients generally receive, which complicates dissection of the vascular and bronchial structures. The robotic approach offers benefits that can help to address these challenges. While not ideal for the surgeon just learning robotic surgery, in experienced hands this is an effective tool to deal with loco-regionally advanced lung cancer safely and with optimal oncologic efficacy.


Effects of Products Containing Bacillus subtilis var. natto on Healthy Subjects with Neck and Shoulder Stiffness, a Double-Blind, Placebo-Controlled, Randomized Crossover Study.
Neck and shoulder stiffness is a typical subjective symptom in developed countries. This stiffness is caused by factors such as muscle tension and poor blood flow, leading to reduce work efficiency and diminish QOL. NKCP®, a natto-derived dietary food supplement whose main component is bacillopeptidase F, has antithrombotic, fibrinolytic, and blood viscosity-lowering effects. Here, we investigated the effect of NKCP® on neck and shoulder stiffness in a double-blind placebo-controlled randomized crossover study. Thirty subjects with neck and shoulder stiffness were randomly divided into 2 groups and ingested 250 mg of NKCP® or placebo daily for 4 weeks. Headache score significantly improved in the NKCP® group compared to the placebo group. Moreover, NKCP® significantly improved the score of visual analogue scale for neck and shoulder stiffness and pain, reduced muscle stiffness of the neck, and increased the skin surface temperature of neck and shoulders, compared to before ingestion. No adverse effects were observed during this study. These results suggest that NKCP® may alleviate headaches and chronic neck and shoulder stiffness and pain.


The lived experiences of operating theatre scrub nurses learning technical scrub skills 'I'm doing this right, aren't I? Am I doing this right?'
Operating theatre scrub nurses (OTSNs) are not required to have undertaken a secondary or specialist post-registration theatre qualification to work in the operating theatre (OT) setting in the UK. From the systematic review there is only very limited literature or research in how technical scrub skills are acquired. This study explores the lived experiences of OTSNs learning technical scrub skills. The study employed the qualitative methodology of interpretative phenomenological analysis. Data was collected from six participating OTSNs using semi-structured interviews. Four superordinate themes emerged: How technical scrub skills are established, Gatekeepers, How the learner feels whilst learning and, Reflections of the experienced scrub nurse. The study found that the experiences of OTSNs learning technical scrub skills are varied and a variety of teaching and learning methods are utilised. These experiences were influenced by the team, mentor and surgeon within the OT environment. Lived experiences were also influenced by organisational structure and service pressures within the NHS.


[The future is in your right hand: an embodied temporal concept].
Previous, studies demonstrated that participants in left-to-right writing cultures showed a strong preference to associate the past with left space and the future with right space. The present studies investigated whether these spatial associations involved body-part-centered or extracorporal space. In Experiment 1, participants categorized words as referring to the past or the future by pressing button on the left with the left hand or a button on the right with the right hand. In Experiments 2 and 3, participants crossed their hands and were instructed to categorize words by pressing the left or right buttons (Experiment 2) or by moving their left or right hand (Experiment 3). Irrespective of the relative spatial positions of the response buttons, past words were more quickly categorized with the left hand and future words with the right hand. In addition, reaction times were slowerr in Experiment 2 than in Experiment 1, whereas there was no significant difference beween Experiments 1 and 3. These results suggest that temporal concepts such as past and future are more strongly associated with embodied space than visual space.


A phase I safety and pharmacokinetic study of OGT 719 in patients with liver cancer.
OGT 719 (Oxford GlycoSciences, Abingdon, UK) is a novel nucleoside analogue with a galactose molecule attached to a fluorinated pyrimidine. OGT 719 has the capacity selectively to bind to asialoglycoprotein receptors that are found exclusively on hepatocytes and hepatocellular carcinoma (HCC) cells. The aim of this study was to establish the safety and to examine the pharmacokinetics of this novel compound in patients with liver cancer. Fourteen patients received a total of 37 cycles of OGT 719 at four dose levels ([500 mg/m2 first cycle, 1 000 mg/m2 subsequent cycles], 1000 mg/m2, 3 300 mg/m2 and 7500 mg/m2). OGT 719 was administered as a 3-h intravenous infusion in a 250 ml saline solution, daily for 5 days every 4 weeks. Pharmacokinetic parameters were studied during the first cycle of dose levels 1 and 2 (500 mg/m2. and 1 000 mg/m2, respectively). The maximum plasma concentration was attained within 5 min of completing the infusion and almost doubled, dose dependently, with a doubling of the infused dose. The plasma level declined rapidly in a monophasic manner with an elimination half-life of 2.1 and 2.5 h for dose level 1 and 2, respectively The mean area under the curve (AUC(o - infinity) area under the curve to 24 h; AUC(o - infinity), area under the curve to infinity) doubled at the higher dose level. None of the patients had a significant tumor response. Elimination half-life of OGT 719 by 3-h intravenous infusion is short and monophasic. Toxicity was minimal at the highest dose level.


