Use of hypnotic medicines by elderly people in residential homes.
Data relating to the use of hypnotic medicines from a descriptive epidemiological study of drug use in 55 residential homes for elderly people were analysed. Of the 1888 residents included in the study, 435 (23.0%) were receiving a total of 448 hypnotic medicines. There was preferential prescribing of short-acting benzodiazepines but long-acting benzodiazepines represented 31.7% of all hypnotic drugs prescribed. The median duration of treatment with temazepam was 0.8 years and with nitrazepam 2.5 years. The proportion of residents receiving hypnotic medicines in each home varied from 3.6% to 60.0% with a median of 24.1%. This study indicates a need for general practitioners to review their prescribing of hypnotic medicines for elderly people, paying particular attention to the duration of treatment.


The combined use of Camellia sinensis and metronomic zoledronate in 4T1 mouse carcinoma against tumor growth and metastasis.
In previous studies, we demonstrated that the green tea Camellia sinensis (CS) water extract had potent antitumor and antimetastatic effects on 4T1 breast cancer. The metronomic regimen (0.0125 mg/kg twice a week for 4 weeks) of zoledronate (ZOL) was found to be effective in decreasing tumor burden and metastasis as compared with conventional regimen. The aim of the present study was to investigate the antitumor, antimetastatic and anti-osteolytic effects of the combined use of CS water extract and metronomic ZOL against 4T1 breast carcinoma in vitro and in vivo. The results demonstrated that the combination of CS+ZOL exerted a more potent effect on lung and liver by decreasing tumor burden and metastasis, when compared to CS or metronomic ZOL as monotherapies. The combination of CS+ZOL demonstrated optimal bone protection against breast cancer-induced osteolysis for the three groups of CS, ZOL and CS+ZOL. The in vitro results further demonstrated that ZOL enhanced CS-induced apoptosis in 4T1 cells as assessed by the Annexin V-FITC/PI staining and caspase-3 activity assays. In addition, the combined use of CS+ZOL significantly inhibited 4T1 cell migration. Mechanistic studies showed that the enzyme levels of matrix metalloproteinases (MMP)-2 and MMP-9 were suppressed significantly by CS+ZOL. In conclusion, to the best of our knowledge, this is the first study to investigate the novel combined application of herbal extract CS and chemotherapy ZOL in 4T1 breast cancer. The combination of CS plus metronomic ZOL demonstrated significant antitumor, antimetastatic and anti-osteolytic effects against breast cancer, and suggested potential clinical application for breast cancer patients.


[Nutritional status of the poor, marginalized adults of the Triqui ethnic group in Oaxaca, Mexico].
To further understanding of the nutritional transition process by studying possible changes over time in the nutritional status of the Triqui ethnic group in the state of Oaxaca, Mexico. A retrospective study was conducted using anthropometric data available from three prior studies (end of the 19th century, 1940, and 2002). Means and z scores for height, weight, and body mass index of Triqui adults were calculated using Frisancho reference data. Statistical analyses of the results were performed with Student's t and chi-square tests. Sociocultural information was collected through interviews and direct observations, as well as from the available literature. The height of Triqui adults has remained very low. A majority of Triqui women were found to be short or very short; this, coupled with the low level of education and high rates of illiteracy and monolingualism, is indicative of a culture that does not favor females. The appearance of overweight and obesity among the men studied in 2002, relative to those studied in 1940, is cause for concern. Overweight was also recorded among the women in 2002. Despite the limitations shared by all retrospective studies, these results confirm that the nutritional status of the Triquis is different now from what it was 60 years ago and that these changes are related to the cultural changes the group is experiencing. To further understand this epidemiologic phenomenon, where malnutrition and obesity coexist, cross-disciplinary studies are needed to analyze the biological, social, and cultural factors involved, so that culturally-appropriate measures can be adopted.


Comparative genomic analysis revealed rapid differentiation in the pathogenicity-related gene repertoires between Pyricularia oryzae and Pyricularia penniseti isolated from a Pennisetum grass.
A number of Pyricularia species are known to infect different grass species. In the case of Pyricularia oryzae (syn. Magnaporthe oryzae), distinct populations are known to be adapted to a wide variety of grass hosts, including rice, wheat and many other grasses. The genome sizes of Pyricularia species are typical for filamentous ascomycete fungi [~ 40 Mbp for P. oryzae, and ~ 45 Mbp for P. grisea]. Genome plasticity, mediated in part by deletions promoted by recombination between repetitive elements [Genome Res 26:1091-1100, 2016, Nat Rev Microbiol 10:417-430,2012] and transposable elements [Annu Rev Phytopathol 55:483-503,2017] contributes to host adaptation. Therefore, comparisons of genome structure of individual species will provide insight into the evolution of host specificity. However, except for the P. oryzae subgroup, little is known about the gene content or genome organization of other Pyricularia species, such as those infecting Pennisetum grasses. Here, we report the genome sequence of P. penniseti strain P1609 isolated from a Pennisetum grass (JUJUNCAO) using PacBio SMRT sequencing technology. Phylogenomic analysis of 28 Magnaporthales species and 5 non-Magnaporthales species indicated that P1609 belongs to a Pyricularia subclade, which is genetically distant from P. oryzae. Comparative genomic analysis revealed that the pathogenicity-related gene repertoires had diverged between P1609 and the P. oryzae strain 70-15, including the known avirulence genes, other putative secreted proteins, as well as some other predicted Pathogen-Host Interaction (PHI) genes. Genomic sequence comparison also identified many genomic rearrangements relative to P. oryzae. Our results suggested that the genomic sequence of the P. penniseti P1609 could be a useful resource for the genetic study of the Pennisetum-infecting Pyricularia species and provide new insight into evolution of pathogen genomes during host adaptation.


Vascular endothelial growth factor overexpression in myelodysplastic syndrome bone marrow cells: biological and clinical implications.
In myelodysplastic syndrome (MDS), vascular endothelial growth factor (VEGF) may have regulatory effects on the hematopoietic system and contribute to disease progression. We analyzed by immunocytochemistry VEGF expression in bone marrow (BM) cells from 188 patients with MDS and 96 non-hemopathic subjects. We also measured VEGF BM plasma levels and in vitro VEGF release. Our aims were to evaluate whether VEGF expression abnormalities were associated with relevant laboratory or clinical findings and their possible prognostic value. In MDS, VEGF expression was higher than in controls (p < .0001) and VEGF release was significantly higher in the low-risk cases. A trend to a positive correlation between VEGF myeloid expression and apoptotic rate was observed. High myeloid VEGF levels were independently associated with longer overall survival (p < .0001) and progression-free survival (p = .0002). Our findings suggest that, in MDS, VEGF production and release may contribute to ineffective hematopoiesis, with a potential prognostic role.


Animal-free toxicology: the use of human tissue to replace the use of animals - examples from human biomonitoring and human placental transport studies.
Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data.


Predictive power of food web models based on body size decreases with trophic complexity.
Food web models parameterised using body size show promise to predict trophic interaction strengths (IS) and abundance dynamics. However, this remains to be rigorously tested in food webs beyond simple trophic modules, where indirect and intraguild interactions could be important and driven by traits other than body size. We systematically varied predator body size, guild composition and richness in microcosm insect webs and compared experimental outcomes with predictions of IS from models with allometrically scaled parameters. Body size was a strong predictor of IS in simple modules (r2 = 0.92), but with increasing complexity the predictive power decreased, with model IS being consistently overestimated. We quantify the strength of observed trophic interaction modifications, partition this into density-mediated vs. behaviour-mediated indirect effects and show that model shortcomings in predicting IS is related to the size of behaviour-mediated effects. Our findings encourage development of dynamical food web models explicitly including and exploring indirect mechanisms.


Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo.
The gastric epithelium consists of tubular glandular units, each containing several differentiated cell types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation of signalling pathways that regulate homeostasis of the diseased organ. Therefore, it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and to identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions, including proliferation, differentiation and migration, and plays a crucial role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo Here, we show that the Wnt receptor frizzled 7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric-specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together, these data provide functional evidence of a crucial role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium.


Renal cell cancer: overview of the current therapeutic landscape.
The last decade has witnessed dramatic improvements in the diagnosis, classification and treatment of renal cell cancer (RCC). Besides improvements in surgical techniques in early stages, introduction of novel targeted agents has resulted in improved outcomes in advanced RCC for which no effective treatment existed until recently. This article reviews epidemiology, pathology and pathogenesis, diagnosis, clinical staging, prognostic factors and treatment modalities of early stage and advanced RCC. Expert commentary: Although treatment options are expanding rapidly, practicing physicians face considerable challenges in the decision-making process. Therapeutic agents may have unique side effects and unexpected drug interactions. RCC represents one of the major success stories of clinical oncology in recent years and the progress appears to be far from having reached a plateau. We aim to present a comprehensive in-depth review of RCC in an attempt to provide evidence-based recommendations and future perspectives for practicing oncologists.


Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts.
To test the hypothesis that genetically low 25-hydroxyvitamin D concentrations are associated with increased mortality. Mendelian randomisation analysis. Copenhagen City Heart Study, Copenhagen General Population Study, and Copenhagen Ischemic Heart Disease Study. 95 766 white participants of Danish descent from three cohorts, with median follow-up times of 19.1, 5.8, and 7.9 years, genotyped for genetic variants in DHCR7 and CYP2R1 affecting plasma 25-hydroxyvitamin D concentrations; 35 334 also had plasma 25-hydroxyvitamin D measurements. Participants were followed from study entry through 2013, during which time 10 349 died. All cause mortality and cause specific mortality, adjusted for common risk factors for all cause mortality based on the World Health Organization's global health status. The multivariable adjusted hazard ratios for a 20 nmol/L lower plasma 25-hydroxyvitamin D concentration were 1.19 (95% confidence interval 1.14 to 1.25) for all cause mortality, 1.18 (1.09 to 1.28) for cardiovascular mortality, 1.12 (1.03 to 1.22) for cancer mortality, and 1.27 (1.15 to 1.40) for other mortality. Each increase in DHCR7/CYP2R1 allele score was associated with a 1.9 nmol/L lower plasma 25-hydroxyvitamin D concentration and with increased all cause, cancer, and other mortality but not with cardiovascular mortality. The odds ratio for a genetically determined 20 nmol/L lower plasma 25-hydroxyvitamin D concentration was 1.30 (1.05 to 1.61) for all cause mortality, with a corresponding observational multivariable adjusted odds ratio of 1.21 (1.11 to 1.31). Corresponding genetic and observational odds ratios were 0.77 (0.55 to 1.08) and 1.13 (1.03 to 1.24) for cardiovascular mortality, 1.43 (1.02 to 1.99) and 1.10 (1.02 to 1.19) for cancer mortality, and 1.44 (1.01 to 2.04) and 1.17 (1.06 to 1.29) for other mortality. The results were robust in sensitivity analyses. Genetically low 25-hydroxyvitamin D concentrations were associated with increased all cause mortality, cancer mortality, and other mortality but not with increased cardiovascular mortality. These findings are compatible with the notion that genetically low 25-hydroxyvitamin D concentrations may be causally associated with cancer and other mortality but also suggest that the observational association with cardiovascular mortality could be the result of confounding.


Repeated exposure to media messages encouraging parent-child communication about sex: differential trajectories for mothers and fathers.
To examine changes in parent-child communication related to sexual behavior after exposure to public health messages. Randomized, controlled trial that was part of precampaign message testing. Exposure occurred online or through DVDs mailed to participants and viewed on their personal computers. Data collection occurred via a secure Web site. Participants included parents (n = 1969) living with a child age 10 to 14 years drawn from a nationally representative sample of U.S. households. Treatment participants were exposed to video, audio, and print advertisements that promoted the benefits of speaking to their children early and often about delaying initiation of sexual activity; messages also directed parents to an informational Web site. The dependent variable assessed frequency of parent-child communication related to sexual behavior. The primary independent variable was treatment assignment. Longitudinal growth modeling that included five waves of data. The trajectory of growth over time differed between fathers in the treatment group and fathers in the control group (F[1, 2357] = 4.15; p < .042), indicating more frequent communication among treatment fathers than among control fathers. Trajectories did not differ between mothers in treatment and control groups. This study demonstrates that father-child and mother-child communication patterns differ over time in response to public health messages. Findings have implication for researchers developing health marketing campaigns.


Co-location of passive gear fisheries in offshore wind farms in the German EEZ of the North Sea: A first socio-economic scoping.
Worldwide the renewable energy sector is expanding at sea to address increasing demands. Recently the race for space in heavily used areas such as the North Sea triggered the proposal of co-locating other activities such as aquaculture or fisheries with passive gears in offshore wind farms (OWFs). Our interdisciplinary approach combined a quantification of spatial overlap of activities by using Vessel Monitoring System and logbook data with a stakeholder consultation to conclude and verify on the actual feasibility of co-location. In the German Exclusive Economic Zone (EEZ) of the North Sea up to 90% of Danish and 40% of German annual gillnet fleet landings of plaice overlapped with areas where OWFs are developed. Our results indicated further that the international gillnet fishery could lose up to 50% in landings within the North Sea German EEZ when OWF areas are closed entirely for fisheries. No spatial overlap was found for UK potters targeting brown crab in the German EEZ. We further identified a number of key issues and obstacles that to date hinder an actual implementation of co-location as a measure in the marine spatial planning process: defining the legal base; implementation of safety regulations; delineation of minimum requirements for fishing vessels such as capacities, quotas, technical equipment; implementation of a licensing process; and scoping for financial subsidies to set up business. The stakeholder consultation verified the scientific findings and highlighted that all those points need to be addressed in a planning process. In the German EEZ we have shown that the socio-economic importance of spatial overlap varies within planning boundaries. Therefore we recommend an interdisciplinary bottom-up approach when scoping for suitable areas of co-location. Hence, an informed marine spatial planning process requires comprehensive and spatial explicit socio-economic viability studies factoring in also ecological effects of OWFs on target species.


Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
The dementia in Alzheimer disease (AD) is usually attributed to widespread neuronal loss in conjunction with the pathologic hallmarks of intracellular neurofibrillary tangles and extracellular plaques containing amyloid (A beta) in fibrillar form. Recently it has been demonstrated that non-fibrillar assemblies of A beta possess electrophysiologic activity, with the corollary that they may produce dementia by disrupting neuronal signaling prior to cell death. We therefore examined the effects of soluble oligomers of A beta(1-42) on long-term potentiation (LTP) and long-term depression (LTD), two cellular models of memory, in the dentate gyrus of rat hippocampal slices. Compared with vehicle controls, slices pre-incubated 60 min in the presence of A beta-derived diffusible ligands (ADDLs) showed no differences in threshold intensity to evoke a synaptic response, slope of field excitatory post-synaptic potentials (EPSPs), or the input/output function. Tetanus-induced LTP and reversal of LTD were strongly inhibited in ADDLs-treated slices whereas LTD was unaffected. These data suggest that soluble non-fibrillar amyloid may contribute to the pathogenesis of AD both by impairing LTP/memory formation at the cellular level and by creating 'neuroplasticity imbalance' manifested by unopposed LTD in the setting of impaired capacity for neural repair via reversal of LTD or LTP.


Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.
Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of B-cell receptors (BCR): transmembrane signaling through BCR-complexes to induce B-cell differentiation and proliferation, and BCR-mediated antigen internalization for class-II MHC-mediated presentation to acquire antigen-specific CD4(+) T-cell help.We identified a variant (L3P) in the B-lymphoid tyrosine kinase (BLK) gene of 2 related CVID-patients, which was absent in healthy relatives. BLK belongs to the Src-kinases family and involved in BCR-signaling. Here, we sought to clarify BLK function in healthy human B-cells and its association to CVID.BLK expression was comparable in patient and healthy B-cells. Functional analysis of L3P-BLK showed reduced BCR crosslinking-induced Syk phosphorylation and proliferation, in both primary B-cells and B-LCLs. B-cells expressing L3P-BLK showed accelerated destruction of BCR-internalized antigen and reduced ability to elicit CD40L-expression on antigen-specific CD4(+) T-cells.In conclusion, we found a novel BLK gene variant in CVID-patients that causes suppressed B-cell proliferation and reduced ability of B-cells to elicit antigen-specific CD4(+) T-cell responses. Both these mechanisms may contribute to hypogammaglobulinemia in CVID-patients.


Biologic Switching Among Nonsystemic Juvenile Idiopathic Arthritis Patients: A Cohort Study in the Childhood Arthritis and Rheumatology Research Alliance Registry.
Biologic medications have significantly improved disease control and outcomes of patients with juvenile idiopathic arthritis (JIA). Current treatment recommendations suggest escalating therapy, including changing biologics if needed, when inactive or low disease activity is not attained. The patterns and reasons for switching biologics in clinical practice in North America are not well described. We used the Childhood Arthritis and Rheumatology Research Alliance Registry and included individuals with JIA if they newly started a biologic after January 1, 2008, and had at least 12 months of subsequent observable time. Subjects with systemic JIA were excluded. We compared characteristics of switchers and nonswitchers using chi-square for categorical variables and Wilcoxon rank-sum test for continuous variables, and used linear regression for time analysis. Of the eligible children, 1361 with JIA in the registry started a biologic (94% tumor necrosis factor inhibitors [TNFi]). Median followup time was 30 months and 349 (26%) switched biologics. Among biologic switchers, ineffectiveness/disease flare was the most common reason for switch (202, 58%). The most common documented switch was from etanercept to another TNFi (221, 63%). The median time to switch to a second biologic decreased substantially from 55.2 months in 2008 to 7.2 months in 2016. In a multicenter cohort of patients with JIA starting a biologic, one-quarter switched to a second biologic, and the time to switching decreased in recent years. Additional studies should evaluate the outcomes and optimal timing of switching and preferred sequence of biologic use.


