Preparation and synbiotic interaction mechanism of microcapsules of Bifidobacterium animalis F1-7 and human milk oligosaccharides (HMO).

Probiotics such as Bifidobacterium spp. generally possess important physiological functions. However, maintaining probiotic viability is a challenge during processing, storage, and digestive transit period. Microencapsulation is widely considered to be an attractive approach. In this study, B. animalis F1-7 microcapsules and B. animalis F1-7-HMO microcapsules were successfully prepared by emulsification/internal gelation with high encapsulation efficiency (90.67 % and 92.16 %, respectively). The current study revealed that HMO-supplemented microcapsules exhibited more stable lyophilized forms and thermal stability. Additionally, a significant improvement in probiotic cell viability was observed in such microcapsules during simulated gastrointestinal (GI) fluids or storage. We also showed that the individual HMO mixtures 6'-SL remarkably promoted the growth and acetate yield of B. animalis F1-7 for 48 h (p < 0.05). The synbiotic combination of 6'-SL with B. animalis F1-7 enhanced SCFAs production in vitro fecal fermentation, decreasing several harmful intestinal bacteria such as Dorea, Escherichia-Shigella, and Streptococcus while enriching the probiotic A. muciniphila. This study provides strong support for HMO or 6'-SL combined with B. animalis F1-7 as an innovative dietary ingredient to bring health benefits. The potential of the synbiotic microcapsules with this combination merits further exploration for future use in the food industry.

Degradation Adaptability Assessment of Semisolid Powder Molded Mg-Zn-Mn Alloys for Orthopedic Applications.

Semisolid powder molding was used to prepare the medical Mg-6Zn alloy; in order to further improve its degradation adaptability, 0.5 and 1 wt % Mn were added. Then, the effect of the forming temperature (540, 560, 580, and 600 °C) on the in vitro degradation behavior of the prepared Mg-6Zn-xMn (x = 0.5, 1 wt %) was analyzed, and the optimized alloy was obtained. Finally, the biocompatibility and in vivo degradation performance of the optimized and Mn-free alloys were evaluated. Importantly, single-photon emission tomographic imaging (SPECT/CT) was first applied to monitor the in vivo degradation process. The results show that the corrosion mechanism of the Mn-free alloy is microgalvanic corrosion control with corrosive pitting. After adding Mn, the in vitro degradation rate decreases by half (0.17 ± 0.01 mm/year) as the forming temperature increases to 600 °C, and Mg-6Zn-1Mn prepared at 600 °C is the optimized alloy. Mn addition improves the corrosion product film protection and discontinuous secondary phases, and thus, the corrosion mechanism is changed to corrosive pitting control. Additionally, semisolid powder molding is an easy method to prepare alloys with low average pore interconnectivity (<10%), which is helpful for slowing down the degradation rate. The Mn-containing alloy has better biocompatibility, with a cytotoxicity of grade 0-1, due to its lower degradation rate. The in vivo corrosion rate of the Mn-free alloy is 0.19 mm/year after 28 days of implantation, which was precisely detected by SPECT/CT in real-time. The long-term in vivo degradation adaptability of Mn-free and Mn-containing alloys was not correctly presented, which may be due to the unreasonable bone defect model causing implant displacement. However, both of these alloys cause no obvious inflammation and show good healing. In summary, semisolid powder molding is a potentially promising technique to prepare medical Mg alloys, and nuclear imaging is an effective in vivo degradation evaluation method.

Implementing comprehensive machine learning models of multispecies toxicity assessment to improve regulation of organic compounds.

Machine learning has made significant progress in assessing the risk associated with hazardous chemicals. However, most models were constructed by randomly selecting one algorithm and one toxicity endpoint towards single species, which may cause biased regulation of chemicals. In the present study, we implemented comprehensive prediction models involving multiple advanced machine learning and end-to-end deep learning to assess the aquatic toxicity of chemicals. The generated optimal models accurately unravel the quantitative structure-toxicity relationships, with the correlation coefficients of all training sets from 0.59 to 0.81 and of the test sets from 0.56 to 0.83. For each chemical, its ecological risk was determined from the toxicity information towards multiple species. The results also revealed the toxicity mechanism of chemicals was species sensitivity, and the high-level organisms were faced with more serious side effects from hazardous substances. The proposed approach was finally applied to screen over 16,000 compounds and identify high-risk chemicals. We believe that the current approach can provide a useful tool for predicting the toxicity of diverse organic chemicals and help regulatory authorities make more reasonable decisions.

A New Approach Methodology (NAM) Based Assessment of Butylated hydroxytoluene (BHT) for Endocrine Disruption Potential.