Materials and mechanics for stretchable electronics.
Recent advances in mechanics and materials provide routes to integrated circuits that can offer the electrical properties of conventional, rigid wafer-based technologies but with the ability to be stretched, compressed, twisted, bent, and deformed into arbitrary shapes. Inorganic and organic electronic materials in microstructured and nanostructured forms, intimately integrated with elastomeric substrates, offer particularly attractive characteristics, with realistic pathways to sophisticated embodiments. Here, we review these strategies and describe applications of them in systems ranging from electronic eyeball cameras to deformable light-emitting displays. We conclude with some perspectives on routes to commercialization, new device opportunities, and remaining challenges for research.


The Effect of Probiotics on Gut Microbiota during the Helicobacter pylori Eradication: Randomized Controlled Trial.
Helicobacter pylori causes chronic gastritis, gastroduodenal ulcers, and gastric cancer, and has been treated with two antibiotics (amoxicillin and clarithromycin) and proton-pump inhibitors (PPIs). However, antibiotic treatment alters the indigenous gut microbiota to cause side effects. Therefore, the effects of probiotic supplementation on therapy have been studied. Although several studies have covered the probiotics' effects, details about the gut microbiota changes after H. pylori eradication have not been evaluated. Therefore, we analyzed the influences of antibiotics and their combination with probiotics on the composition of the gut microbiota using high-throughput sequencing. Subjects were divided into two groups. The antibiotics group was treated with general therapy, and the probiotics group with general therapy and probiotic supplementation. Fecal samples were collected from all subjects during treatments, and the influences on gut microbiota were analyzed by 16S rRNA gene-pyrosequencing. Three phyla, Firmicutes, Bacteroidetes, and Proteobacteria, were predominant in the gut microbiota of all subjects. After treatment, the relative abundances of Firmicutes were reduced, whereas those of Proteobacteria were increased in both groups. However, the changed proportions of the gut microbiota in the antibiotics group were higher than those in the probiotics group. In addition, the increase in the levels of antibiotic-resistant bacteria was higher in the antibiotics group than in the probiotics one. Probiotic supplementation can reduce the antibiotic-induced alteration and imbalance of the gut microbiota composition. This effect may restrict the growth of antibiotic-resistant bacteria in the gut and improve the H. pylori eradication success rate.


Effects of varying diagnostic criteria on prevalence of mild cognitive impairment in a community based sample.
Mild cognitive impairment (MCI) is proposed to be a prodrome to dementia in some older adults. However, the presentation of MCI in the community can differ substantially from clinic-based samples. The aim of the current study is to demonstrate the effects of different operational definitions of MCI on prevalence estimates in community-dwelling older adults. A consecutive series of 200 participants aged 65 and over from the Adult Changes in Thought (ACT) community-based cohort were approached to undergo comprehensive neuropsychological and medical evaluation; 159 were included in the final analyses. Nondemented subjects were categorized using various diagnostic criteria for MCI. In a novel approach, neuropsychological test scores were evaluated using an individualized benchmark as a point of test comparison, as well as traditional methods that entail comparison to age-based normative data. Diagnostic criteria were further subdivided by severity of impairment (1.0 vs. 1.5 standard deviations [sd] below the benchmark) and extent of impairment (based on a single test or an average of tests within a cognitive domain). MCI prevalence rates in the sample were highly dependent on these diagnostic factors, and varied from 11% to 92% of the sample. Older groups tended to show higher prevalence rates, although this was not the case across all diagnostic schemes. The use of an individualized benchmark, less severe impairment cutoff, and impairment on only a single test all produced higher rates of MCI. Longitudinal follow-up will determine whether varying diagnostic criteria improves sensitivity and specificity of the MCI diagnosis as a predictor for dementia.


Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle.
Previous results indicate that intra-amygdala infusions of NMDA receptor antagonists block the extinction of conditioned fear. Mitogen-activated protein kinase (MAPK) can be activated by NMDA receptor stimulation and is involved in excitatory fear conditioning. Here, we evaluate the role of MAPK within the basolateral amygdala in the extinction of conditioned fear. Rats received 10 light-shock pairings. After 24 hr, fear was assessed by eliciting the acoustic startle reflex in the presence of the conditioned stimulus (CS) (CS-noise trials) and also in its absence (noise-alone trials). Rats subsequently received an intra-amygdala or intrahippocampal infusion of either 20% DMSO or the MAPK inhibitor PD98059 (500 ng/side) followed 10 min later by 30 presentations of the light CS without shock (extinction training). After 24 hr, they were again tested for fear-potentiated startle. PD98059 infusions into the basolateral amygdala but not the hippocampus significantly reduced extinction, which was otherwise evident in DMSO-infused rats. Control experiments indicated that the effect of intra-amygdala PD98059 could not be attributed to lasting damage to the amygdala or to state dependency. These results suggest that a MAPK-dependent signaling cascade within or very near the basolateral amygdala plays an important role in the extinction of conditioned fear.


Meeting report: signaling schemes for TGF-beta.
The transforming growth factor-beta (TGF-beta) superfamily of signaling molecules regulates many developmental processes in a range of organisms from worms to humans. Understanding the mechanisms by which they exert their repertoire of effects has required identification of the components of signaling pathways that they control. Roberts and Derynck focus on this aspect of TGF-beta biology in their review of a recent Federation of American Societies for Experimental Biology (FASEB) meeting on TGF-beta signaling and development and summarize current signaling paradigms and future prospects in TGF-beta signaling from the cell surface to the nucleus.


The high prevalence of chronic kidney disease-mineral bone disorders: A hospital-based cross-sectional study.
Mineral bone disorder (MBD) is an important complication of chronic kidney disease (CKD). However, there are limited data on the pattern of MBD in Indian CKD population. The aim of this study was to describe spectrum of MBD in patients with CKD in our center. This was a hospital-based cross-sectional observational study. Patients with stage 4 and 5 CKD were included in this study. Those receiving calcium supplement, vitamin D or its analogues, and calcimimetic were excluded. Serum/plasma levels of creatinine, albumin, calcium, phosphate, total alkaline phosphatase (TAP), intact parathormone (iPTH), and 25-OH vitaminD (25-vitD) were measured. Radiological survey of bones was carried out in all cases, and echocardiography done in selected patients. Statistical analysis was done using Sigmaplot 10.0 software. A total of 150 patients (114 males, 36 females) were included in this study. Mean age was 45.67±16.96 years. CKD stage 4 and 5D were found in 26% (n=39) and 74% (n=111) of study population, respectively. The most common underlying native kidney diseases in patients of CKD 4 and 5D were diabetic nephropathy (41.03%) and CGN (41.44%), respectively. Median (first quartile, third quartile) values for serum levels of corrected calcium (cCa), phosphate, cCaXPO4 product, TAP, plasma iPTH, and 25-vitD in stage 4 CKD were 8.36 (7.79, 8.91) mg/dL, 4.9 (3.92, 6.4) mg/dL, 41.11 (34.01, 53.81) mg(2)/dL(2), 97 (76.5, 184.25) IU/L, 231 (124.5, 430.75) pg/mL, and 12 (6.98, 23.55) ng/mL, respectively; and in stage 5D CKD were 8.36 (7.66, 8.95) mg/dL, 5.7 (4.23, 6.95) mg/dL, 46.5 (37.16, 54.47) mg(2)/dL(2), 180 (114.5, 276.25) IU/L, 288 (169.75, 625.0) pg/mL, and 18.4 (10.0, 26.4) ng/mL, respectively. Prevalence of hypocalcemia (56.41% vs. 54.95%), hyperphosphatemia (64.10% vs. 70.27%), and hyperparathyroidism (84.62% vs. 88.29%) was not different between patients with CKD 4 and 5D. However, iPTH level outside the target range and increased TAP level were significantly (P<0.001) more common in CKD stage 5D. Multiple logistic regression analysis for hyperparathyroidism revealed significant inverse correlation with cCa in CKD 5D. There were no significant differences in vitamin D status and prevalence of valvular calcification between CKD stage 4 and 5D. X-ray revealed renal osteodystrophy in 8 (5.33%) patients, while it was normal in 118 (78.67%) patients. Secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, increased TAP, and 25-OH vitamin D deficiency and insufficiency were quite common in CKD 4 and 5 patients. The commonest type of MBD in CKD 4 and 5D was secondary hyperparathyroidism.