Femtosecond laser induced underwater superaerophilic and superaerophobic PDMS sheets with through microholes for selective passage of air bubbles and further collection of underwater gas.
Controlling underwater bubble behavior on a solid surface is of great research significance, particularly in extreme cases. However, the realization of artificial underwater superaerophobic or superaerophilic surfaces is still a challenge. Herein, a micro/nanoscale hierarchical rough structure was formed on polydimethylsiloxane (PDMS) surface by one-step femtosecond laser ablation. The as-prepared surface showed superhydrophobicity in air and superaerophilicity in water. Interestingly, the wettability of such a PDMS surface could be easily switched to in-air superhydrophilicity and underwater superaerophobicity once it was further irradiated by oxygen plasma because the surface chemistry changed. The original femtosecond laser-structured underwater superaerophilic PDMS surface could absorb/capture bubbles, while the plasma-treated underwater superaerophobic surface had excellent anti-bubble ability in water. A rough through-microhole-array PDMS sheet was prepared by a mechanical drilling process and subsequent femtosecond laser ablation. The sheet could selectively allow bubbles to pass, that is, the porous underwater superaerophilic sheet allowed bubbles to pass through, while the porous underwater superaerophobic sheet was able to intercept bubbles in a water medium. Using the porous underwater superaerophilic PDMS sheet as the core component, a device that has great ability of collecting underwater bubbles/gas was also designed.


Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics.
Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting 6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months; treatment failure; hospitalization; and dropout owing to any cause, non-adherence and intolerability. Pooled relative risk (RR) (±95% confidence intervals (CIs)) was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4504, mean duration=61.9±22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidone's superiority at 3 and 6 months when requiring ≥3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0 versus 37.5%, RR=0.80, CI: 0.70-0.91, P=0.0007, I(2)=37%; NNT=17, CI: 10-50, P=0.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (P=0.04, P<0.0001, P=0.0001), treatment failure (P=0.003) and hospitalization (P=0.004). SGAs showed trend-level superiority for dropout owing to intolerability (P=0.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several key outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.


Oxidative stress, genotoxicity, and vascular cell adhesion molecule expression in cells exposed to particulate matter from combustion of conventional diesel and methyl ester biodiesel blends.
Our aim was to compare hazards of particles from combustion of biodiesel blends and conventional diesel (D(100)) in old and improved engines. We determined DNA damage in A549 cells, mRNA levels of CCL2 and IL8 in THP-1 cells, and expression of ICAM-1 and VCAM-1 in human umbilical cord endothelial cells (HUVECs). Viability and production of reactive oxygen species (ROS) were investigated in all cell types. We collected particles from combustion of D(100) and 20% (w/w) blends of animal fat or rapeseed oil methyl esters in light-duty vehicle engines complying with Euro2 or Euro4 standards. Particles emitted from the Euro4 engine were smaller in size and more potent than particles emitted from the Euro2 engine with respect to ROS production and DNA damage, but similarly potent concerning cytokine mRNA expression. Particles emitted from combustion of biodiesel blends were larger in size, and less or equally potent than particles emitted from combustion of D(100) concerning ROS production, DNA damage and mRNA of CCL2 and IL8. ICAM-1 and VCAM-1 expression in HUVECs was only increased by D(100) particles from the Euro4 engine. This suggests that particle emissions from biodiesel in equal mass concentration are less toxic than conventional diesel.


Genotypic homogeneity of multidrug resistant S. Typhimurium infecting distinct adult and childhood susceptibility groups in Blantyre, Malawi.
Nontyphoidal Salmonella (NTS) serovars are a common cause of bacteraemia in young children and HIV-infected adults in Malawi and elsewhere in sub-Saharan Africa. These patient populations provide diverse host-immune environments that have the potential to drive bacterial adaptation and evolution. We therefore investigated the diversity of 27 multidrug resistant (MDR) Salmonella Typhimurium strains isolated over 6 years (2002-2008) from HIV-infected adults and children and HIV-uninfected children. Sequence reads from whole-genome sequencing of these isolates using the Illumina GA platform were mapped to the genome of the laboratory strain S. Typhimurium SL1344 excluding homoplastic regions that contained prophage and insertion elements. A phylogenetic tree generated from single nucleotide polymorphisms showed that all 27 strains clustered with the prototypical MDR strain D23580. There was no clustering of strains based on host HIV status or age, suggesting that these susceptible populations acquire S. Typhimurium from common sources or that isolates are transmitted freely between these populations. However, 7/14 of the most recent isolates (2006/2008) formed a distinct clade that branched off 22 SNPs away from the cluster containing earlier isolates. These data suggest that the MDR bacterial population is not static, but is undergoing microevolution which might result in further epidemiology change.


[Occupational diseases notified in men and women in Spain in 2004].
The knowledge of the occupational diseases incidence is an essential requisite for the adoption of rational control measures. The official statistics of the occupational diseases don't include the sex variable. The objective of this study is to describe occupational diseases recognized by the Spanish social security system in 2004 and assess the differences between men and women. We describe the information of the Spanish Occupational Disease Registry notified in 2004. The considered variables are: sex, age, economic activity, occupation, and time in the workplace, size of the company and Autonomous Community. Percentages, crude and specific incidence rates per 100.000 workers and rates ratios have been computed as indicators. 28.728 occupational diseases were recorded in Spain in 2004. Women's incidence rate was 188,7 per 100.000 workers and 217,8 for men. The average age of occurrence was 39.4 +/- 1 years for men and 37.6 +/- 11 years for women. The exposure time was lower than 3 years for 52.7% of the recorded diseases in women, and 44,6% in men. We appreciate gender differences in the occupational diseases notified and recorded in Spain in 2004. The global incidence rate was higher in men, but the specific incidence rates in most of the economic activities and occupations were higher in women. Occupational diseases in women are mostly notified by big companies.


Transforming nanomedicine manufacturing toward Quality by Design and microfluidics.
Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doing so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field.


Immunogenicity of a recombinant infectious hematopoietic necrosis virus glycoprotein produced in insect cells.
A recombinant infectious hematopoietic necrosis virus (IHNV) glycoprotein (G protein), produced in Spodoptera frugiperda (Sf9) cells following infection with a baculovirus vector containing the full-length (1.6 kb) glycoprotein gene, provided very limited protection in rainbow trout Oncorhynchus mykiss challenged with IHNV. Fish were injected intraperitoneally (i.p.) with Sf9 cells grown at 20 degrees C (RecGlow) or 27 degrees C (RecGhigh) expressing the glycoprotein gene. Various antigen (Ag) preparations were administered to adult rainbow trout or rainbow trout fry. Sera collected from adult fish were evaluated for IHNV neutralization activity by a complement-dependent neutralization assay. Anti-IHNV neutralizing activity was observed in sera, but the percent of fish responding was significantly lower (p < 0.05) in comparison to fish immunized with a low virulence strain of IHNV (LV-IHNV). A small number of fish immunized with RecGlow or RecGhigh possessed IHNV G protein specific antibodies (Abs) in their serum. Cumulative mortality (CM) of rainbow trout fry (mean weight, 1 g) vaccinated by i.p. injection of freeze/thawed Sf9 cells producing RecGlow was 18% in initial trials following IHNV challenge. This level of protection was significant (p < 0.05) but was not long lasting, and neutralizing Abs were not detected in pooled serum samples. When trout fry (mean weight, 0.6 g) were vaccinated with supernatant collected from sonicated Sf9 cells, Sf9 cells producing RecGlow, or Sf9 cells producing RecGhigh, CM averaged 46%. Protection was enhanced over negative controls, but not the positive controls (2% CM), suggesting that in the first trial soluble cellular proteins may have provided some level of non-specific protection, regardless of recombinant protein expression. Although some immunity was elicited in fish, and RecGlow provided short-term protection from IHNV, Ab-mediated protection could not be demonstrated. The results suggest that recombinant G proteins produced in insect cells lack the immunogenicity associated with vaccination of fish with an attenuated strain of IHNV.


Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.
Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells.