Butylated hydroxytoluene (BHT) is a synthetic antioxidant widely used in many industrial sectors. BHT is a well-studied compound for which there are many favorable regulatory decisions. However, a recent opinion by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) hypothesizes a role for BHT in endocrine disruption (ANSES (2021). This opinion is based on observations in mostly rat studies where changes to thyroid physiology are observed. Enzymatic induction of Cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism for these observations, however, a causal relationship has not been proven. Other evidence proposed in the document includes a read across argument to butylated hydroxyanisole (BHA), another Community Rolling Action Plan (CoRAP)-listed substance with endocrine disruption concerns. We tested the hypothesis that BHT is an endocrine disruptor by using a Next Generation Risk Assessment (NGRA) method. Four different cell lines: A549, HCC1428, HepG2, and MCF7 were treated with BHT and a series of BHT analogs at 5 different concentrations, RNA was isolated from cell extracts and run on the L1000 gene array platform. A toxicogenomics-based assessment was performed by comparing BHT's unique genomic signature to a large external database containing signatures of other compounds (including many known endocrine disruptors) to identify if any endocrine disruption-related modes of action (MoAs) are prevalent among BHT and other compounds with similar genomic signatures. In addition, we performed a toxicogenomics-based structure activity relationship (SAR) assessment of BHT and a series of structurally similar analogs to understand if endocrine disruption is a relevant MoA for chemicals that are considered suitable analogs to BHT using the P&G read across framework (Wu et al., 2010). Neither BHT nor any of its analogs connected to compounds that had endocrine activity for estrogens, androgens, thyroid, or steroidogenesis.

The Correlation Between Gross Domestic Product Per Capita and the Success Rate of Assisted Reproductive Technologies Worldwide.

OBJECTIVE: Although there has been increased utilization of assisted reproductive technologies (ART) in the world, there is no conclusive definition about the relationship between the success rate of ART and national wealth. METHODS: In this study, using the data from the International Committee for Monitoring Assisted Reproductive Technologies (ICMART), we sought to determine whether there is a correlation between the success rate of ART (represented by pregnancy and delivery rates) and national wealth represented by the gross domestic product (GDP) per capita. Moreover, to further understand the effect of GDP per capita on ART effectiveness, we analyzed the association between ART success rate and GDP per capita in 50 US states. RESULTS: Our data showed that the number of ART treatment cycles increased as the GDP per capita increased. However, we found a negative correlation between ART success rates and GDP per capita in ICMART countries, although no correlation was seen in the US states. Using rough estimation, we derived that the success rate of ART was not related to GDP per capita in the ICMART countries with a GDP per capita greater than USD 13,000. CONCLUSIONS: In conclusion, for the first time, we showed that when the GDP per capita of an economic territory reaches (or exceeds) USD 13,000, ART pregnancy and delivery rates were not associated with GDP per capita, and ART success rates remained stable.

Article title: Transcriptional profiling efficacy to define biological activity similarity for cosmetic ingredients' safety assessment based on next-generation read-across.

The objective of this work was to use transcriptional profiling to assess the biological activity of structurally related chemicals to define their biological similarity and with that, substantiate the validity of a read-across approach usable in risk assessment. Two case studies are presented, one with 4 short alkyl chain parabens: methyl (MP), ethyl (EP), butyl (BP), and propylparaben (PP), as well as their main metabolite, p-hydroxybenzoic acid (pHBA) with the assumption that propylparaben was the target chemical; and a second one with caffeine and its main metabolites theophylline, theobromine and paraxanthine where CA was the target chemical. The comprehensive transcriptional response of MCF7, HepG2, A549 and ICell cardiomyocytes was evaluated (TempO-Seq) after exposure to vehicle-control, each paraben or pHBA, CA or its metabolites, at 3 non-cytotoxic concentrations, for 6 h. Differentially expressed genes (FDR ≥0.05, and fold change ±1.2≥) were identified for each chemical, at each concentration, and used to determine similarities. Each of the chemicals is able to elicit changes in the expression of a number of genes, as compared to controls. Importantly, the transcriptional profile elicited by each of the parabens shares a high degree of similarity across the group. The highest number of genes commonly affected was between butylparaben and PP. The transcriptional profile of the parabens is similar to the one elicited by estrogen receptor agonists, with BP being the closest structural and biological analogue for PP. In the CA case, the transcriptional profile elicited of all four methylxanthines had a high degree of similarity across the cell types, with CA and theophylline being the most active. The most robust response was obtained in the cardiomyocytes with the highest transcriptional profile similarity between CA and TP. The transcriptional profile of the methylxanthines is similar to the one elicited by inhibitors of phosphatidylinositol 3-kinase as well as other kinase inhibitors. Overall, our results support the approach of incorporating transcriptional profiling in well-designed in vitro tests as one robust stream of data to support biological similarity driven read-across procedures and strengthening the traditional structure-based approaches useful in risk assessment.

[Application value of lung ultrasound in the diagnosis and severity assessment of ventilator-associated pneumonia].