Daily follow-up of bacterial communities in the human gut reveals stable composition and host-specific patterns of interaction.
In the last decade, an extensive effort has been made to characterize the human intestinal microbiota by means of SSU rRNA gene sequence and metagenomic analysis. Relatively few studies have followed intestinal bacterial communities over time to assess their stability in the absence of perturbation. In this study, we have monitored the faecal bacteria of three healthy subjects during 15 consecutive days. The global community structure was analysed through SSU rRNA gene sequencing. In agreement with previous studies, we found that the between-subject variation in community structure was larger than within. The composition was fairly stable throughout, although daily fluctuations were detected for all genera and phylotypes at 97% of sequence identity. While the core shared between subjects was very small, each subject harboured a stable high-abundance core composed of a small number of bacterial groups (9% of the phylotypes accounted for between 74% and 93% of the sequences). This may suggest that studies aimed at linking the microbiota composition with disease risk should be limited to the numerically most dominant phylotypes, as the rest appears transient. Networks of potential interactions between co-occurring genera were also subject-specific, even for the same bacterial genus, which might be reflecting host-specific selective pressures and historic events.


Engineering highly sensitive whole-cell mercury biosensors based on positive feedback loops from quorum-sensing systems.
Mercury contamination represents a global threat. A simple, sensitive, and rapid means of detecting trace mercury is urgently needed. Herein, we have developed a series of mercury biosensors by combining quorum sensing-based positive feedback systems with a mercury-specific operon, merR. Our results have demonstrated that the sensitivity and fluorescence intensity of the engineered E. coli cells were greatly improved thanks to the positive feedback system. In addition, by fitting the fluorescence signals to the classic Hill equation, we discovered that the responses of the engineered E. coli cells were close to ultrasensitive curves. Our work highlights quorum-sensing systems as a powerful tool in biosensor designs.


Race, ethnicity, and management of pain from long-bone fractures: a prospective study of two academic urban emergency departments.
The objective was to test the hypothesis that African American and Hispanic patients are less likely to receive analgesics than white patients in two academic urban emergency departments (EDs). This was a prospective observational study of a convenience sample of patients with long-bone fractures from April 2002 to November 2006 in two academic urban EDs. Eligibility criteria were age 18-55 years, isolated long-bone fracture, and race and ethnicity (Hispanic, African American, and white). The primary outcome was receipt of analgesics; secondary outcomes included receipt of opioids, dose, route, time to first analgesic, and change in pain. Logistic regression was used to adjust the risk of receiving analgesics for patients' initial rating of pain and demographic characteristics. Of 1,239 patients with suspected long-bone fractures, 345 patients were eligible: 177 (51%) were Hispanic, 98 (28%) were African American, and 70 (20%) were white. Administration of analgesics was not associated with race or ethnicity. Sixteen percent (95% confidence interval [CI] = 11% to 22%) of Hispanic, 15% (95% CI = 10% to 24%) of African American, and 14% (95% CI = 8% to 24%) of white patients did not receive any analgesics. Seventy-four percent of Hispanic (95% CI = 67% to 80%), 66% of African American (95% CI = 57% to 75%), and 69% (95% CI = 57% to 78%) of white patients received opioid analgesics. After adjustment for covariates, there was no evidence of an association between receipt of analgesics or opioid analgesics and the race or ethnicity of the patients. There were no significant differences in time to treatment, dose, route, or change in pain. Receipt of analgesics for pain from long-bone fractures was not associated with patient race or ethnicity in two academic urban EDs.


Mortality assessment of patients with pancreatic cancer in Mexico, 2000-2014.
The five-year survival rate remains low for pancreatic cancer (PC). The objective of this study was to describe PC mortality rates in Mexico and its seven socioeconomic regions. The data for the deaths were obtained from the National Institute of Statistics and Geography databases. The adjusted rates were calculated using the world standard population. During the study period, the average mortality rate was 4.29 per 100,000 inhabitants. By gender, the rate was 4.35 and 4.29 per 100,000 inhabitants for men and women, respectively. Socioeconomic region 7 had the highest mortality rates. There was a significant decline in mortality rates in all of the groups.


Evolutionary, ecological and biotechnological perspectives on plasmids resident in the human gut mobile metagenome.
Numerous mobile genetic elements (MGE) are associated with the human gut microbiota and collectively referred to as the gut mobile metagenome. The role of this flexible gene pool in development and functioning of the gut microbial community remains largely unexplored, yet recent evidence suggests that at least some MGE comprising this fraction of the gut microbiome reflect the co-evolution of host and microbe in the gastro-intestinal tract. In conjunction, the high level of novel gene content typical of MGE coupled with their predicted high diversity, suggests that the mobile metagenome constitutes an immense and largely unexplored gene-space likely to encode many novel activities with potential biotechnological or pharmaceutical value, as well as being important to the development and functioning of the gut microbiota. Of the various types of MGE that comprise the gut mobile metagenome, plasmids are of particular importance since these elements are often capable of autonomous transfer between disparate bacterial species, and are known to encode accessory functions that increase bacterial fitness in a given environment facilitating bacterial adaptation. In this article current knowledge regarding plasmids resident in the human gut mobile metagenome is reviewed, and available strategies to access and characterize this portion of the gut microbiome are described. The relative merits of these methods and their present as well as prospective impact on our understanding of the human gut microbiota is discussed.