Atypical Clinical Presentation of Sporotrichosis Caused by Sporothrix globosa Resistant to Itraconazole.
Sporotrichosis is a polymorphic disease of humans and animals, which is acquired via traumatic inoculation of Sporothrix propagules into cutaneous or subcutaneous tissue. The etiological agents are in a clinical complex, which includes Sporothrix brasiliensis, Sporothrix schenckii, Sporothrix globosa, and Sporothrix luriei, each of which has specific epidemiological and virulence characteristics. Classical manifestation in humans includes a fixed localized lesion at the site of trauma plus lymphocutaneous sporotrichosis with fungal spreading along the lymphatic channels. Atypical sporotrichosis is a challenge to diagnosis because it can mimic many other dermatological diseases. We report an unusual, itraconazole-resistant cutaneous lesion of sporotrichosis in a 66-year-old Brazilian man. Histopathological examination of the skin revealed vascular and fibroblastic proliferation with chronic granulomatous infiltrate composed of multinucleated giant cells. Sporothrix were isolated from the skin lesion, and phylogenetic analyses confirmed it to be sporotrichosis due to S. globosa, a widespread pathogen. Immunoblotting analysis showed several IgG-reactive molecules in autochthonous preparations of the whole cellular proteins (160, 80, 60, 55, 46, 38, 35, and 30 kDa) and exoantigen (35 and 33 kDa). The patient was first unsuccessfully treated with daily itraconazole, and then successfully treated with potassium iodide.


Host susceptibility to schistosomes: effect of host sera on cell proliferation of Schistosoma mansoni schistosomula.
To determine effects of the sera on cell proliferation, schistosomula of Schistosoma mansoni (20-days-old) were incubated in medium containing fetal calf serum plus hamster (highly susceptible host) portal or peripheral venous serum, or rat (poorly susceptible host) portal or peripheral venous serum in the presence of bromodeoxyuridine (BrdU). Compared with schistosomula cultured in presence of control medium containing fetal calf serum alone, BrdU labeling indices (BLIs) were increased by 39% in the presence of portal, but not in peripheral, serum of hamsters. In contrast, no significant differences were observed in the BLIs in rat portal, or peripheral, sera or in control media. In vivo BrdU labeling results revealed that there was no detectable cell proliferation in S. mansoni schistosomula (6 days old) in the lungs. However, cell proliferation was detected in schistosomula beginning at 17 days. The results indicated that portal venous serum from a highly susceptible host, but not from a poorly susceptible host, stimulated schistosome cell proliferation in vitro. The timing of the increase in cell proliferation in terms of development corresponded to liver portal-mesenteric localization of schistosomula. Together, the data support the conclusion that in susceptible hosts, portal serum may play a role in schistosome cell proliferation, possibly resulting in termination of schistosome migration. This may explain the colocalization of adults, and the known organ selectivity of disease.


Automatic source speaker selection for voice conversion.
This paper focuses on the importance of source speaker selection for a weighted codebook mapping based voice conversion algorithm. First, the dependency on source speakers is evaluated in a subjective listening test using 180 different source-target pairs from a database of 20 speakers. Subjective scores for similarity to target speaker's voice and quality are obtained. Statistical analysis of scores confirms the dependence of performance on source speakers for both male-to-male and female-to-female transformations. A source speaker selection algorithm is devised given a target speaker and a set of source speaker candidates. For this purpose, an artificial neural network (ANN) is trained that learns the regression between a set of acoustical distance measures and the subjective scores. The estimated scores are used in source speaker ranking. The average cross-correlation coefficient between rankings obtained from median subjective scores and rankings estimated by the algorithm is 0.84 for similarity and 0.78 for quality in male-to-male transformations. The results for female-to-female transformations were less reliable with a cross-correlation value of 0.58 for both similarity and quality.


Responses to light after retinal degeneration.
Transgenic rodless mice were given 1-h pulses of light of varying brightness at times of the night when they were normally active. The rodless mice showed decreases in locomotor activity during light pulses brighter than 2 lux; these decreases were significantly greater than those in wildtypes (ANOVA, P < 0.01). However, with very dim light, rodless mice showed no changes in activity, whereas wildtype mice actually increased their activity. It is suggested that irradiance detection could be enhanced by absence of image-forming vision. Enhanced inhibition of activity around twilight may be adaptive for mice in some circumstances and so help maintain genes for retinal degeneration in natural populations.


Examining the unit costs of COVID-19 vaccine delivery in Kenya.
Vaccines are considered the path out of the COVID-19 pandemic. The government of Kenya is implementing a phased strategy to vaccinate the Kenyan population, initially targeting populations at high risk of severe disease and infection. We estimated the financial and economic unit costs of procuring and delivering the COVID-19 vaccine in Kenya across various vaccination strategies. We used an activity-based costing approach to estimate the incremental costs of COVID-19 vaccine delivery, from a health systems perspective. Document reviews and key informant interviews(n = 12) were done to inform the activities, assumptions and the resources required. Unit prices were derived from document reviews or from market prices. Both financial and economic vaccine procurement costs per person vaccinated with 2-doses, and the vaccine delivery costs per person vaccinated with 2-doses were estimated and reported in 2021USD. The financial costs of vaccine procurement per person vaccinated with 2-doses ranged from $2.89-$13.09 in the 30% and 100% coverage levels respectively, however, the economic cost was $17.34 across all strategies. Financial vaccine delivery costs per person vaccinated with 2-doses, ranged from $4.28-$3.29 in the 30% and 100% coverage strategies: While the economic delivery costs were two to three times higher than the financial costs. The total procurement and delivery costs per person vaccinated with 2-doses ranged from $7.34-$16.47 for the financial costs and $29.7-$24.68 for the economic costs for the 30% and 100% coverage respectively. With the exception of procurement costs, the main cost driver of financial and economic delivery costs was supply chain costs (47-59%) and advocacy, communication and social mobilization (29-35%) respectively. This analysis presents cost estimates that can be used to inform local policy and may further inform parameters used in cost-effectiveness models. The results could potentially be adapted and adjusted to country-specific assumptions to enhance applicability in similar low-and middle-income settings.


Surface-reflection-initiated pulse-contrast degradation in an optical parametric chirped-pulse amplifier.
We study a novel mechanism of pre-pulse generation in an optical parametric chirped-pulse amplification (OPCPA) system through an analytical approach together with numerical simulations. The acquired pre-pulses are initiated from the surface-reflection-induced modulation of the seed spectrum and occur as a consequence of high-order distortion of such modulated spectrum due to the instantaneous gain saturation effect. We demonstrate that the intensities of pre-pulses increase quadratically with the initial temporal modulation-depth of the stretched signal pulse as well as the conversion efficiency prior to substantial pump-depletion. Explicit formulas for estimating the contrast limit due to surface reflections are present. We also discuss the impact of group-velocity mismatch on the pre-pulse generation. The results of this work may deepen our cognition on the complexity of the pulse-contrast problem in OPCPA systems.


Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. None.


Association between different Non-Invasively Derived Thresholds with Lactate Threshold during graded incremental exercise.
We compared lactate threshold (TLac) with non-invasive markers of an aerobic-anaerobic transition; namely, ventilatory (VT) and tissue saturation index (TSIT) thresholds. While identification of a breakpoint in blood lactate concentration ([BLa]) is common for determination of an aerobic-anaerobic transition, non-invasive measures, VT and NIRS, have also received attention as a means of determining this critical exercise intensity. We hypothesised that one or other of these non-invasive measures would have a strong association with TLac. Thirty-one (n=31) competitive male athletes (mean ± SD, age 29±9 yr, height 1.81±0.1 m, body mass 77.7±10.0 kg) performed graded incremental cycling to volitional exhaustion. Heart rate, TSI and gas exchange data were measured throughout and [BLa] was determined at fixed intervals. Threshold detection involved a segmented linear regression analysis minimising the squared sum of the residuals to determine TLac, TSIT and VT. Workload and HR at TLac, VT and TSIT were analysed using repeated measures ANOVA and correlation assessed using Pearson's and interclass correlation coefficients. Thresholds at TSIT and TLac were not significantly different (255±35 vs. 249±30 W, P>0.05), suggesting that limitations in O2 delivery could be closely linked to an aerobic-anaerobic transition. However, poor correlation (r=0.55, ICC=0.54 and 95%LoA of +67 and -54 W) suggested other factors may exert an influence. Mean VT occurred at a significantly higher workload than TLac (271 ±35 vs 249±30 W, P<0.001). Consequently, VT proved less useful, giving an indication of when an aerobic-anaerobic transition had already occurred. In conclusion, non-invasive markers of the aerobic transition are not concurrent with TLac.


Granulomatous keratic precipitates in birdshot retinochoroiditis.
With the purpose of facilitating clinical studies of this infrequent disease, an expert panel published research criteria for birdshot retinochoroiditis (RCBRC). The aim of our study was to investigate the sensitivity of the exclusion criteria of the RCBRC as applied to all patients seen in our center with a diagnosis of BRC. This was a single center retrospective study involving all patients with an ocular inflammatory disease seen at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, between 1995 and 2012. The percentage of patients with a diagnosis of BRC was identified. The exclusion criteria of the RCBRC were applied to all patients and the percentage of patients with absence of keratic precipitates (KPs) and absence of posterior synechiae were calculated. Out of 1,504 new patients, 25 patients (1.66 %; 19 female, 6 male) were diagnosed with BRC and 19 patients had sufficient data to be included in the study (1.26 %, 13 female). All patients were positive for HLA-A29 testing. The sensitivity of the RCBRC with respect to the exclusion criteria applied to our patient cohort was 84.2 % due to the exclusion of three patients showing KPs. Our study supports the motion to re-evaluate the RCBRC, since granulomatous KPs can be present and are more frequent than previously estimated and stringent application of the criteria would lead to a substantial loss of study patients.


