Time-Varying mHAP-III Is the Most Accurate Predictor of Survival in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.
The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10-1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.


Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing.
Bone injuries such as fractures are one major cause of morbidities worldwide. A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects. Herein, we tested the hypothesis that the purine molecule, adenosine, can simultaneously alleviate pain and promote healing in a mouse model of tibial fracture by targeting distinctive adenosine receptor subtypes in different cell populations. To achieve this, a biomaterial-assisted delivery of adenosine is utilized to localize and prolong its therapeutic effect at the injury site. The results demonstrate that local delivery of adenosine inhibited the nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigated pain as demonstrated by weight bearing and open field movement tests. Concurrently, local delivery of adenosine at the fracture site promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) resulting in improved bone healing as shown by histological analyses and microCT imaging. This study demonstrates the dual role of adenosine and its material-assisted local delivery as a feasible therapeutic approach to treat bone trauma and associated pain.


Opportunistic infections and Kaposi's sarcoma among Haitians: evidence of a new acquired immunodeficiency state.
Twenty Haitian patients, hospitalized from 1 April 1980 to 20 June 1982, had Pneumocystis carinii pneumonia, central nervous system toxoplasmosis, esophageal candidiasis, cryptococcosis, disseminated cytomegalovirus, progressive herpes simplex virus, chronic enteric coccidiosis, or invasive Kaposi's sarcoma. Ten patients died. Opportunistic infections were frequently multiple and were recurrent in three patients. In seven patients disseminated tuberculosis preceded the other infections by 2 to 15 months. There was no evidence of an underlying immunosuppressive disease, and no history of homosexuality or intravenous drug abuse. At least three patients probably acquired the syndrome in Haiti. Lymphadenopathy was common. Seventeen patients tested had anergy, and 18 had lymphopenia. Monoclonal antibody analysis of peripheral-blood T-cell subsets done on 11 patients showed a marked decrease in T-helper cells and an inversion of the normal ratio of T-helper cells to T-suppressor cells. This syndrome among heterosexual Haitians is strikingly similar to the syndrome of immunodeficiency described recently among American homosexuals.


Ileal smooth muscle motility depression on rabbit induced by toxin A from Clostridium difficile.
This study is aimed at elucidating with in vitro experiments the time course of alteration of ileal motility caused by in vivo exposure of ligated loops of ileum to toxin A (1 microg/ligated loop) of Clostridium difficile. In the sham-operated animals no significant alteration of motility was observed. In ligated loops directly injected with toxin A and in loops neighboring those administered with this toxin, a biphasic time course of motility alterations was observed. There was initially (2 h after toxin administration) an increase in spontaneous motility and in the amplitude of maximal contraction induced by potassium and acetylcholine. Afterwards there was a progressive depression of motility, which was more severe in loops directly injected. These results suggested a significant progressive depression of rabbit ileal motility induced by toxin A from C. difficile.


First evaluation of the threat posed by antifouling biocides in the Southern Adriatic Sea.
The CARISMA project (characterization and ecological risk analysis of antifouling biocides in the Southern Adriatic Sea) aims to appraise the quality of the Southern Adriatic Sea between Italy (Apulia region) and Albania and, in particular, the impact due to the use of biocidal antifouling coatings. Under this project, a preliminary survey at the main hot spots of contamination (e.g. ports and marinas) was conducted at the end of the nautical season in 2012. Chemical seawater analyses were complemented with ecotoxicological assays and the results were analyzed by principal component analysis (PCA). As expected, PCA splits the Albanian and Italian ports, according to the different degrees of contamination indicated for the two countries by the experimental data, highlighting the most critical situation in one port of Apulia. In addition, in order to assess the potential adverse ecological effects posed by antifouling agents (i.e. tributyltin (TBT)-irgarol-diuron) on non-target marine organisms, hazard quotients (HQ) were calculated. The results showed a low risk posed by irgarol and diuron whereas the probability of adverse effects was high in the case of TBT.


Evaluation of a directly observed six months fully intermittent treatment regimen for tuberculosis in patients suspected of poor compliance.
Although a priority for tuberculosis control is to achieve the maximum cure rate, compliance with chemotherapy in specific high risk groups (homeless, intravenous drug abusers, chronic alcoholics) is usually poor. From January 1990 to December 1994 102 patients with tuberculosis (96 pulmonary, six extrapulmonary) who were poorly compliant with treatment were treated with a six month fully intermittent (twice weekly) directly observed regimen. They comprised 71 homeless subjects, 50 chronic alcoholics, 23 intravenous drug abusers, nine infected with HIV, and 11 who had previously abandoned a daily antituberculosis regimen; 53 had more than one of these risk factors. Treatment included isoniazid and rifampicin for six months and pyrazinamide during the first two months. Patients who failed to take their medication on two consecutive occasions were actively sought by telephone or by personal search. After two months of treatment 95 of the 102 patients had taken their medication regularly and 90 of them had negative cultures. Four of the remaining patients had negative cultures after three months. At the end of the six months 87 patients had completed treatment and were considered cured. Only 15 patients abandoned the treatment (13 of whom had more than one risk factor). Only three relapses occurred in the 102 patients at one year follow up and in the 88 patients followed for two years. Two patients required a change of treatment due to major side effects. Although intravenous drug abuse was the only predictor of non-compliance in the multivariate analysis, if the available variables in the second month of treatment were analysed, current poor compliance and abandonment of treatment in the past were found to be significantly associated with non-compliance. This study shows the efficacy of this intermittent regimen and the effectiveness of a directly observed treatment programme.


Microfluidic multiculture assay to analyze biomolecular signaling in angiogenesis.
Angiogenesis (the formation of blood vessels from existing blood vessels) plays a critical role in many diseases such as cancer, benign tumors, and macular degeneration. There is a need for cell culture methods capable of dissecting the intricate regulation of angiogenesis within the microenvironment of the vasculature. We have developed a microscale cell-based assay that responds to complex pro- and antiangiogenic soluble factors with an in vitro readout for vessel formation. The power of this system over traditional techniques is that we can incorporate the whole milieu of soluble factors produced by cells in situ into one biological readout (vessel formation), even if the identity of the factors is unknown. We have currently incorporated macrophages, endothelial cells, and fibroblasts into the assay, with the potential to include additional cell types in the future. Importantly, the microfluidic platform is simple to operate and multiplex to test drugs targeting angiogenesis in a more physiologically relevant context. As a proof of concept, we tested the effect of an enzyme inhibitor (targeting matrix metalloproteinase 12) on vessel formation; the triculture microfluidic assay enabled us to capture a dose-dependent effect entirely missed in a simplified coculture assay (p < 0.0001). This result underscores the importance of cell-based assays that capture chemical cross-talk occurring between cell types. The microscale dimensions significantly reduce cell consumption compared to conventional well plate platforms, enabling the use of limited primary cells from patients in future investigations and offering the potential to screen therapeutic approaches for individual patients in vitro.


Navigating the cultural transition alone: psychosocial adjustment of Korean early study abroad students.
Precollege study abroad in English-speaking countries is an increasingly popular educational strategy among Asian families. We used grounded theory method to construct a model of cultural adjustment process for unaccompanied minors based the retrospective narratives of 10 (8 male) South Korean adolescents who came to the United States, unaccompanied by parents, to attend middle schools or high schools. We found that unaccompanied minors' cultural adjustment progressed from their predeparture ambivalence to initial sense of vulnerability to an eventual sense of reengagement. Unaccompanied minor students' pervasive sense of vulnerability upon arrival was heightened not only by their lack of English fluency but also their reluctance to seek the support of parents in Korea and of local Korean peers. This study has implications for educators and counselors in secondary schools who work with international students who are unaccompanied minors.


Chemoreduction of Orbital Recurrence of Uveal Melanoma by Intra-Arterial Melphalan.
The treatment of orbital melanoma poses a management challenge. This case explores the delivery of high-dose melphalan to an orbital recurrence of uveal melanoma via intra-arterial delivery of melphalan to the orbit. A 62-year-old man developed recurrent orbital disease 7 months after enucleation for a large uveal melanoma. He received 6 monthly intra-arterial infusions of melphalan to the orbit, ranging in dose from 20 to 30 mg per infusion. Following the last infusion, mild temporary erythema was noted on the forehead along the distribution of the supratrochlear artery. The orbital recurrence was reduced in size by 66% in the longest dimension as measured by magnetic resonance imaging (MRI). However, 9 months following intra-arterial melphalan, tumor regrowth was detected on MRI, and additional treatment options were pursued. This case demonstrates that intra-arterial melphalan can result in nonsustained tumor regression of recurrent orbital uveal melanoma. It suggests that local delivery of high-dose melphalan may be helpful as a neoadjuvant treatment for uveal melanoma, and future studies will be useful to confirm the value of this approach in additional cases of recurrent and possibly in primary uveal melanoma.


Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.
A recently determined set of 20 NMR-derived conformations of a 48-residue all-alpha-helical protein, (PDB ID code 2JVD), is validated here by comparing the observed (13)C(alpha) chemical shifts with those computed at the density functional level of theory. In addition, a recently introduced physics-based method, aimed at determining protein structures by using NOE-derived distance constraints together with observed and computed (13)C(alpha) chemical shifts, was applied to determine a new set of 10 conformations, (Set-bt), as a blind test for the same protein. A cross-validation of these two sets of conformations in terms of the agreement between computed and observed (13)C(alpha) chemical shifts, several stereochemical quality factors, and some NMR quality assessment scores reveals the good quality of both sets of structures. We also carried out an analysis of the agreement between the observed and computed (13)C(alpha) chemical shifts for a slightly longer construct of the protein solved by x-ray crystallography at 2.0-A resolution (PDB ID code 3BHP) with an identical amino acid residue sequence to the 2JVD structure for the first 46 residues. Our results reveal that both of the NMR-derived sets, namely 2JVD and Set-bt, are somewhat better representations of the observed (13)C(alpha) chemical shifts in solution than the 3BHP crystal structure. In addition, the (13)C(alpha)-based validation analysis appears to be more sensitive to subtle structural differences across the three sets of structures than any other NMR quality-assessment scores used here, and, although it is computationally intensive, this analysis has potential value as a standard procedure to determine, refine, and validate protein structures.


Seasonality and the persistence of vector-borne pathogens.
Many vector-borne diseases are affected by the seasonality of the environment. Yet, seasonality can act on distinct steps of the life cycle of the pathogen and it is often difficult to predict the influence of the periodic fluctuations of the environment on the basic reproduction ratio R0 of vector-borne pathogens. Here, we analyse a general vector-borne disease model and we account for periodic fluctuations of different components of the pathogen's life cycle. We develop a perturbation analysis framework to obtain useful approximations to evaluate the overall consequences of seasonality on the R0 of the pathogen. This analysis reveals when seasonality is expected to increase or to decrease pathogen persistence. We show that seasonality in vector density or in the biting rate of the vector can have opposite effects on persistence and we provide a useful biological explanation for this result based on the covariance between key compartments of the epidemiological model. This framework could be readily extended to explore the influence of seasonality on other components of the life cycle of vector-borne pathogens.


A compendium of genome-wide associations for cancer: critical synopsis and reappraisal.
Since 2007, genome-wide association (GWA) studies have identified numerous well-supported, novel genetic risk loci for common cancers; however, there are concerns that this technology is reaching its limits. We provide an overview of GWA-identified genetic associations with solid tumors. We simulated the distribution of population risk alleles for colorectal, prostate, testicular, and thyroid cancers based on genetic variants identified in GWA studies. We also evaluated whether statistical power to detect typical genetic effects could be improved with studies performing GWA analyses of all available samples rather than multistage designs. Fifty-six eligible articles yielded 92 eligible associations between cancer phenotypes and genetic variants with a median per-allele odds ratio (OR) of 1.22 (interquartile range = 1.15-1.36). Half of the associations pertained to prostate, colorectal, or breast cancer. Individuals at the upper quartile of simulated risk had only 2.1- to 4.2-fold higher relative risk than those in the lower quartile. Comprehensive evaluation of currently available samples with GWA platforms would yield few additional variants with per-allele OR = 1.4, but many more variants with OR = 1.2 could be detected; statistical power to detect weak associations (OR = 1.07) would still be negligible. The GWA approach is effective in identifying common genetic variants with moderate effect; however, identifying loci with very small effects and rare variants will require major new efforts. At present, the utility of GWA-identified risk loci in risk stratification for cancer is limited.


The contribution of acidic residues to the conformational stability of common-type acylphosphatase.
Common-type acylphosphatase is a small cytosolic enzyme whose catalytic properties and three-dimensional structure are known in detail. All the acidic residues of the enzyme have been replaced by noncharged residues in order to assess their contributions to the conformational stability of acylphosphatase. The enzymatic activity parameters and the conformational free energy of each mutant were determined by enzymatic activity assays and chemically induced unfolding, respectively. Some mutants exhibit very similar conformational stability, DeltaG(H2O), and specific activity values as compared to the wild-type enzyme. By contrast, six mutants show a significant reduction of conformational stability and two mutants are more stable than the wild-type protein. Although none of the mutated acidic residues is directly involved in the catalytic mechanism of the enzyme, our results indicate that mutations of residues located on the surface of the protein are responsible for a structural distortion which propagate up to the active site. We found a good correlation between the free energy of unfolding and the enzymatic activity of acylphosphatase. This suggests that enzymatic activity measurements can provide valuable indications on the conformational stability of acylphosphatase mutants, provided the mutated residue lies far apart from the active site. Moreover, our results indicate that the distortion of hydrogen bonds rather than the loss of electrostatic interactions, contributes to the decrease of the conformational stability of the protein.


Silicon-chip mid-infrared frequency comb generation.
Optical frequency combs are a revolutionary light source for high-precision spectroscopy because of their narrow linewidths and precise frequency spacing. Generation of such combs in the mid-infrared spectral region (2-20 μm) is important for molecular gas detection owing to the presence of a large number of absorption lines in this wavelength regime. Microresonator-based frequency comb sources can provide a compact and robust platform for comb generation that can operate with relatively low optical powers. However, material and dispersion engineering limitations have prevented the realization of an on-chip integrated mid-infrared microresonator comb source. Here we demonstrate a complementary metal-oxide-semiconductor compatible platform for on-chip comb generation using silicon microresonators, and realize a broadband frequency comb spanning from 2.1 to 3.5 μm. This platform is compact and robust and offers the potential to be versatile for use outside the laboratory environment for applications such as real-time monitoring of atmospheric gas conditions.


Unexpected effect of urate on hydrogen peroxide-induced oxidative damage in embryonic chicken cardiac cells.
Uric acid (UA) is a potent scavenger of oxidants in most mammalian and avian species. The aim of this study was to obtain more comprehensive information regarding the relationship between different concentrations of UA and oxidative balance in chicken cardiac cells. First, oxidative damage parameters were measured in chicken cardiac cells treated with different concentrations of UA. UA concentrations within the normal physiological range had no effect, while treatment with a high level of UA, i.e. 1200 μM, increased the malondialdehyde (MDA) and protein carbonyl contents, decreased the superoxide dismutase (SOD) and catalase (CAT) activities, and had no effect on glutathione (GSH) in cardiac muscle cells. In addition, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was stimulated in cells treated with 1200 μM UA. Next, the role of UA in protecting cells from oxidative damage was investigated in hydrogen peroxide (H2O2)-damaged chicken cardiac cells. Treatment with UA within the normal physiological range reduced the increased MDA and protein carbonyl contents and SOD enzymatic activity induced by H2O2 exposure to some extent and inhibited reactive oxygen species (ROS) formation, presumably as a result of the Nrf2 pathway activation in H2O2-damaged cells. By contrast, the MDA and protein carbonyl contents were increased, SOD enzymatic activity was depressed, and the Nrf2 pathway was further down-regulated in H2O2-damaged cells treated with 1200 μM UA. In conclusion, the results indicated that physiological UA concentration partially alleviated oxidative stress in chicken cardiac muscle cells treated with H2O2. However, supraphysiological UA concentrations promoted oxidative damages directly in primary cultured chicken cardiac muscle cells and aggravated oxidative stress in H2O2-damaged cells.


Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.


Acute intraocular pressure elevation produced by argon laser trabeculoplasty in the cynomolgus monkey.
The short-term effect of argon laser trabeculoplasty (ALT) was studied in a nonhuman primate model. The ALT treatment produced a consistent intraocular pressure elevation in the treated eye for eight hours. A statistically significant indomethacin-resistant increase in aqueous humor protein concentration was also observed. Morphologic observations using light microscopy and scanning and transmission electron microscopy revealed evidence of a fibrinous material covering the trabecular openings four hours after ALT. Cells and tissue debris appeared to be trapped in this fibrinlike net and may be the cause of the acute rise in IOP. Twenty-eight hours after ALT, the fibrin net was shown to be discontinuous, with fewer cells and less debris present. These acute morphologic alterations were not seen in control eyes or the laser-treated eyes observed later.


Organization and dynamics of SNARE proteins in the presynaptic membrane.
Our view of the lateral organization of lipids and proteins in the plasma membrane has evolved substantially in the last few decades. It is widely accepted that many, if not all, plasma membrane proteins and lipids are organized in specific domains. These domains vary widely in size, composition, and stability, and they represent platforms governing diverse cell functions. The presynaptic plasma membrane is a well-studied example of a membrane which undergoes rearrangements, especially during exo- and endocytosis. Many proteins and lipids involved in presynaptic function are known, and major efforts have been made to understand their spatial organization and dynamics. Here, we focus on the mechanisms underlying the organization of SNAREs, the key proteins of the fusion machinery, in distinct domains, and we discuss the functional significance of these clusters.


Extraskeletal Ewing's sarcoma. Diagnosis of a case by fine needle aspiration cytology.
A retroperitoneal mass was subjected to fine needle aspiration biopsy for cytologic evaluation. The aspirate consisted of a monotonous population of undifferentiated tumor cells whose cytologic appearance was consistent with a small-cell (Ewing's) sarcoma. The differential diagnosis of extraskeletal Ewing's sarcoma from other small-cell neoplasms, such as lymphoma, neuroblastoma and other soft-tissue sarcoma, cannot be made solely on the basis of morphologic studies. As in this case, histochemical studies and consideration of the clinical features are needed to make the final diagnosis.