Assessing bed net use and non-use after long-lasting insecticidal net distribution: a simple framework to guide programmatic strategies.
Insecticide-treated nets (ITNs) are becoming increasingly available to vulnerable populations at risk for malaria. Their appropriate and consistent use is essential to preventing malaria, but ITN use often lags behind ITN ownership. In order to increase ITN use, it is necessary to devise strategies that accurately identify, differentiate, and target the reasons and types of non-use. A simple method based on the end-user as the denominator was employed to classify each individual into one of four ITN use categories: 1) living in households not owning an ITN; 2) living in households owning, but not hanging an ITN; 3) living in households owning and hanging an ITN, but who are not sleeping under one; and 4) sleeping under an ITN. This framework was applied to survey data designed to evaluate long-lasting insecticidal nets (LLINs) distributions following integrated campaigns in five countries: Togo, Sierra Leone, Madagascar, Kenya and Niger. The percentage of children <5 years of age sleeping under an ITN ranged from 51.5% in Kenya to 81.1% in Madagascar. Among the three categories of non-use, children living in households without an ITN make up largest group (range: 9.4%-30.0%), despite the efforts of the integrated child health campaigns. The percentage of children who live in households that own but do not hang an ITN ranged from 5.1% to 16.1%. The percentage of children living in households where an ITN was suspended, but who were not sleeping under it ranged from 4.3% to 16.4%. Use by all household members in Sierra Leone (39.9%) and Madagascar (60.4%) indicate that integrated campaigns reach beyond their desired target populations. The framework outlined in this paper provides a helpful tool to examine the deficiencies in ITN use. Monitoring and evaluation strategies designed to assess ITN ownership and use can easily incorporate this approach using existing data collection instruments that measure the standard indicators.


Difficulties arising from the variety of testing schemes used for bovine viral diarrhoea virus (BVDV).
Globally, the eradication of bovine viral diarrhoea virus (BVDV) is still in its infancy, but eradication has been, or is being, adopted by several countries or regions. Comparisons between countries' schemes allow others to assess best practice, and aggregating published results from eradication schemes provides greater statistical power when analysing data. Aggregating data requires that results derived from different testing schemes be calibrated against one another. The authors aimed to evaluate whether relationships between published BVDV test results could be created and present the outcome of a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The results are tabulated, providing a summary of papers where there is potential cross-calibration and a summary of the obstacles preventing such data aggregation. Although differences in measuring BVDV present barriers to academic progress, they may also affect progress within individual eradication schemes. The authors examined the time taken to retest following an initial antibody BVDV test in the Scottish eradication scheme. The authors demonstrate that retesting occurred quicker if the initial not negative test was from blood rather than milk samples. Such differences in the response of farmers/veterinarians to tests may be of interest to the design of future schemes.


Direct time-resolved study of the gas-phase reactions of germylene with ethyl- and diethylgermane: absolute rate constants, temperature dependences, and mechanism.
Time-resolved studies of germylene, GeH2, generated by the 193 nm laser flash photolysis of 3,4-dimethyl-1-germacyclopent-3-ene, have been carried out to obtain rate constants for its bimolecular reactions with ethyl- and diethylgermanes in the gas phase. The reactions were studied over the pressure range 1-100 Torr with SF6 as bath gas and at five temperatures in the range 297-564 K. Only slight pressure dependences were found for GeH2 + EtGeH3 (399, 486, and 564 K). The high pressure rate constants gave the following Arrhenius parameters: for GeH2 + EtGeH3, log A = -10.75 +/- 0.08 and Ea = -6.7 +/- 0.6 kJ mol-1; for GeH2 + Et2GeH2, log A = -10.68 +/- 0.11 and Ea = -6.95 +/- 0.80 kJ mol-1. These are consistent with fast, near collision-controlled, association processes at 298 K. RRKM modeling calculations are, for the most part, consistent with the observed pressure dependence of GeH2 + EtGeH3. The ethyl substituent effects have been extracted from these results and are much larger than the analogous methyl substituent effects in the SiH2 + methylsilane reaction series. This is consistent with a mechanistic model for Ge-H insertion in which the intermediate complex has a sizable secondary barrier to rearrangement.