Interstitial Ectopic Pregnancy and Laparoscopic Removal of the Interstitial Portion of the Tube: the New Frontier?
We present a case of a 40-year-old lady with 9 weeks of amenorrhea diagnosed with an interstitial pregnancy and multiple uterine fibroids. She underwent laparoscopic salpingectomy including the interstitial part of fallopian tube with products of conception without myomectomy and cornuostomy. Intra-operative blood loss was minimal. She was followed up post-operatively with weekly serum beta human chorionic gonadotropin (serum β-hCG), which down-trended optimally at day 23 of surgery. Histopathology confirmed ectopic pregnancy with underlying salpingitis isthmica nodosa. Patient recovered well.


Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice.
Ultraviolet B (UVB) irradiation may cause inflammation- and oxidative-stress-dependent skin cancer and premature aging. Naringenin (1) has been reported to have anti-inflammatory and antioxidant properties, but its effects and mechanisms on UVB irradiation-induced inflammation and oxidative stress are still not known. Thus, the present study aimed to investigate the potential of naringenin to mitigate UVB irradiation-induced inflammation and oxidative damage in the skin of hairless mice. Skin edema, myeloperoxidase (neutrophil marker) and matrix metalloproteinase-9 (MMP-9) activity, and cytokine production were measured after UVB irradiation. Oxidative stress was evaluated by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging ability, ferric reducing antioxidant power (FRAP), reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, and gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR. The intraperitoneal treatment with naringenin reduced skin inflammation by inhibiting skin edema, neutrophil recruitment, MMP-9 activity, and pro-inflammatory (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-22, and IL-23) and anti-inflammatory (TGF-β and IL-10) cytokines. Naringenin also inhibited oxidative stress by reducing superoxide anion production and the mRNA expression of gp91phox. Therefore, naringenin inhibits UVB irradiation-induced skin damage and may be a promising therapeutic approach to control skin disease.


Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.


Analysis of the reliability of patient COVID-19 screening data compared against their actual test data.
This study aimed to evaluate the truthfulness of patients about their pre-appointment COVID-19 screening tests at a dental clinic. A total of 613 patients were recruited for the study from the dental clinic at the Faculty of Dentistry, Najran University, Saudi Arabia. The data collection was done in three parts from the patients who visited the hospital to receive dental treatment. The first part included the socio-demographic characteristics of the patients and the COVID-19 swab tests performed within the past 14 days. The second part was the clinical examination, and the third part was a confirmation of the swab test taken by the patient by checking the Hesen website using the patient ID. After data collection, statistical analysis was carried out using SPSS 26.0. Descriptive analysis was done and expressed as mean, standard deviation, frequency, and percentage (%). A cross-tabulation, also described as a contingency table, was used to identify trends and patterns across data and explain the correlation between different variables. It was seen from the status of the swab test within 14 days of the patient's arrival at the hospital for the dental treatment that 18 (2.9%) patients lied about the pre-treatment swab test within 14 days, and 595 (97.1%) were truthful. The observed and expected counts showed across genders and diagnosis a statistically significant difference (p < 0.001), and there was no significant difference seen across different age groups (p = 0.064) of the patients. Dental healthcare workers are worried and assume a high risk of COVID-19 infection as the patients are not truthful about the pre-treatment COVID-19 swab test. Routine rapid tests on patients and the healthcare staff are a feasible option for lowering overall risks.


Solvent-accessibility of discrete residue positions in the polypeptide hormone glucagon by 19F-NMR observation of 4-fluorophenylalanine.
The amino acid 4-fluoro-L-phenylalanine (4F-Phe) was introduced at the positions of Phe6 and Phe22 in the 29-residue polypeptide hormone glucagon by expressing glucagon in E. coli in the presence of an excess of 4F-Phe. Glucagon regulates blood glucose homeostasis by interaction with the glucagon receptor (GCGR), a class B GPCR. By referencing to the 4F-Phe chemical shifts at varying D2O concentrations, the solvent exposure of the two Phe sites along the glucagon sequence was determined, showing that 4F-Phe6 was fully solvent exposed and 4F-Phe22 was only partially exposed. The incorporation of fluorine atoms in polypeptide hormones paves the way for novel studies of their interactions with membrane-spanning receptors, specifically by differentiating between effects on the solvent accessibility, the line shapes, and the chemical shifts from interactions with lipids, detergents and proteins. Studies of interactions of GCGR with ligands in solution is at this point of keen interest, given that recent crystallographic studies revealed that an apparent small molecule antagonist actually binds as an allosteric effector at a distance of ~20 Å from the orthosteric ligand binding site (Jazayeri et al., in Nature 533:274-277, 2016).


Acceptance and Attitude toward COVID-19 Vaccination among the Public in Saudi Arabia: A Cross-sectional Study.
This cross-sectional study aimed to investigate vaccine acceptance and attitude to novel coronavirus disease 2019 (COVID-19) vaccine among the general population in Saudi Arabia. The present study was conducted among the general population in Saudi Arabia above 18 years of age. The data were collected online, by questionnaire containing 20 questions using Google form, in both Arabic and English, and were distributed to friends, families, and relatives through mail, WhatsApp groups, and Twitter. The questionnaire was randomly given out to the people living in five provinces of Saudi Arabia. A sum of 1,713 participants responded to the online survey. The greatest number of participants were at the age between 31 years and 45 years (36.6%) and 56.4% were females. The results showed that 74.6% have not registered for the vaccination and 44.9% responded not to take the vaccine. About 60.80% were concerned about the side effects, and 48.2% were worried about the allergic reaction to COVID-19 vaccine. About 49.1% of participants agreed that preventive measures, such as wearing mask, social distance, and using sanitizers, keep the virus away, and 53.20% believes that being exposed to disease naturally is safer for the immune system. Around 23.90% believes that vaccination cannot reduce the possibility of getting COVID-19. In the present study, the negative attitudes and afraid of the side effects of the vaccine are the most reasons for indecision and rejection about COVID-19 vaccine. For the future COVID-19 vaccination campaign not to fail, the Ministry of Saudi Arabia should closely follow the vaccination development processes, inform the public transparently, and consider public's concerns. The results of the current study will help the Ministry of Health in Saudi Arabia to attempt proactive missions by featuring the significance of immunization to the population and empowering vaccine take-up and acceptance.


Review of thrombotic microangiopathy (TMA), and post-renal transplant TMA.
Thrombotic microangiopathy (TMA) is a rare but devastating disorder; it involves small vessels and is characterized by intravascular thrombi of aggregated platelets leading to thrombocytopenia and variable degrees of organ ischemia and anemia, which is due to erythrocyte fragmentation in microcirculation. Childhood cases with predominant renal involvement are referred as the hemolytic uremic syndrome (HUS), and adults with major central neurological involvement are labeled as thrombotic thrombocytopenia purpura (TTP). Endothelial damage due to toxins and/or lack of defense against complement activation have a central role. Recent discovery of the von Willebrand Factor cleaving protease (ADAMTS 13) has offered new insight into the pathogenesis of TMA. TMA is also a well-recognized serious complication of renal transplantation. Clinical features of intravascular hemolysis are not always found. It may occur as de novo or recurrent and the majority of de novo cases are related to cyclosporin therapy. Viral infections, severe renal ischemia and acute vascular rejection are less frequent causes. Recurrence is negligible in diarrhea-associated HUS in childhood, but non-diarrheal HUS recurs in majority of adults following renal transplantation. Renal transplantation is contraindicated in familial/relapsing recurrent forms of HUS.


Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort.
Epigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features. Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children. We examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available. Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)] <0.05 associated with performance on the Autism Observational Scale for Infants (AOSI) at 12 months of age in offspring. The DMRs clustered near genes involved in developmental processes, including many genes in the SNORD family, within the Prader-Willi syndrome gene cluster. These results were consistent among the 75 probes on the Illumina 450K array that cover AOSI-associated DMRs from CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent differences in the cerebellums of autistic individuals compared with controls. These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring, and provide evidence that directionally consistent, potentially related epigenetic mechanisms may be operating in the cerebellum of individuals with autism.