Towards building a Self-Sovereign Identity Framework for Healthcare.
Drifted by the hype of new and efficient machine learning and artificial intelligence models aiming to unlock the information wealth hidden inside heterogeneous datasets across different markets and disciplines, healthcare data are in the center of novel technological advancements in predictive health diagnostics, remote healthcare, assistive leaving and wellbeing. Nevertheless, this emerging market has underlined the necessity of developing new methods and updating existing ones for preserving the privacy of the data and their owners, as well as, ensuring confidentiality and trust throughout the health care data processing pipelines. This paper presents one of the key innovations of a Horizon Europe funded project named "TRUSTEE", which focuses on building a trust and privacy framework for cross-European data exchange by employing a secure and private federated framework to empower companies, organizations, and individuals to securely access data across different disciplines, use and re-use data and metadata to extract knowledge with trust. In particular we present our work on implementing strong authentication and continuous authorization schemes based on the duality of eIDAS trust framework and Self Sovereign Identity (SSI) management to ensure security and trust over authentication, authorization and accounting processes for healthcare.


Sales promotions and food consumption.
Sales promotions are widely used to market food to adults, children, and youth. Yet, in contrast to advertising, practically no attention has been paid to their impacts on dietary behaviors, or to how they may be used more effectively to promote healthy eating. This review explores the available literature on the subject. The objective is to identify if and what literature exists, examine the nature of this literature, and analyze what can be learned from it about the effects of sales promotions on food consumption. The review finds that while sales promotions lead to significant sales increases over the short-term, this does not necessarily lead to changes in food-consumption patterns. Nevertheless, there is evidence from econometric modeling studies indicating that sales promotions can influence consumption patterns by influencing the purchasing choices of consumers and encouraging them to eat more. These effects depend on the characteristics of the food product, sales promotion, and consumer. The complexity of the effects means that sales promotions aiming to encourage consumption of nutritious foods need to be carefully designed. These conclusions are based on studies that use mainly sales data as a proxy for dietary intake. The nutrition (and economics) research communities should add to this existing body of research to provide evidence on the impact of sales promotions on dietary intake and related behaviors. This would help support the development of a sales promotion environment conducive to healthy eating.


Monitoring SARS-CoV-2 Activity with Sentinel Surveillance: Lessons Learned from the First Wave in Israel.
Guidelines for pandemic preparedness emphasize the role of sentinel and syndromic surveillance in monitoring pandemic spread. To examine advantages and obstacles of utilizing a sentinel influenza surveillance system to monitor community severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity based on Israel's experience from mid-March to mid-May 2020. Several modifications were applied to the influenza surveillance system. The clinical component relied mainly on pneumonia and upper respiratory infection (URI) consultations with primary care physicians as well as visits to emergency departments (ED) due to pneumonia. The virological data were based on nasopharyngeal swabs obtained from symptomatic patients who visited outpatient clinics. By week 12 of the pandemic, the crude and age-specific primary physician consultation rates due to URI and pneumonia declined below the expected level, reaching nadir that lasted from week 15 until week 20. Similarly, ED visits due to pneumonia were significantly lower than expected from weeks 14 and 15 to week 20. The virological surveillance started on week 13 with 6/253 of the swabs (2.3%) positive for SARS-CoV-2. There was a peak of 13/225 positive swabs on week 145.8%. During weeks 17-20, none of the swabs (47-97 per week) were positive for SARS-CoV-2. This trend was similar to national data. The virological component of the surveillance system showed the SARS-CoV-2 community spread, but had low sensitivity when virus activity was low. The clinical component, however, had no yield. Sentinel surveillance can assist in monitoring future novel pandemics and should be augmented in revised preparedness plans.


NBR1-mediated selective autophagy targets insoluble ubiquitinated protein aggregates in plant stress responses.
Plant autophagy plays an important role in delaying senescence, nutrient recycling, and stress responses. Functional analysis of plant autophagy has almost exclusively focused on the proteins required for the core process of autophagosome assembly, but little is known about the proteins involved in other important processes of autophagy, including autophagy cargo recognition and sequestration. In this study, we report functional genetic analysis of Arabidopsis NBR1, a homolog of mammalian autophagy cargo adaptors P62 and NBR1. We isolated two nbr1 knockout mutants and discovered that they displayed some but not all of the phenotypes of autophagy-deficient atg5 and atg7 mutants. Like ATG5 and ATG7, NBR1 is important for plant tolerance to heat, oxidative, salt, and drought stresses. The role of NBR1 in plant tolerance to these abiotic stresses is dependent on its interaction with ATG8. Unlike ATG5 and ATG7, however, NBR1 is dispensable in age- and darkness-induced senescence and in resistance to a necrotrophic pathogen. A selective role of NBR1 in plant responses to specific abiotic stresses suggest that plant autophagy in diverse biological processes operates through multiple cargo recognition and delivery systems. The compromised heat tolerance of atg5, atg7, and nbr1 mutants was associated with increased accumulation of insoluble, detergent-resistant proteins that were highly ubiquitinated under heat stress. NBR1, which contains an ubiquitin-binding domain, also accumulated to high levels with an increasing enrichment in the insoluble protein fraction in the autophagy-deficient mutants under heat stress. These results suggest that NBR1-mediated autophagy targets ubiquitinated protein aggregates most likely derived from denatured or otherwise damaged nonnative proteins generated under stress conditions.


Esophageal symptoms with negative influence on social life. Radiographic and manometric findings.
To correlate the functional changes of the esophagus determined by manometry and radiography using bread and barium with the severity of esophageal symptoms. Fifty-seven patients, mean age 44.4 years, suspected of primary esophageal motility disorders underwent simultaneous video-radiography and manometry. Based on interviews the patients were divided into subgroups according to predominant symptom - gastro-esophageal reflux symptoms, dysphagia, or chest pain - and to severity of symptoms, i.e., symptoms with negative or no influence on daily life. The manometric diagnosis and esophageal emptying were based on both liquid and solid swallows. There was significant difference in the incidence of esophageal dysmotility disorders both globally and in the subgroup of patients with dysphagia between patients with and those without severe symptoms, but only after solid swallows. We suggest employment of bread in esophageal function tests to improve the correlation between symptomatology and positive diagnostics findings.


The contribution of foliar endophytes to quantitative resistance to Melampsora rust.
Foliar endophytes of Populus do not induce the hypersensitive response associated with major genes for resistance to Melampsora leaf rust. But they could contribute to the quantitative resistance that represents a second line of defense. Quantitative resistance is thought to be determined by suites of minor genes in both host and pathogen that are influenced by the abiotic environment. Here, we determined the relative importance to quantitative resistance of foliar endophytes, one element of the biotic environment. Leaves of six host genotypes differing in genetic resistance to Melampsora × columbiana were inoculated first with one of four foliar endophytes (Stachybotrys sp., Trichoderma atroviride, Ulocladium atrum or Truncatella angustata), and then with Melampsora. These endophytes greatly reduced rust severity within inoculated leaves (i.e. local effects), but they had no systemic effect on rust of leaves not inoculated with endophytes. Differences among endophytes and their controls explained 54% of the total variation in quantitative resistance (i.e. rust severity); the six host/pathogen genotypes explained just 5%. In terms of magnitude of effect on rust severity, Stachybotrys, Trichoderma, Ulocladium and Truncatella were ranked in this order on all host/pathogen genotypes. Endophytes may contribute significantly to quantitative resistance to Melampsora in leaves of Populus.


Validation of the Hepatocellular Carcinoma Early Detection Screening (HES) Algorithm in a Cohort of Veterans With Cirrhosis.
Early detection of hepatocellular carcinoma (HCC) through surveillance reduces mortality associated with this cancer. Guidelines recommend HCC surveillance every 6 months for patients with cirrhosis, via ultrasonography, with or without measurement of serum level of alpha fetoprotein (AFP). We previously developed and internally validated an HCC early detection screening (HES) algorithm that included patient's current level of AFP, rate of AFP change, age, level of alanine aminotransferase, and platelet count in a department of Veterans affairs (VA) cohort with active hepatitis C virus-related cirrhosis. HES score was associated with 3.84% absolute improvement in sensitivity of detection of HCC compared with AFP alone, at 90% specificity, within 6 months prior to diagnosis of this cancer. We externally validated the HES algorithm in a cohort of 38,431 patients with cirrhosis of any etiology evaluated at a VA medical center from 2010 through 2015. A total of 4804 cases of HCC developed during a median follow-up time of 3.12 years. At 90% specificity, the HES algorithm identified patients with HCC with 52.56% sensitivity, compared to 48.13% sensitivity for the AFP assay alone, within 6 months prior to diagnosis; this was an absolute improvement of 4.43% (P < .0005). In HCC screening, a positive result leads to follow-up evaluation by computed tomography or magnetic resonance imaging. We estimated that the number of HCC cases detected per 1000 imaging analyses was 198.57 for the HES algorithm vs 185.52 for the AFP assay alone, or detection of 13 additional cases of HCC (P < .0005). We validated the HES algorithm in detection of HCC in patients with cirrhosis of any etiology evaluated at VA medical centers. The algorithm offers a modest but useful advantage over AFP alone in HCC surveillance.