Fibromyalgia patients and controls are equally accurate in detecting tactile stimuli while observing another in pain: an experimental study.
This study investigated the effects of observing pain in others upon vicarious somatosensory experiences and the detection of somatosensory stimuli in both fibromyalgia (FM) patients and controls. The putative modulatory role of dispositional empathy, hypervigilance to pain, and central sensitization was examined. FM patients (n = 39) and controls (n = 38) saw videos depicting pain-related (hands being pricked) and non-pain-related scenes, while occasionally experiencing vibrotactile stimuli themselves on the left, right, or both hands. Participants reported the location at which they felt a somatosensory stimulus. Tactile and visual scenes were presented in the same spatial location (congruent; e.g., left-left) or from opposite locations (incongruent; e.g., left-right). We calculated the proportion of correct responses, vicarious somatosensory experiences (i.e., trials on which an illusory somatosensory experience was reported while observing pain-related scenes), and neglect errors (i.e., reporting only the site congruent to the visual pain-related information when both hands had been stimulated). Observing another in pain resulted in an equal numbers of vicarious somatosensory experiences in both groups and facilitated the detection of tactile stimuli, especially during spatially congruent trials. Counter to our expectations, this facilitation was not moderated by group. FM patients made fewer neglect errors. Hypervigilance for pain, dispositional empathy, and central sensitization did not exert a modulatory role. Observing pain facilitates the detection of tactile stimuli in FM patients and controls. Overall, a low incidence of vicarious experiences was observed. Further research is needed to understand the role of attentional body focus in the elicitation of vicarious experiences.


Evaluation of pediatric thoracic disorders: comparison of unenhanced fast-imaging-sequence 1.5-T MRI and contrast-enhanced MDCT.
The purpose of this study was to investigate the efficacy of thoracic MRI with fast imaging sequences without contrast administration at 1.5 T for evaluating thoracic abnormalities by comparing MRI findings with contrast-enhanced MDCT findings. A prospective study included consecutively registered pediatric patients who from December 2009 to January 2012 underwent thoracic MDCT followed within 2 days by MRI for evaluation of thoracic abnormalities. The final study sample consisted of 71 children (36 boys, 35 girls; mean age, 8.6 ± 4.5 years; range, 2 months-16 years) and 71 paired thoracic MRI and MDCT studies. Thoracic MRI was performed in the axial and coronal planes with the following fast imaging sequences: T1-weighted fast-field echo inversion prepulse, T2-weighted balanced fast-field echo multiple 2D, T1- and T2-weighted turbo spin-echo cardiac-triggering parallel imaging technique without cardiac monitoring, and STIR. Thoracic MDCT was performed with i.v. contrast administration. Two pediatric radiologists independently reviewed each MRI and MDCT study for abnormalities in the lung, large airways, and mediastinal, pleural, and musculoskeletal structures. The sensitivity, specificity, and overall accuracy of MRI were calculated. Interobserver agreement was measured with the kappa coefficient. With MDCT as the reference standard, 51 of 71 (72%) patients had abnormal findings on MDCT studies, including infections in 21 (42%) cases, neoplasms in 19 (37%) cases, interstitial lung disease in seven (14%) cases, pleural effusion in three (6%) cases, and congenital bronchogenic cyst in one (2%) case. The overall diagnostic accuracy, sensitivity, and specificity of MRI for detecting thoracic abnormalities were 69 of 71 (97%), 49 of 51 (96%), and 20 of 20 (100%). Two undiagnosed findings with MRI that were detected with MDCT were mild bronchiectasis and small pulmonary nodule (3 mm). Almost perfect interobserver agreement was found between two reviewers with 70 of 71 agreements (κ = 0.97; 95% CI, 0.92-1.00; p < 0.001). CONCLUSION; MRI with fast imaging sequences without contrast administration is comparable to contrast-enhanced MDCT for detecting thoracic abnormalities in pediatric patients. Use of MRI with fast imaging sequences without contrast administration as a first-line cross-sectional imaging study in lieu of contrast-enhanced MDCT has the potential to benefit this patient population owing to reduced radiation exposure and i.v. contrast administration.


Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders.
One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways--the cyclooxygenase (CO) and the 5-lipoxygenase (5-LO)--leading to the production of prostaglandins and leukotrienes respectively. Amongst the CO products, PGE2 and amongst the 5-LO products, LTB4 are considered important mediators of inflammation. More than 200 potential drugs ranging from non-steroidal anti-inflammatory drugs, corticosteroids, gold salts, disease modifying anti-rheumatic drugs, methotrexate, cyclosporine are being tested. None of the drugs has been found safe; all are known to produce from mild to serious side-effects. Ginger is described in Ayurvedic and Tibb systems of medicine to be useful in inflammation and rheumatism. In all 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort) used powdered ginger against their afflictions. Amongst the arthritis patients more than three-quarters experienced, to varying degrees, relief in pain and swelling. All the patients with muscular discomfort experienced relief in pain. None of the patients reported adverse effects during the period of ginger consumption which ranged from 3 months to 2.5 years. It is suggested that at least one of the mechanisms by which ginger shows its ameliorative effects could be related to inhibition of prostaglandin and leukotriene biosynthesis, i.e. it works as a dual inhibitor of eicosanoid biosynthesis.


COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.
Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France). An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities. Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death. This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients.


A Window into brain development: hdEEG methods to track visual development in nonhuman primates.
Electroencephalography (EEG) is widely used to study human brain activity, and is a useful tool for bridging the gap between invasive neural recording assays and behavioral data. High-density EEG (hdEEG) methods currently used for human subjects for use with infant macaque monkeys, a species that exhibits similar visual development to humans over a shorter time course was adapted. Unlike monkeys, human subjects were difficult to study longitudinally and were not appropriate for direct within-species comparison to neuronal data. About 27-channel electrode caps, which allowed collection of hdEEG data from infant monkeys across development were designed. Acuity and contrast sweep VEP responses to grating stimuli was obtained and a new method for objective threshold estimation based on response signal-to-noise ratios at different stimulus levels was established. The developmental trajectories of VEP-measured contrast sensitivity and acuity to previously collected behavioral and neuronal data were compared. The VEP measures showed similar rates of development to behavioral measures, both of which were slower than direct neuronal measures; VEP thresholds were higher than other measures. This is the first usage of non-invasive technology in non-human primates. Other means to assess neural sensitivity in infants were all invasive. Use of hdEEG with infant monkeys opens many possibilities for tracking development of vision and other functions in non-human primates, and can expand our understanding of the relationship between neuronal activity and behavioral capabilities across various sensory and cognitive domains. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1342-1359, 2016.


Cross-Layer Adaptive Feedback Scheduling of Wireless Control Systems.
There is a trend towards using wireless technologies in networked control systems. However, the adverse properties of the radio channels make it difficult to design and implement control systems in wireless environments. To attack the uncertainty in available communication resources in wireless control systems closed over WLAN, a cross-layer adaptive feedback scheduling (CLAFS) scheme is developed, which takes advantage of the co-design of control and wireless communications. By exploiting crosslayer design, CLAFS adjusts the sampling periods of control systems at the application layer based on information about deadline miss ratio and transmission rate from the physical layer. Within the framework of feedback scheduling, the control performance is maximized through controlling the deadline miss ratio. Key design parameters of the feedback scheduler are adapted to dynamic changes in the channel condition. An eventdriven invocation mechanism for the feedback scheduler is also developed. Simulation results show that the proposed approach is efficient in dealing with channel capacity variations and noise interference, thus providing an enabling technology for control over WLAN.


Biogenic amines modulate synaptic transmission between identified giant interneurons and thoracic interneurons in the escape system of the cockroach.
In the escape system of the cockroach, Periplaneta americana, a population of uniquely identifiable thoracic interneurons (type A or TIAs) receive information about wind via chemical synapses from a population of ventral giant interneurons (vGIs). The TIAs are involved in the integration of sensory information necessary for orienting the animal during escape. It is likely that there are times in an animal's life when it is advantageous to modify the effectiveness of synaptic transmission between the vGIs and the TIAs. Given the central position of the TIAs in the escape system, this would greatly alter associated motor outputs. We tested the ability of octopamine, serotonin, and dopamine to modulate synaptic transmission between vGIs and TIAs. Both octopamine and dopamine significantly increased the amplitude of vGI-evoked excitatory postsynaptic potentials (EPSPs) in TIAs at 10(-4)-10(-2) M, and 10(-3) M, respectively. On the other hand, serotonin significantly decreased the vGI-evoked EPSPs in TIAs at 10(-4)-10(-3) M. These results indicate that octopamine, serotonin, and dopamine are capable of modulating the efficacy of transmission of important neural connections within this circuit.


Post-translational modification of cyclin A1 is associated with staurosporine and TNFalpha induced apoptosis in leukemic cells.
Understanding of molecular mechanisms underlying the effects of cell cycle proteins in response to the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to chemotherapeutic agents. Staurosporine and tumor necrosis factor alpha (TNFalpha) are the therapeutic agents that inhibit tumor cell growth by inducing cell death. Staurosporine induces apoptosis through the intrinsic pathway, while TNFalpha trigger the cell death via the extrinsic apoptotic pathway. We have previously demonstrated that the cell cycle regulatory protein, cyclin A1 played an important role in the development of acute myeloid leukemia (AML), and cyclin A1 expression correlated with disease characteristics and patient outcome in leukemia. However, it remains unknown how cyclin A1 expression is regulated in leukemic cells treated with the therapeutic agents. Here, we demonstrate that cyclin A1 protein is regulated by proteasome-mediated ubiquitination and degradation in untreated U-937 cells. Interestingly, ubiquitination- and proteasomal-mediated degradation of cyclin A1 is prevented in cells treated with staurosporine or TNFalpha. Induction of apoptosis in U-937 cells by staurosporine or TNFalpha resulted in an increase in cyclin A1 protein expression, which correlated well with cyclin A1 protein modification and the activation of caspase-3. Blocking caspases activity by Z-VAD-FMK had no effect on the increased cyclin A1 expression, suggesting that cyclin A1 might be regulated by caspase-3 independent pathways. We further propose that CDC25C may be associated with cyclin A1 protein modification in response to staurosporine or TNFalpha treatment. Our results suggest that cyclin A1 protein is stabilized via post-transcriptional modification in response to apoptosis induced by staurosporine or TNFalpha.


Chameleon-like behaviour of cyclo[n]paraphenylenes in complexes with C70: on their impressive electronic and structural adaptability as probed by Raman spectroscopy.
A series of four 1 : 1 host-guest supramolecular complexes of [n]CPPs and C(70) have been analyzed by Raman spectroscopy in the solid state and complemented with the analysis of their spectroscopic responses under mechanical and thermal stresses. By following the frequency behaviour of the G and RBM modes we have found that [10]CPP in the [10]CPP@C(70) complex displays a more "ordered" structure. However, in [11]CPP@C(70), the nanoring becomes oval-shaped with closer contacts with the C(70) poles and less conformational restriction in the flattened region. By mechanical and thermal stresses we are able to modify the lying conformation of [10]CPP@C(70) towards a standing orientation. [11]CPP@C(70) resists pressure changes, although it tends to shift from the standing to the lying orientation by heating. As for the crystal cell, the [n]CPPs occupy the residual empty spaces while the main crystallographic positions are reserved for C(70). These are new examples of the impressive adaptability of the [n]CPP molecules to different physico-chemical environments, a chameleon-like property which reveals the delicate equilibrium provided by cyclic conjugation and ring strain.


Evaluating the efficacy of lavender aromatherapy on peripheral venous cannulation pain and anxiety: A prospective, randomized study.
This study was designed to evaluate the effectiveness of lavender aromatherapy on pain, anxiety, and level of satisfaction associated with the peripheral venous cannulation (PVC) in patients undergoing surgery. One hundred and six patients undergoing surgery were randomized to receive aromatherapy with lavender essential oil (the lavender group) or a placebo (the control group) during PVC. The patients' pain, anxiety, and satisfaction scores were measured. There was no statistically significantly difference between the groups in terms of demographic data. After cannulation, the pain and anxiety scores (anxiety 2) of the patients in the lavender group were significantly lower than the control group (for p = 0.01 for pain scores; p < 0.001 for anxiety 2 scores). In addition, patient satisfaction was significantly higher in the lavender group than in the control group (p = 0.003). Lavender aromatherapy had beneficial effects on PVC pain, anxiety, and satisfaction level of patients undergoing surgery.


Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet.
Dietary intake of linoleic acid (LNA, 18:2n-6) has increased dramatically during the 20th century and is associated with greater prevalence of obesity. The endocannabinoid system is involved in regulation of energy balance and a sustained hyperactivity of the endocannabinoid system may contribute to obesity. Arachidonic acid (ARA, 20:4n-6) is the precursor for 2-AG and anandamide (AEA), and we sought to determine if low fat diets (LFD) could be made obesogenic by increasing the endocannabinoid precursor pool of ARA, causing excessive endocannabinoid signaling leading to weight gain and a metabolic profile associated with obesity. Mice (C57BL/6j, 6 weeks of age) were fed 1 en% LNA and 8 en% LNA in low fat (12.5 en%) and medium fat diets (MFD, 35 en%) for 16 weeks. We found that increasing dietary LNA from 1 to 8 en% in LFD and MFD significantly increased ARA in phospholipids (ARA-PL), elevated 2-AG and AEA in liver, elevated plasma leptin, and resulted in larger adipocytes and more macrophage infiltration in adipose tissue. In LFD, dietary LNA of 8 en% increased feed efficiency and caused greater weight gain than in an isocaloric reduction to 1 en% LNA. Increasing dietary LNA from 1 to 8 en% elevates liver endocannabinoid levels and increases the risk of developing obesity. Thus a high dietary content of LNA (8 en%) increases the adipogenic properties of a low fat diet.


The conserved Phe GH5 of importance for hemoglobin intersubunit contact is mutated in gadoid fish.
Functionality of the tetrameric hemoglobin molecule seems to be determined by a few amino acids located in key positions. Oxygen binding encompasses structural changes at the interfaces between the α1β2 and α2β1 dimers, but also subunit interactions are important for the oxygen binding affinity and stability. The latter packing contacts include the conserved Arg B12 interacting with Phe GH5, which is replaced by Leu and Tyr in the αA and αD chains, respectively, of birds and reptiles. Searching all known hemoglobins from a variety of gnathostome species (jawed vertebrates) revealed the almost invariant Arg B12 coded by the AGG triplet positioned at an exon-intron boundary. Rare substitutions of Arg B12 in the gnathostome β globins were found in pig, tree shrew and scaled reptiles. Phe GH5 is also highly conserved in the β globins, except for the Leu replacement in the β1 globin of five marine gadoid species, gilthead seabream and the Comoran coelacanth, while Cys and Ile were found in burbot and yellow croaker, respectively. Atlantic cod β1 globin showed a Leu/Met polymorphism at position GH5 dominated by the Met variant in northwest-Atlantic populations that was rarely found in northeast-Atlantic cod. Site-specific analyses identified six consensus codons under positive selection, including 122β(GH5), indicating that the amino acid changes identified at this position may offer an adaptive advantage. In fact, computational mutation analysis showed that the replacement of Phe GH5 with Leu or Cys decreased the number of van der Waals contacts essentially in the deoxy form that probably causes a slight increase in the oxygen binding affinity. The almost invariant Arg B12 and the AGG codon seem to be important for the packing contacts and pre-mRNA processing, respectively, but the rare mutations identified might be beneficial. The Leu122β1(GH5)Met and Met55β1(D6)Val polymorphisms in Atlantic cod hemoglobin modify the intradimer contacts B12-GH5 and H2-D6, while amino acid replacements at these positions in avian hemoglobin seem to be evolutionary adaptive in air-breathing vertebrates. The results support the theory that adaptive changes in hemoglobin functions are caused by a few substitutions at key positions.


Clinical pharmacists on medical care of pediatric inpatients: a single-center randomized controlled trial.
To explore the best interventions and working patterns of clinical pharmacists in pediatrics and to determine the effectiveness of clinical pharmacists in pediatrics. We conducted a randomized controlled trial of 160 pediatric patients with nerve system disease, respiratory system disease or digestive system disease, who were randomly allocated into two groups, with 80 in each group. Interventions by clinical pharmacists in the experimental group included answering questions of physicians and nurses, giving advice on treating patients, checking prescriptions and patient counseling at discharge. In the control group, patients were treated without clinical pharmacist interventions. Of the 109 interventions provided by clinical pharmacists during 4 months, 47 were consultations for physicians and nurses, 31 were suggestions of treatment, with 30 accepted by physicians (96.77%) and 31 were medical errors found in 641 prescriptions. Five adverse drug reactions were submitted to the adverse drug reaction monitoring network, with three in the experimental group and two in the control group. The average length of stay (LOS) for patients with respiratory system diseases in the experimental group was 6.45 days, in comparison with 10.83 days in the control group, which was statistically different (p value<0.05); Average drug compliance rate in the experimental group was 81.41%, in comparison with 70.17% of the control group, which was statistically different (p value<0.05). Cost of drugs and hospitalization and rate of readmission in two weeks after discharge in the two groups were not statistically different. Participation by clinical pharmacists in the pharmacotherapy of pediatric patients can reduce LOS of patients with respiratory system disease and improve compliance rate through discharge education, showing no significant effects on prevention of ADR, reduction of cost of drugs and hospitalization and readmission rate in two weeks. Chinese Clinical Trial Registry ChiCTR-TRC-10001081.