[Gastroscopy plus cytology for the diagnosis of gastric cancer or precancerous diseases--report of 127 cases].
One hundred and twenty-seven patients with gastric tumor or precancerous diseases were examined by gastroscopy plus cytology, and the results were compared with that of histopathology after operation. Out of 127 cases, 70 were diagnosed as gastric cancer (15 cases as early cancer, 55 as advanced cancer). The positive rate for early cancer was 21.4%, it comprised 11.2% of all gastric cancers diagnosed by gastroscopy during the same period. The preoperative positive rate of early gastric cancer was 100% (13/13) as examined by the combination of touch, brush cytology and mucosal biopsy. The combined method may increase the positive rate and the accuracy, not only for advanced but also for early gastric cancers. It is suggested that the combination of these methods be routinely used in the diagnosis of suspicious cancer in the gastric mucosa.


Solid-phase reactors as high stability reagent sources in flow analysis: selective flow injection spectrophotometric determination of cysteine in pharmaceutical formulations.
The flow injection spectrophotometric determination of cysteine was carried out by reaction with cobalt(II) ions entrapped in a polymeric material and filling a packed-bed reactor; the released cobalt(II) complexed with the amino acid was monitored at 360 nm. The method worked with a high repeatability, even with independent reactors, days and solutions. Selectivity of the procedure was tested with twenty different foreign compounds found in pharmaceutical formulations containing cysteine, parent amino acids included; no serious interferences were observed. The calibration graph for cysteine was linear over the range 1-90 micrograms ml-1 with a relative standard deviation of 0.8% at 60 micrograms ml-1 (n = 158). The calculated sample throughput was 90 h-1. The method was applied to determine the content of cysteine in pharmaceutical formulations.


Injection of protein kinase inhibitor into cultured heart cells blocks calcium slow channels.
An inhibitor of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase was injected into cultured heart cells (reaggregates) by the phosphatidylcholine liposome method. The inhibitor blocked both the isoproterenol-induced slow action potentials and the spontaneously occurring slow action potentials of these cells. The inhibitory effect of protein kinase inhibitor was prevented by denaturation or reversed by the injection of the catalytic subunit of cAMP-dependent protein kinase. These findings support the phosphorylation hypothesis for the myocardial slow channels, namely that the slow channel protein must be phosphorylated for the channel to be available for voltage activation.


Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients.
Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day-1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day-1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC.


The mechanical response of hIAPP nanowires based on different bending direction simulations.
Amyloid proteins, implicated in numerous aging-related diseases, possess remarkable mechanical properties. Polymorphism leads to different arrangements of β sheets in amyloid fibrils, which changes the characteristics of the hydrogen bond network that determines their mechanical properties and structural characteristics. We performed bending simulations using molecular dynamics methods under constant-velocity conditions in different bending directions. Two different fibril structures, parallel/homo and parallel/hetero, of hIAPP amyloids were considered. Though the bending configuration influences the toughness of the material, our results indicate that the basic material behavior is affected by the β-sheet arrangement that is determined by the type of polymorphism in amyloid fibrils.


Effect of route of infection on outcome of Toxoplasma gondii infection in hu-PBL SCID mice.
Toxoplasma gondii (T. gondii) causes serious infection, especially in immunocompromised hosts. The relevance of animal models of toxoplasmosis to human disease is unclear, but have indicated that the route of Toxoplasma infection may affect the outcome. A humanized model of toxoplasmosis of immunocompromised mice (i.e. hu-PBL SCID), using the intraperitoneal (IP) route demonstrated long-term engraftment of human cells and worsening of inflammation compared to controls. In this study, we examined the effect of route of infection on this hu-PBL SCID model using a Toxoplasma strain (i.e. DAG) isolated from an immunocompromised human. Oral infection led to an asymptomatic infection, whereas animals infected by the IP route succumbed more quickly to infection. Human cells, detected through species-specific β-actin mRNA, were not as prominent in IP-infected animals as compared to orally infected and uninfected animals. There was evidence of control of toxoplasmosis in some orally infected animals, and this was associated with the presence of human cells in multiple tissues. Thus, the route of infection dramatically affects the outcome of infection, either by affecting parasite replication or expansion of human immune cells. Further studies of oral Toxoplasma infection using hu-PBL SCID mice may help in developing chemotherapies and immunotherapeutic strategies for toxoplasmosis.


A qualitative descriptive study of the group prenatal care experience: perceptions of women with low-risk pregnancies and their midwives.
Group prenatal care (GPC) originated in 1994 as an innovative model of prenatal care delivery. In GPC, eight to twelve pregnant women of similar gestational age meet with a health care provider to receive their prenatal check-up and education in a group setting. GPC offers significant health benefits in comparison to traditional, one-on-one prenatal care. Women in GPC actively engage in their healthcare and experience a supportive network with one another. The purpose of this study was to better understand the GPC experience of women and care providers in a lower risk group of women than often has been previously studied. This qualitative descriptive study collected data through three focus group interviews--two with women who had completed GPC at a midwifery clinic in Ontario, Canada and one with the midwives at the clinic. Data was analyzed through open coding to identify themes. Nine women and five midwives participated in the focus groups, from which eight categories as well as further subcategories were identified: The women and midwives noted reasons for participating (connections, education, efficiency). Participants suggested both benefits (learning from the group, normalizing the pregnancy experience, preparedness for labour and delivery, and improved relationships as all contributing to positive health outcomes) and concerns with GPC (e.g. sufficient time with the midwife) which generally diminished with experience. Suggestions for change focused on content, environment, partners, and access to the midwives. Challenges to providing GPC included scheduling and systems-level issues such as funding and regulation. Flexibility and commitment to the model facilitated it. Comparison with other models of care identified less of a relationship with the midwife, but more information received. In promoting GPC, women would emphasize the philosophy of care to other women and the midwives would promote the reduction in workload and women's independence to colleagues. Overall, women and midwives expressed a high level of satisfaction with their GPC experience. This study gained insight into previously unexplored areas of the GPC experience, perceptions of processes that contribute to positive health outcomes, strategies to promote GPC and elements that enhance the feasibility of GPC.


The role of serum and glucocorticoid-regulated kinase 1 in cellular signaling: Implications for drug development.
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a ubiquitously expressed protein belonging to the Ser/Thr kinase family. It regulates diverse physiological processes, including epithelial sodium channel activity, hypertension, cell proliferation, and insulin sensitivity. Due to its significant role in the pathogenesis of numerous diseases, SGK1 can be exploited as a potential therapeutic target to address challenging health problems. SGK1 is associated with the development of obesity, and its overexpression enhances the sodium-glucose co-transporter 1 activity, which absorbs intestinal glucose. This review highlighted the detailed functional significance of SGK1 signaling and role in different diseases and subsequent therapeutic targeting. We aim to provide deeper mechanistic insights into understanding the pathogenesis and recent advancements in the SGK1 targeted drug development process. Small-molecule inhibitors are being developed with excellent binding affinity and improved SGK1 inhibition with desired selectivity. We have discussed small molecule inhibitors designed explicitly as potent SGK1 inhibitors and their therapeutic implications in various diseases. We further addressed the therapeutic potential and mechanism of action of these SGK1 inhibitors and provided a strong scientific foundation for developing effective therapeutics.


[Hyperinsulinemia in obesity: significance of adipose tissue cell size].
Adipose tissue biopsy and an oral glucose tolerance test (OGTT) (50 g) were performed in 17 non-hyperlipoproteinemic subjects without overt diabetes mellitus. All the persons were weight stable at the time of investigation. A significant correlation between fasting insulin concentration and the mean adipocyte size was observed, whereas no correlation was noted between the ideal body weight index and fasting insulin level. Persons with larger adipocytes had elevated insulin levels as well as higher and longer lasting increments following the glucose challenge. They also exhibited significantly higher mean glucose levels during the OGTT. When these patients were matched for glucose tolerance with the subgroup having smaller mean adipocyte sizes, the difference in insulin levels was still demonstrable. The importance of adipose cell enlargement regulating basal and stimulated insulin output is underlined.


Cryptococcosis mimicking cutaneous cellulitis in a patient suffering from rheumatoid arthritis: a case report.
Cryptococcus neoformans is an encapsulated yeast and the most frequent cryptococcal species found in humans. Cryptococcosis is considered an opportunistic infection as it affects mainly immunosuppressed individuals. In humans, C. neoformans causes three types of infections: pulmonary cryptococcosis, cryptococcal meningitis and wound or cutaneous cryptococcosis. An 81-year-old woman developed severe necrotizing cellulitis on her left arm without any preceding injury. The patient had been treated with systemic corticosteroids over twenty years for rheumatoid arthritis (RA). Skin biopsies of the wound area were initially interpreted as cutaneous vasculitis of unknown etiology. However, periodic acid Schiff staining and smear analysis later revealed structures consistent with Cryptococcus neoformans, and the infection was subsequently confirmed by culture. After the initiation of therapy with fluconazole 400 mg per day the general condition and the skin ulcers improved rapidly and the patient was discharged to a rehabilitation facility. Subsequently surgical debridement and skin grafting were performed. Opportunistic infections such as cryptococcosis can clinically and histologically mimic cutaneous vasculitis and have to be investigated rigorously as a differential diagnosis in immunosuppressed patients.


Loss of interstitial cells and a fibromuscular layer on the luminal side of the colonic circular muscle presenting as megacolon in an adult patient.
Animal studies have shown that the neuromuscular structures on the luminal side of the colonic circular muscle coordinate circular muscle activity. These structures have been identified by electron microscopy in the normal human colon, but have never been thoroughly studied in patients with acquired intestinal hypoganglionosis. To perform histological, immunocytochemical, and electron microscopic examinations of the colon of a patient with acquired intestinal hypoganglionosis presenting as megacolon. A 32 year old man with a one year history of constipation and abdominal distention, a massively dilated ascending and transverse colon, and a normal calibre rectum and descending and sigmoid colon. He had a high titre of circulating serum anti-neuronal nuclear antibodies. Histology, immunocytochemistry (for neurofilaments, neurone specific enolase, synaptophysin, glial fibrillar acidic protein, S100 protein, and smooth muscle alpha-actin), and electron microscopic examinations on the resected colon. The number of ganglion cells and nerve trunks was decreased throughout the colon. Disruption of the neural network and a loss of interstitial cells of Cajal were observed on the luminal side of the circular muscle; in their place, the non-dilated colon contained a hypertrophic fibromuscular layer. Striking architectural alterations occurred at the site regarded as the source of the coordination of colonic circular muscle activity in an adult patient with acquired intestinal hypoganglionosis presenting as megacolon.


PARP expression in germ cell tumours.
Poly(ADP-ribose)polymerase (PARP) inhibitors represent a new class of promising drugs in anticancer therapy. To evaluate PARP expression in testicular germ cell tumours (GCTs) and to correlate expression patterns with clinicopathological variables. In this translational study, tumour specimens from 124 patients with GCTs (114 patients with testicular primary tumours and 10 with extragonadal GCTs) were identified. PARP expression was detected by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method and compared to PARP expression in normal testicular tissue. We observed higher expression of PARP in testicular tumours compared to normal testicular tissue (mean QS=10.04 vs 3.31, p<0.0000001). Mean QS±SD for each histological subtype was as follows: intratubular germ cell neoplasia unclassified (IGCNU)=18.00±0.00, embryonal carcinoma=9.62±5.64, seminoma=9.74±6.51, yolk sac tumour=7.8±7.20, teratoma=5.87±5.34, and choriocarcinoma=4.50±8.33. The PARP overexpression (QS>9) was most often detected in IGCNU (100% of specimen with PARP overexpression), seminona (52.6%), embryonal carcinoma (47.0%), yolk sac tumour (33.3%), teratoma (26.7%) and choriocarcinoma (25.0%), compared to 1.9% of normal testicular tissue specimens. There was no association between PARP expression and clinical variables. In this pilot study, we showed for the first time, that PARP is overexpressed in testicular germ cell tumours compared to normal testis.


Changes in K+ currents induced by Ba2+ in guinea pig ventricular muscles.
Effects of Ba2+ on the K+ currents of guinea pig ventricular muscle were studied using the single sucrose-gap voltage-clamp technique. Ba2+ decreased the late (1- or 2-s) current at any potential level, with stronger suppression in the slope conductance at resting potential level than at depolarized voltages above 0 mV. During depolarizing pulses beyond -40 mV, Ba2+ reduced both the time-dependent and time-independent current components, indicating suppression of both outward and background K+ currents (IK and IK1, respectively), whereas tail currents after repolarization to -40 mV increased, with their time courses having double exponentials. These apparent conflicting results between IK and the tail current could not be explained by extracellular K+ fluctuation, because 20 mM Cs+ alone depressed both factors, but an additional application of Ba2+ caused an increase in both components compared with those in the former condition. On hyperpolarization below -60 mV, a time-dependent decrease in the inward current was observed after Ba2+ application without an activation of If. The decrease was stronger and faster at negative potential levels. These results are compatible with a time- and voltage-dependent blocking action of Ba2+ on the inward rectifier K+ current reported in other cardiac and noncardiac tissues. In two components of the tail currents after repolarization from depolarizing voltage steps during Ba2+ application, the faster one can probably be attributed to this blocking action of IK1, whereas the slower one can be attributed to the deactivation of IK. This time-dependent component of IK1 may contribute to the generation of Ba2+-induced automaticity at the depolarized state.


"We're certainly not in our comfort zone": a qualitative study of GPs' dementia-care educational needs.
Rising dementia prevalence rates rise combined with the policy objective of enabling people with dementia to remain living at home, means that there will be a growing demand for dementia care in the community setting. However, GPs are challenged by dementia care and have identified it as an area in which further training is needed. Previous studies of GPs dementia care educational needs have explored the views of GPs alone, without taking the perspectives of people with dementia and family carers into account. The aim of the study was to explore GPs' dementia care educational needs, as viewed from multiple perspectives, in order to inform the design and delivery of an educational programme for GPs. A qualitative study of GPs, people with dementia and family carers in a community setting was undertaken. Face-to-face interviews were performed with GPs, people with dementia and with family carers. Interviews were audio-recorded, transcribed verbatim and thematically analysed. Thirty-one people were interviewed, consisting of fourteen GPs, twelve family carers and five people with dementia. GPs expressed a wish for further education, preferentially through small group workshops. Five distinct educational needs emerged from the interviews, namely, diagnosis, disclosure, signposting of local services, counselling and the management of behavioural and psychological symptoms (BPSD). While GPs focused on diagnosis, disclosure and BPSD in particular, people with dementia and family carers emphasised the need for GPs to engage in counselling and signposting of local services. The triangulation of data from multiple relevant sources revealed a broader range of GPs' educational needs, incorporating both medical and social aspects of dementia care. The findings of this study will inform the content and delivery of a dementia educational programme for GPs that is practice-relevant, by ensuring that the curriculum meets the needs of GPs, patients and their families.


What is the future of third molar removal? A serious presentation for not performing the removal of third molars.
There are three causes for third molar removal: pain, anterior crowding and the 'time-bomb' theory, which are used to justify the removal of otherwise asymptomatic third molars. Arguments are presented to show that these may not be as true as we think and perhaps we need to reconsider our whole approach to third molar removal. Carrying out a procedure which has a significant risk of morbidity without good reason is unacceptable.


A predictive model for neutropenia associated with cancer chemotherapy.
Studies of primary prophylaxis of febrile neutropenia (FN) with recombinant human granulocyte colony-stimulating factor (rHu-G-CSF, filgrastim) administered to all patients starting their initial course of chemotherapy have demonstrated clinical effectiveness and an economic advantage in a wide range of settings. A recent meta-analysis confirmed the ability of filgrastim to reduce the risk of FN and documented infection in a variety of malignancies in both adults and children. The threshold risk for FN at which a cost saving is achieved by using filgrastim is inversely related to the daily cost of the drug and duration of hospitalization. Clinical practice guidelines for the use of filgrastim were developed based on these observations. Recent studies incorporating indirect institutional costs demonstrated that a cost saving can be achieved at substantially lower FN risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further increased by appropriately selecting patients and better understanding the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in FN risk thresholds and treatment costs in patients receiving cancer chemotherapy. These models also may be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim. A clinical prediction model recently was presented and validated incorporating both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of $34,297/year of life saved was estimated based on dose-response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit the rational and cost-effective identification of patients for filgrastim support. Existing clinical practice guidelines should be reevaluated in light of new information available on both the total costs associated with FN as well as the cost-effectiveness of these agents in patients receiving chemotherapy for sensitive and potentially curable malignancies.


Watershed-Scale Land Use Activities Influence the Physiological Condition of Stream Fish.
Land use changes within watersheds can have large effects on stream ecosystems, but the mechanistic basis of those effects remains poorly understood. While changes to population size presumably reflect underlying variation in organismal health and condition, such individual-level metrics are rarely evaluated in the context of ecosystem disturbance. To address this deficiency, we combined physiological sampling with geographic information systems to quantify the effects of land use on physiological indicators of health in largemouth bass. More specifically, we first quantified blood metrics relating to nutrition, oxidative stress, and the glucocorticoid stress response from largemouth bass residing in eight watersheds. We then used Akaike's information criterion to define relationships between these blood metrics and land cover, including forests, agricultural areas, urban areas, and wetlands. The proportion of forest cover in a watershed was the best predictor of blood metrics representing recent feeding and resistance to oxidative stress, whereas the proportion of wetlands was the best predictor of glucocorticoid function; however, further investigation is needed, as the explanatory power of the models was relatively low. Patterns in energy reserves were not influenced by any land use practices. Interestingly, anthropogenic land use categories, such as urban and agricultural areas, were not the best predictor for any blood metrics. Together, our results indicate that fish health is most related to natural features of a landscape rather than anthropogenic land uses. Furthermore, these findings suggest that physiological methods could supplement traditional population and community assessments to develop a more comprehensive understanding of ecosystem interactions and improve stream management.