Rapid Divergence of Wing Volatile Profiles Between Subspecies of the Butterfly Pieris rapae (Lepidoptera: Pieridae).
Complex signaling traits such as pheromone profiles can play an important role in the early stages of reproductive isolation between populations. These signals can diverge along multiple trait axes, and signal receivers are often sensitive to subtle differences in signal properties. In the Lepidoptera, prior research has highlighted that natural selection can drive rapid chemical signal divergence, for instance via mate recognition to maintain species boundaries. Much less is known about the occurrence of such changes for predominantly sexually selected chemical signals, such as those released by many male lepidopterans. We evaluated the divergence in male and female wing volatile profiles between two recently isolated subspecies of the pierid butterfly Pieris rapae Linnaeus (Lepidoptera: Pieridae): P. rapae rapae and P. rapae crucivora. In laboratory settings, these subspecies exhibit strong premating isolation, with females rejecting males of the opposite subspecies despite the fact that males direct equivalent courtship effort toward females of either subspecies. Using gas chromatography-mass spectrometry, we analyzed the volatile chemical profiles of individual males and females of each subspecies. We find that males of each subspecies differ in their wing volatile profiles, including quantitative differences in a male sex pheromone, ferrulactone. In contrast, female wing volatiles profiles have diverged significantly less. These sex-specific patterns suggest that male chemical profiles may play a role in the observed premating isolation between these two subspecies, providing support for future investigations of sexually selected chemical traits in population divergence.


The Moderating Role of Gender in the Relationship Between Tobacco Outlet Exposure and Tobacco Use Among African American Young Adults.
Tobacco outlet exposure is a correlate of tobacco use with potential differences by gender that warrant attention. The aim of this study is to explore the moderating role of gender in the relationship between tobacco outlet exposure and past month tobacco use among African American young adults 21 to 24 years old. This cross-sectional study (n = 283) used geospatial methods to determine the number of tobacco outlets within walking distance (i.e., a quarter mile) of participants' homes and distance to the nearest outlet. Logistic regression models were used to test interactions between gender and tobacco outlet exposure (i.e., density and proximity). Tobacco outlets were classified based on whether or not they were licensed to sell tobacco only (TO outlets) or tobacco and alcohol (TA outlets). Neither density nor proximity was associated with past month tobacco use in the pooled models. However, gender modified the relationship between TO outlet density and tobacco use, and this relationship was significant only among women (OR = 1.02; p < 0.01; adjusted OR = 1.01; p < 0.05). This study underscores the importance of reducing tobacco outlet density in residential neighborhoods, especially TO outlets, as well as highlights potential gender differences in the relationship between tobacco outlet density and tobacco use.


Olfactory aversive conditioning during sleep reduces cigarette-smoking behavior.
Recent findings suggest that novel associations can be learned during sleep. However, whether associative learning during sleep can alter later waking behavior and whether such behavioral changes last for minutes, hours, or days remain unknown. We tested the hypothesis that olfactory aversive conditioning during sleep will alter cigarette-smoking behavior during ensuing wakefulness. A total of 66 human subjects wishing to quit smoking participated in the study (23 females; mean age, 28.7 ± 5.2 years). Subjects completed a daily smoking diary detailing the number of cigarettes smoked during 7 d before and following a 1 d or night protocol of conditioning between cigarette odor and profoundly unpleasant odors. We observed significant reductions in the number of cigarettes smoked following olfactory aversive conditioning during stage 2 and rapid eye movement (REM) sleep but not following aversive conditioning during wakefulness (p < 0.05). Moreover, the reduction in smoking following aversive conditioning during stage 2 (34.4 ± 30.1%) was greater and longer lasting compared with the reduction following aversive conditioning during REM (11.9 ± 19.2%, p < 0.05). Finally, the reduction in smoking following aversive conditioning during sleep was significantly greater than in two separate control sleep experiments that tested aversive odors alone and the effects of cigarette odors and aversive odors without pairing. To conclude, a single night of olfactory aversive conditioning during sleep significantly reduced cigarette-smoking behavior in a sleep stage-dependent manner, and this effect persisted for several days.


Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampulla of Vater: preliminary report.
Adjuvant chemoradiotherapy decreases the risk of local recurrence in patients with adenocarcinoma of the ampulla of Vater and high-risk features. Adjuvant chemoradiotherapy for this population can be administered safely and without much morbidity. Controlled, prospective, single-arm study. Tertiary care referral hospital. From June 1995 to March 1999, 12 patients (7 men and 5 women; median age, 66 years; age range, 38-78 years) with "unfavorable" ampullary carcinoma were treated with adjuvant chemoradiotherapy. All patients underwent pancreaticoduodenectomy, and all pathologic findings were confirmed at Stanford University Medical Center, Stanford, Calif. Unfavorable features were defined as involved lymph nodes (n = 10), involved surgical margins (n = 1), poorly differentiated histological features (n = 3), tumor size greater than 2 cm (n = 6), or the presence of neurovascular invasion (n = 4). Four to 6 weeks after undergoing pylorus-preserving pancreaticoduodenectomy with regional lymphadenectomy, patients began adjuvant chemoradiotherapy consisting of concurrent radiotherapy (45 Gy) and fluorouracil by protracted venous infusion (225-250 mg/m(2) per day, 7 days per week) for 5 weeks. Local recurrence, distant recurrence, overall survival rate, and treatment-related toxic effects. All patients completed the prescribed treatment course. Toxic effects were assessed twice a week during treatment and graded according to the National Cancer Institute Common Toxicity Criteria Scale. One patient required a treatment interruption of 1 week for grade III nausea/vomiting. No grade IV or V toxic effects were observed. At median follow-up of 24 months (range, 13-50 months), 8 of 12 patients were alive and disease free. One patient was alive but had disease recurrence. Three patients died of this disease (liver metastases). Actuarial overall survival at 2 years was 89%, and median survival was 34 months. One surviving patient developed a local recurrence and a lung lesion. Actuarial overall survival and median survival were better than in a parallel cohort with resected high-risk pancreatic cancer (n = 26) treated with the same adjuvant chemoradiotherapy regimen (median survival, 34 vs 14 months; P<.004). Adjuvant chemoradiotherapy for carcinoma of the ampulla of Vater is well tolerated and might improve control of this disease in patients with unfavorable features.


Physical load exposure at construction sites.
This field study analyzed work-related causes of musculoskeletal disorders to investigate the structure of physical workload in different occupations in the construction industry and rank different tasks with respect to the load on the lumber spine. An observation instrument (Arbeitswissenschaftliches Erhebungsverfahren für Bauarbeiten) and a specially devised data retrieval system (Allgemeines Datenerfassungs- und Analysesystem für Bauarbeit) provided material for a large database which allowed a differentiated analysis of load exposures. The study was comprised of data from 340 construction workers (bricklayers, scaffolders, carpenters, plumbers, and painters). On the basis of a regular daily worktime of 8 hours, specific statistical aspects were studied concerning manual materials handling, biomechanical pressure on lumbar disc L5/S1, and posture constraints during kneeling, squatting, bending and overhead positions. The scaffolders (13.7% of the regular daily worktime), bricklayers using bricks requiring two hands (7.1%), and carpenters (6.7%) handled weights of > 10 kg. With respect to lumbar disc L5/S1, the scaffolders and bricklayers often showed pressures in excess of 3.4 kN. Bricklaying required bent postures for 20.7-35.6% of the daily worktime. The painters (23.8%), plumbers (16.7%), and carpenters (7.2%) often worked in kneeling postures. The painters often used overhead positions (18.3%). The bricklayers and scaffolders had high frequencies of materials handling. The recovery time for this repetitive work was longer than threefold the load time. This study showed that it is possible to rank different construction tasks with respect to load exposure. In addition it was shown that preventive measures such as improved ergonomic design, organizational structure, training, and medical health care are needed.


Seric chemokines and chemokine receptors in eosinophils during acute human schistosomiasis mansoni.
The recruitment of circulating eosinophils by chemokines and chemokine receptors plays an important role in the inflammation process in acute human schistosomiasis. Our main focus has been on the plasma chemokines (CXCL8/CCL2/CCL3/CCL24) and chemokine receptors (CCR2/CCR3/CCR5/CXCR1/CXCR2/CXCR3/CXCR4) expressed by circulating eosinophils from acute Schistosoma mansoni infected patients (ACT). Our studies compared ACT patients and healthy individuals as a control group. Our major findings demonstrated a plethora of chemokine secretion with significantly increased secretion of all chemokines analysed in the ACT group. Although no differences were detected for beta-chemokine receptors (CCR2, CCR3 and CCR5) or alpha-chemokine receptors (CXCR3 and CXCR4), a significantly lower frequency of CXCR1+ and CXCR2+ eosinophils in the ACT group was observed. The association between chemokines and their chemokine receptors revealed that acutely infected schistosome patients displaying decreased plasma levels of CCL24 are the same patients who presented enhanced secretion of CCL3, as well as increased expression of both the CCR5 and CXCR3 chemokine receptors. These findings suggest that CCL24 may influence the kinetics of chemokines and their receptors and eosinophils recruitment during human acute schistosomiasis mansoni.