Comparison of dynamic compression plating and reamed intramedullary nailing in the treatment of aseptic tibial shaft nonunions.
Among 105 tibial shaft aseptic nonunions followed for a mean of 32 months, 30 were treated with dynamic compression plating and 75 were treated with either Küntscher or Grosse-Kempf interlocking intramedullary nailing. With the plating technique, the union rate was 90.0% (27/30), the period of time to union was 5.2 +/- 1.7 months, the complication rate was 16.7% (5/30), the infection rate was 13.3% (4/30), and the surgical time was 110 +/- 30 minutes. With the intramedullary nailing technique, the union rate was 93.3% (70/75), the period of time to union was 5.0 +/- 1.6 months, the complication rate was 17.3% (13/75), the infection rate was 13.3% (10/75), and the surgical time was 70 +/- 30 minutes. Thus, while the union rate was high with both techniques, the complication rate also was high, especially deep infection. However, the technique for nailing was simpler and required less surgical time than plating (p less than 0.001). With open reamed intramedullary nailing, a higher infection rate was noted in the cases initially treated with an external fixator than for cases in which other forms of treatment initially were used (p less than 0.05).


Evaluating the Feasibility of a Novel Firearm Injury Prevention Program for Pre-adolescent Children Through Health Care and Community-Based Partnerships: The Future Healers Program Pilot Study.
Firearm violence is an American public health crisis that negatively impacts children and disproportionately affects Black youth. Few firearm injury prevention programs have been described in pre-adolescent children. The Future Healers Program is a novel collaboration constructed via partnership between the medical school, trauma center, academic surgery department, and local non-profit community organization. Our study sought to evaluate if (1) partnering with community organizations facilitated recruitment of children with prior exposure to firearm violence and (2) the health care community was a potential trusted partner appropriate for program delivery. Children aged 4-13 were recruited to join the program via news outlets and social media and in partnership with a local non-profit organization. Of the children and parents participating in the program, 48% (44/92) and 59% (38/64), respectively, completed an IRB-approved survey study. Pearson's chi-square, percentages, and 95% confidence intervals evaluated differences between children and caregivers on sociodemographic characteristics, firearm exposure (FE), firearm violence exposure (FVE), and perception of health care. Participant's residence was geocoded in relationship to incidents of firearm injury (2008-2021) in the same region. Caregivers (95%) and children (84%) reported substantial exposure to firearm violence and resided in areas with frequent firearm injury incidents. Notably, 82% of caregivers and 66% of children reported having a family member injured by gunfire. A high percentage of caregivers (79%) and children (91%) self-reported trust in the health care system. Partnerships between community organizations and health care systems can develop prevention programs that effectively recruit and engage pre-adolescent children impacted by firearm violence.


Burden of skin disease and associated socioeconomic status in Asia: A cross-sectional analysis from the Global Burden of Disease Study 1990-2017.
Skin diseases have a significant global impact on quality of life, mental health, and loss of income. The burden of dermatologic conditions and its relationship with socioeconomic status in Asia is currently not well understood. We selected Global Burden of Disease Study datasets to analyze disability-adjusted life years (DALYs) in 50 Asian countries, including Central Asia, northern Asia, eastern Asia, western Asia, southeastern Asia, and southern Asia, between 1990 and 2017. We compared DALYs to the socioeconomic status using the sociodemographic index and gross domestic product per capita of a country. Statistical analysis was performed using Pearson's correlation. Some countries had higher or lower than expected age-standardized DALY rates of skin diseases. Asian countries, especially high-income countries, had a high burden of inflammatory dermatoses, including acne, alopecia areata, atopic dermatitis, contact dermatitis, decubitus ulcers, psoriasis, pruritus, and seborrheic dermatitis. The burden of infectious dermatoses was greater in low-income Asian countries. The burden of skin cancer in Asia was relatively low. There is a high burden of skin disease, especially inflammatory conditions, in Asian countries, but the burden of individual dermatoses in Asia varies by country and socioeconomic status. DALYs can potentially serve as a purposeful measure for directing resources to improve the burden of skin disease in Asia.


Atypical atrioventricular nodal reentrant tachycardia: prevalence, electrophysiologic characteristics, and tachycardia circuit.
This study aimed at assessing the prevalence, electrophysiologic characteristics, and mechanism of atypical atrioventricular nodal reentrant tachycardia (AVNRT). We studied 925 consecutive patients with AVNRT. Atrial-His (AH) and His-atrial (HA) intervals were measured during atypical AVNRT (HA > 70 ms), and compared with measurements in 34 patients with typical (slow-fast) AVNRT. Assuming that conduction velocity over the fast pathway is similar in the anterograde and retrograde directions, the AH interval during the fast-slow form should be smaller than the HA during slow-fast. Atypical AVNRT was diagnosed in 59 patients (6.4%), median age 50 years (range 19-79 years), and 37 (59.7%) of them female. Fast-slow AVNRT was diagnosed in 44 patients (74.5%), and slow-slow AVNRT in 9 patients (15.2%). The remaining six patients (10.2%) could not be reliably classified due to inconsistent AH, and HA/AH patterns or variable intervals. Tachycardia induction with anterograde conduction jumps was seen in two patients with the fast-slow, and in three patients with slow-slow or intermediate forms. Atrial-His in the fast-slow group was significantly longer than HA in the slow-fast group, 99.7 ± 40.5 ms vs. 45.8 ± 7.7 ms, P < 0.001. Tachycardia cycle length was longer in fast-slow compared with slow-fast, 379.1 ± 68.5 ms vs. 317.1 ± 42.8 ms, P < 0.001. Of AVNRT cases, 6.4% are atypical and may display patterns that do not necessarily correspond to the fast-slow or slow-slow conventional types. Atypical fast-slow and typical AVNRT do not appear to utilize the same limb for fast conduction.


Allelic reprogramming of the histone modification H3K4me3 in early mammalian development.
Histone modifications are fundamental epigenetic regulators that control many crucial cellular processes. However, whether these marks can be passed on from mammalian gametes to the next generation is a long-standing question that remains unanswered. Here, by developing a highly sensitive approach, STAR ChIP-seq, we provide a panoramic view of the landscape of H3K4me3, a histone hallmark for transcription initiation, from developing gametes to post-implantation embryos. We find that upon fertilization, extensive reprogramming occurs on the paternal genome, as H3K4me3 peaks are depleted in zygotes but are readily observed after major zygotic genome activation at the late two-cell stage. On the maternal genome, we unexpectedly find a non-canonical form of H3K4me3 (ncH3K4me3) in full-grown and mature oocytes, which exists as broad peaks at promoters and a large number of distal loci. Such broad H3K4me3 peaks are in contrast to the typical sharp H3K4me3 peaks restricted to CpG-rich regions of promoters. Notably, ncH3K4me3 in oocytes overlaps almost exclusively with partially methylated DNA domains. It is then inherited in pre-implantation embryos, before being erased in the late two-cell embryos, when canonical H3K4me3 starts to be established. The removal of ncH3K4me3 requires zygotic transcription but is independent of DNA replication-mediated passive dilution. Finally, downregulation of H3K4me3 in full-grown oocytes by overexpression of the H3K4me3 demethylase KDM5B is associated with defects in genome silencing. Taken together, these data unveil inheritance and highly dynamic reprogramming of the epigenome in early mammalian development.


Cell membrane based biomimetic nanocomposites for targeted therapy of drug resistant EGFR-mutated lung cancer.
The therapeutic efficacy of anti-cancer nanomedicines is generally constrained due to limited accumulation in the solid tumors. In this study, we developed a biomimetic nano-carrier to enhance the chemo-therapeutic efficacy of doxorubicin and icotinib in a chemo-resistant non-small cell lung cancer (NSCLC) cell line harboring a mutation in the epidermal growth factor receptor (EGFR). The unique nanomedicine was prepared by coating with targeting cancer cell membrane proteins as highly specific ligands. The resulting biomimetic nanoparticles were highly stable and exhibited superior homologous targeting ability in vitro compared with control groups. In a mouse EGFR-mutated NSCLC xenograft model, intravenous injection of the biomimetic nanomedicine led to a high tumour inhibition rate (87.56%). Histopathological analysis demonstrated that the biomimetic nanomedicine had minimal side effects. Taken together, a cancer cell membrane-based biomimetic drug carrier can significantly enhance drug accumulation and improve therapeutic efficacy in cancers.


Macrophage migration inhibitory factor: critical role in obesity, insulin resistance, and associated comorbidities.
Obesity is associated with insulin resistance, disturbed glucose homeostasis, low grade inflammation, and comorbidities such as type 2 diabetes and cardiovascular disease. The cytokine macrophage migration inhibitory factor (MIF) is an ubiquitously expressed protein that plays a crucial role in many inflammatory and autoimmune disorders. Increasing evidence suggests that MIF also controls metabolic and inflammatory processes underlying the development of metabolic pathologies associated with obesity. This is a comprehensive summary of our current knowledge on the role of MIF in obesity and obesity-associated comorbidities, based on human clinical data as well as animal models of disease.


Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS.
As part of an ongoing effort to discover novel small-molecule antifolates combining the enzyme-binding species selectivity of trimethoprim (TMP) with the potency of piritrexim (PTX), 10 previously unreported 2,4-diamino-5-(2'-methoxy-5'-substituted)benzylpyrimidines (2-11) containing a carboxyl group at the distal end of the 5'-substituent were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic pathogens frequently responsible for life-threatening illness in people with impaired immune systems as a result of HIV infection or immunosuppressive chemotherapy. The selectivity index of DHFR inhibition was evaluated by comparing the potency of each compound against the parasite enzymes with its potency against rat liver DHFR. 2,4-Diamino-5-[5'-(5-carboxy-1-pentynyl)-2'-methoxybenzyl]pyrimidine (3) inhibited Pc DHFR with a selectivity index of 79 and was 430 times more potent than TMP. 2,4-Diamino-5-[5'-(4-carboxy-1-butynyl)-2'-methoxybenzyl]pyrimidine (2), with one less carbon than 3 in the side chain, had a selectivity index of 910 against Ma DHFR and was 43 times more potent than TMP. 2,4-Diamino-5-[5'-(5-carboxypentyl)-2'-methoxybenzyl]pyrimidine (6) had a selectivity index of 490 against Tg DHFR and was 320 times more potent than TMP. 2,4-Diamino-5-[5'-(6-carboxy-1-hexynyl)-2'-methoxybenzyl]pyrimidine (4), with one more carbon than 3, was less potent against all three of the parasite enzymes than either 3 or 6 and also had a lower selectivity index than 3 against the Pc enzyme. However, 4 was the only member of the series with a selectivity index of >300 against both Tg and Ma DHFR. Given that PTX is at least 10 times more potent against rat DHFR than against P. carinii or T. gondii DHFR and that the selectivity index of several of the compounds matches or exceeds that of TMP as well as PTX, our results suggest that it may be possible to develop clinically useful nonclassical antifolates that are both potent and selective against the major opportunistic pathogens of AIDS.


Novel bimodal effects of the G-protein tissue transglutaminase on adrenoreceptor signalling.
Tissue transglutaminase (tTG) is a novel G-protein that previous studies showed can couple ligand-bound activated alpha(1B) adrenoreceptors to phospholipase C-delta, resulting in phosphoinositide (PI) hydrolysis. In human neuroblastoma SH-SY5Y cells we found that although endogenous tTG can facilitate alpha(1B) adrenoreceptor-stimulated PI hydrolysis, its contribution is minor compared with the classical heterotrimeric G-protein G(q/11). Further, we show that the alpha(1B) adrenoreceptor recruits tTG to the membrane and that this recruitment is enhanced by agonist occupancy of the receptor. In addition, the effects of tTG on signalling are bimodal. At low expression levels, tTG enhanced alpha(1B) adrenoreceptor-stimulated PI hydrolysis, whereas at higher expression levels tTG attenuated significantly this response. These findings are the first to demonstrate that a protein can both facilitate and attenuate receptor-stimulated PI hydrolysis.


LFQ-Analyst: An Easy-To-Use Interactive Web Platform To Analyze and Visualize Label-Free Proteomics Data Preprocessed with MaxQuant.
Relative label-free quantification (LFQ) of shotgun proteomics data using precursor (MS1) signal intensities is one of the most commonly used applications to comprehensively and globally quantify proteins across biological samples and conditions. Due to the popularity of this technique, several software packages, such as the popular software suite MaxQuant, have been developed to extract, analyze, and compare spectral features and to report quantitative information of peptides, proteins, and even post-translationally modified sites. However, there is still a lack of accessible tools for the interpretation and downstream statistical analysis of these complex data sets, in particular for researchers and biologists with no or only limited experience in proteomics, bioinformatics, and statistics. We have therefore created LFQ-Analyst, which is an easy-to-use, interactive web application developed to perform differential expression analysis with "one click" and to visualize label-free quantitative proteomic data sets preprocessed with MaxQuant. LFQ-Analyst provides a wealth of user-analytic features and offers numerous publication-quality result graphics to facilitate statistical and exploratory analysis of label-free quantitative data sets. LFQ-Analyst, including an in-depth user manual, is freely available at https://bioinformatics.erc.monash.edu/apps/LFQ-Analyst .


Baclofen-induced psychosis: two cases and a review.
The authors describe two patients who were being treated with baclofen for tardive dyskinesia. One patient developed withdrawal symptoms after baclofen was stopped, and the other developed a manic attach while receiving the drug. The authors review the literature concerning these side effects and explore the possible mechanisms responsible for these effects.


Short- and long-term behavioral effects of exposure to 21%, 40% and 100% oxygen after perinatal hypoxia-ischemia in the rat.
Until recently, supplementation with 100% oxygen was standard therapy for newborns who required resuscitation at birth or suffered later hypoxic-ischemic events. Exposure to high concentrations of oxygen, however, may worsen oxidative stress induced by ischemic injury. In this study we investigated the short- and long-term behavioral outcomes in rats that had undergone hypoxic-ischemic brain injury on postnatal day 7, followed by 2h exposure to 21%, 40%, or 100% oxygen, compared to normal controls. There were no differences in the development of walking, head lifting and righting reflexes from postnatal days 9 to 15. Cliff avoidance showed some abnormal responses in the H21 animals. From postnatal days 28 to 56, three tests of sensorimotor coordination were performed weekly: ledged tapered beam, cylinder, and bilateral tactile stimulation. The ledged tapered beam test without prior training of animals was sensitive to injury, but did not distinguish between treatment groups. The cylinder test showed a greater use of the unimpaired limb in female 21% and 40% oxygen groups compared to controls. Performance in both cylinder and the beam tests showed a correlation with the degree of brain injury. The bilateral tactile stimulation test showed that the male 21% oxygen groups had worse sensory asymmetry than male 40% or 100% oxygen groups, but was not statistically significantly different from controls. We thus found a minor benefit to post-hypoxia-ischemic treatment with 100% and 40% oxygen compared to 21% in one test of early motor skills. Our results for long-term sensorimotor behavior, however, showed conflicting results, however, as males treated with 40% or 100% oxygen had less sensory asymmetry (better performance) in the bilateral tactile stimulation test than males treated with 21% oxygen, while females had impaired motor performance in the cylinder test with both 21% and 40% oxygen.


Anticardiolipin antibodies in acute poststreptococcal glomerulonephritis and streptococcal impetigo.
Anticardiolipin (aCL) antibodies have been described in diverse clinical situations, linked to the risk of thrombosis in different vascular locations. They have been rarely studied in renal diseases, and occasionally they have been associated with glomerular thrombosis. We analyzed the incidence of aCL (isotypes IgG, IgA, and IgM) in samples, taken during the acute phase of the disease, from 27 well-documented patients having acute poststreptococcal glomerulonephritis. Twelve cases were positive on IgG testing, 1 case on IgA testing only, and no one was positive on IgM testing. A serological follow-up was performed with a second sample taken about 7 months later, for the patients initially positive on IgG testing showing persistence in 9. Clinical variables during the acute phase and after a follow-up period of 25 (range 6-89) months were analyzed for possible associations with the presence of these antibodies, but non was significantly related. Renal histopathological investigation did not reveal particular findings in the aCL-positive patients, and glomerular thrombosis was not found in any case. In addition, serum samples from 12 streptococcal impetigo patients without renal involvement were analyzed, showing similar incidence (4 positive on IgG testing, 1 of them positive on IgM testing as well, and no one positive on IgA testing) and titers of aCL antibodies. We conclude that the presence of aCL antibodies in acute poststreptococcal glomerulonephritis may be a marginal immunological phenomenon unrelated to the glomerular disease, triggered by the streptococcal infection.


Association between obesity, high-sensitivity C-reactive protein ≥2 mg/L, and subclinical atherosclerosis: implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis.
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however, the association of hsCRP and atherosclerosis, independent of obesity, remains unknown. We studied 6760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: nonobese/low hsCRP, nonobese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean body mass index was 28.3±5.5 kg/m(2), and median hsCRP was 1.9 mg/L (0.84 to 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independently of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2083 JUPITER-eligible individuals. High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independently of hsCRP status.


Management of bladder cancer: current and emerging strategies.
Cancer of the urinary bladder is the fifth most prevalent solid tumour in the US. Urothelial carcinoma is the most common form of bladder cancer, accounting for about 90% of cases. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. Urothelial carcinoma is a chemo-sensitive disease, with a high overall and complete response rate to combination chemotherapy. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. The role of adjuvant chemotherapy in this setting is yet to be validated. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients. Currently, there is no standard second-line therapy for patients in whom first-line chemotherapy for metastatic disease has failed. Many newer chemotherapeutic agents have shown modest activity in urothelial carcinoma. Improved understanding of molecular biology and pathogenesis of urothelial carcinoma has opened avenues for the use of molecularly targeted therapies, several of which are being tested in clinical trials. Currently, several novel drugs seem particularly promising including inhibitors of the epidermal growth factor receptor pathway, such as cetuximab, and inhibitors of tumour angiogenesis, such as bevacizumab and sunitinib. Development of reliable molecular predictive markers is expected to improve treatment decisions, therapy development and outcomes in urothelial carcinoma. Funding of and participation in clinical trials are key to advancing the care of urothelial cancer patients. Current and emerging strategies in the medical management of urothelial carcinoma are reviewed.


Manipulation of IRE1-Dependent MAPK Signaling by a Vibrio Agonist-Antagonist Effector Pair.
Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (N. M. Alto and K. Orth, Cold Spring Harbor Perspect Biol 4:a006114, 2012, https://doi.org/10.1101/cshperspect.a006114). The type III secretion system 1 of the marine pathogen Vibrio parahaemolyticus utilizes the sequential action of four effectors to induce a rapid, proinflammatory cell death uniquely characterized by a prosurvival host transcriptional response (D. L. Burdette, M. L. Yarbrough, A Orvedahl, C. J. Gilpin, and K. Orth, Proc Natl Acad Sci USA 105:12497-12502, 2008, https://doi.org/10.1073/pnas.0802773105; N. J. De Nisco, M. Kanchwala, P. Li, J. Fernandez, C. Xing, and K. Orth, Sci Signal 10:eaa14501, 2017, https://doi.org/10.1126/scisignal.aal4501). Herein, we show that this prosurvival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase, resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ, causing a disruption in membrane integrity. Additionally, we observed that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR), resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveals new connections between V-ATPase function, UPR, and MAPK signaling.IMPORTANCE Vibrio parahaemolyticus is a seafood-borne pathogen that encodes two type 3 secretion systems (T3SS). The first system, T3SS1, is thought to be maintained in all strains of V. parahaemolyticus to maintain survival in the environment, whereas the second system, T3SS2, is linked to clinical isolates and disease in humans. Here, we found that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within 3 h. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host survival signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector, VopS, reverses activation and inhibition of these signaling systems, ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.


Application of digital-intelligence technology in the processing of Chinese materia medica.
Processing of Chinese Materia Medica (PCMM) is the concentrated embodiment, which is the core of Chinese unique traditional pharmaceutical technology. The processing includes the preparation steps such as cleansing, cutting and stir-frying, to make certain impacts on the quality and efficacy of Chinese botanical drugs. The rapid development of new computer digital technologies, such as big data analysis, Internet of Things (IoT), blockchain and cloud computing artificial intelligence, has promoted the rapid development of traditional pharmaceutical manufacturing industry with digitalization and intellectualization. In this review, the application of digital intelligence technology in the PCMM was analyzed and discussed, which hopefully promoted the standardization of the process and secured the quality of botanical drugs decoction pieces. Through the intellectualization and the digitization of production, safety and effectiveness of clinical use of traditional Chinese medicine (TCM) decoction pieces were ensured. This review also provided a theoretical basis for further technical upgrading and high-quality development of TCM industry.


Experiences of family members after a suicide.
Survivors of suicide are the family members and significant others in the life of the person who commits suicide. A recent study by the author explored the life experiences of survivors of suicide, affirmed the severity of postsuicide bereavement, and revealed the critical role of the family physician in intervention. Thirty-five adult survivors participated in in-depth audiotaped interviews during the 3- to 9-month period after the suicide death of a family member. Demographic data and the transcribed interview data were analyzed through descriptive statistics and systematic methods of qualitative data analysis. Subjects stressed the importance of the family physician understanding the nature of their experiences in order to intervene effectively. All survivors experienced profound disruptions in their lives, including changes in physical, emotional, cognitive, and social functioning. Variations among survivors of suicide, based on the survivor's perception of the victim before his or her death, were evident and are illustrated by three case studies. Interventions for the family physician, including specific suggestions from survivors, are proposed. Survivors of suicide experience a very severe bereavement, yet significant variations exist among their responses. The family physician is identified as the key individual to initiate and ensure follow-up care for this bereaved population.


Impact of Introduction of Arbuscular Mycorrhizal Fungi on the Root Microbial Community in Agricultural Fields.
Arbuscular mycorrhizal (AM) fungi are important members of the root microbiome and may be used as biofertilizers for sustainable agriculture. To elucidate the impact of AM fungal inoculation on indigenous root microbial communities, we used high-throughput sequencing and an analytical pipeline providing fixed operational taxonomic units (OTUs) as an output to investigate the bacterial and fungal communities of roots treated with a commercial AM fungal inoculum in six agricultural fields. AM fungal inoculation significantly influenced the root microbial community structure in all fields. Inoculation changed the abundance of indigenous AM fungi and other fungal members in a field-dependent manner. Inoculation consistently enriched several bacterial OTUs by changing the abundance of indigenous bacteria and introducing new bacteria. Some inoculum-associated bacteria closely interacted with the introduced AM fungi, some of which belonged to the genera Burkholderia, Cellulomonas, Microbacterium, Sphingomonas, and Streptomyces and may be candidate mycorrhizospheric bacteria that contribute to the establishment and/or function of the introduced AM fungi. Inoculated AM fungi also co-occurred with several indigenous bacteria with putative beneficial traits, suggesting that inoculated AM fungi may recruit specific taxa to confer better plant performance. The bacterial families Methylobacteriaceae, Acetobacteraceae, Armatimonadaceae, and Alicyclobacillaceae were consistently reduced by the inoculation, possibly due to changes in the host plant status caused by the inoculum. To the best of our knowledge, this is the first large-scale study to investigate interactions between AM fungal inoculation and indigenous root microbial communities in agricultural fields.


Synthesis of specific deuterated derivatives of the long chained stratum corneum lipids [EOS] and [EOP] and characterization using neutron scattering.
The synthesis of specific deuterated derivatives of the long chained ceramides [EOS] and [EOP] is described. The structural differences with respect to the natural compounds are founded in the substitution of the 2 double bonds containing linoleic acid by a palmitic acid branched with a methyl group in 10-position. The specific deuteration is introduced both in the branched and in the terminal methyl group, which was realized by common methods of successive deuteration of carboxylic groups in 3 steps. These modified fatty acids resp. the corresponding ceramides [EOS] and [EOP] were prepared for neutron scattering investigations. First results of these investigations were presented in this manuscript showing that the deuterated compounds could be detected in the stratum corneum lipid model membranes. The deuterated ceramides [EOS] and [EOP] are valuable tools to investigate the influence of these long chained ceramide species on the nanostructure of stratum corneum lipid model membranes.


Concentrations of air toxics in motor vehicle-dominated environments.
We at the Desert Research Institute (DRI*) measured volatile organic compounds (VOCs), including several mobile-source air toxics (MSATs), particulate matter with a mass mean aerodynamic diameter < or = 2.5 pm (PM2.5), black carbon (BC), nitrogen oxides (NOx), particulate matter (PM), and carbon monoxide (CO) on highways in Los Angeles County during summer and fall 2004, to characterize the diurnal and seasonal variations in measured concentrations related to volume and mix of traffic. Concentrations of on-road pollutants were then compared to corresponding measurements at fixed monitoring sites. The on-road concentrations of CO and MSATs were higher in the morning under stable atmospheric conditions and during periods of higher traffic volumes. In contrast, BC concentrations, measured as particulate light absorption, were higher on truck routes during the midday sampling periods despite more unstable atmospheric conditions. Compared to the measurements at the three near-road sites, the 1-hour averages of on-road BC concentrations were as much as an order of magnitude higher. The peak 1-minute average concentrations were two orders of magnitude higher for BC and were between two and six times higher for PM2.5 mass. The on-road concentrations of benzene, toluene, ethylbenzene, and xylenes (BTEX) during the summer were 3.5 +/- 0.7 and 1.2 +/- 0.6 times higher during morning and afternoon commuting periods, respectively, compared to annual average 24-hour concentrations measured at air toxic monitoring network sites. These ratios were higher during the fall, with smaller diurnal differences (4.8 +/- 0.7 and 3.9 +/- 0.6 for morning and afternoon commuting periods, respectively). Ratios similar to those for BTEX were obtained for 1,3-butadiene (BD) and styrene. On-road concentrations of formaldehyde and acetaldehyde were up to two times higher than at air toxics monitoring sites, with fall ratios slightly higher than summer ratios. Chemical mass balance (CMB) receptor model calculations attributed the sum of BTEX almost exclusively to gasoline engine exhaust for on-road samples and all but 5% to 10% of the BTEX at the three near-road sites. CMB analysis attributed 46% to 52% (+/- 7) of the ambient total particulate carbon (TC) at the three near-road sites to diesel exhaust and 10% to 17% (+/- 7) to gasoline exhaust; it attributed about 90% of the ambient elemental carbon (EC) concentrations (measured as refractory carbon using the thermal evolution method) to diesel exhaust. Diesel particulate carbon (DPC) concentrations were estimated by multiplying the mean ratio of TC to EC from the source-dominated ambient samples collected on road on Terminal Island (1.30 +/- 0.28), which is located between the Long Beach and Los Angeles ports, with the measured ambient EC concentrations at the three near-road sites. DPC estimates from EC measurements correlate well with the diesel source contributions calculated with the CMB model. The indication from these apportionments that BC or EC is a good surrogate for diesel exhaust is further supported by the positive correlation of on-road BC concentrations with volumes of truck traffic. Traffic counts have been used in past health assessment studies as surrogates for estimating near-road exposure concentrations with appropriate weighting for proximity to the road. However, the results of this study show that it is necessary to account for the proportion of diesel trucks to total vehicular traffic because of the disproportionate contribution of diesel exhaust to BC and to directly emitted PM. Alternatively, easily measured pollutants such as CO and BC can serve as reasonable surrogates for MSATs (e.g., BTEX and BD) and DPC, respectively. Measuring CO and BC is a reasonably cost-effective approach to quantifying hot-spot exposure concentrations of MSATs that is perhaps more accurate than what is possible using only data from regional air quality monitoring stations or air quality modeling results.