OBJECTIVE: To explore the value of bedside lung ultrasound in the early diagnosis and severity assessment of ventilator-associated pneumonia (VAP). METHODS: A prospective observational study was conducted in 60 patients with VAP (VAP group) and 62 patients without VAP (control group) who were admitted to department of intensive care unit of General Hospital of Ningxia Medical University from September 2018 to July 2020. The gender, age and underlying diseases of non-VAP group were matched with VAP group. The general clinical data such as gender, age, underlying diseases, department source of the patient, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score were recorded. The body temperature, white blood cell count (WBC), procalcitonin (PCT), oxygenation index (PaO2/FiO2), alveolar artery oxygen differential pressure (PA-aDO2) were recorded. During mechanical ventilation, the patient's body temperature, WBC, sputum characteristics, and the change of the lung ultrasound were dynamically observed. With or without dynamic air bronchogram, lung ultrasound was considered to be positive as long as there were small subpleural consolidation or tissue-like sign. Ventilator-associated pneumonia lung ultrasound score (VPLUS) and lung ultrasound score (LUSS) were performed, and chest CT scan was completed on the same day. Use positive chest CT scan as the standard to evaluate the diagnostic efficacy of lung ultrasound, VPLUS score, and the combination of the two with PCT for VAP. LUSS was used to assess the severity of disease in patients with VAP. The correlation between LUSS and PaO2/FiO2, PA-aDO2, APACHE II score and SOFA score were analyzed. RESULTS: (1) General information: compared with non-VAP group, VAP group had more emergency surgery patients [51.7% (31/60) vs. 33.9% (21/62), P = 0.047], APACHE II score and SOFA score were significantly higher (APACHE II score: 15.4±5.7 vs. 13.4±3.4, P = 0.021; SOFA score: 8.8±4.2 vs. 6.3±3.3, P < 0.001), body temperature tended to rise (centigrade: 38.3±0.8 vs. 38.0±0.9, P = 0.054), more patients had airway purulent secretions [65.0% (39/60) vs. 41.9% (26/62), P = 0.011], and mechanical ventilation time and length of ICU stay were longer [mechanical ventilation time (days): 10.5 (6.6, 15.0) vs. 4.3 (3.0, 6.0), P < 0.001; length of ICU stay (days): 14.8 (9.0, 18.0) vs. 6.0 (4.0, 9.1), P < 0.001], 28-day mortality rate was higher [31.7% (19/60) vs. 9.7% (6/62), P = 0.003]. (2) Diagnostic efficacy evaluation: when lung ultrasound was positive, VPLUS ≥ 3 and PCT > 0.5 µg/L were used separately for the diagnosis of VAP, the sensitivity was 73.3%, 75.0%, 61.7%, respectively; the specificity was 80.6%, 58.1% and 59.7%, respectively; the 95% confidence interval (95%CI) was 0.685-0.842, 0.574-0.748, 0.514-0.694, respectively,all P < 0.05, positive lung ultrasound had good sensitivity and specificity. When positive lung ultrasound or VPLUS ≥ 3 were combined with PCT > 0.5 µg/L for tandem test, the specificity of VAP diagnosis was increased to 95.2% and 83.9%, respectively; but the specificity of VAP diagnosis of positive lung ultrasound combined with PCT > 0.5 µg/L was higher than VPLUS ≥ 3 combined with PCT > 0.5 µg/L (95.2% vs. 83.9%, P < 0.05). (3) Correlation analysis: LUSS showed a significant positive correlation with APACHE II and SOFA score (r values were 0.407, 0.399, P values were 0.001, 0.002, respectively), LUSS had no relation with PaO2/FiO2 and PA-aDO2 (r values were 0.189, -0.064, P values were 0.629, 0.149, respectively). CONCLUSIONS: Lung ultrasound can early detect VAP , and its diagnostic specificity is significantly improved when combined with PCT > 0.5 µg/L. LUSS is closely related to the severity of disease in VAP patients, therefore, lung ultrasound may be an effective method for early diagnosis and efficacy evaluation of VAP patients.

Effects of National New District on economic development and air pollution in China: empirical evidence from 69 large and medium-sized cities.

This study attempts to investigate the effect of the establishment of National New District (NND) on economic development and air pollution in China. For this purpose, this study adopts the difference-in-differences (DID) model, the propensity-score-matched difference-in-differences (PSM-DID) model, and the spatial difference-in-differences (SDID) model, using a panel data set of 69 large and medium-sized cities during the period of 2003-2018. The results show that NND promotes economic development but fails to reduce the emission of air pollution including per capita SO2 and per capita smoke without the consideration of spatial spillover effect. However, the promotion effect of NND on economic development is not supported after PSM matching. On the other hand, the advantage of the SDID model in policy evaluation is proved. For instance, with the consideration of spatial spillover effect, the win-win of promoting economic development and reducing air pollution are partially supported. Based on the above empirical findings, several policy implementations and research prospects are outlined.

How does environmental information disclosure affect economic development and haze pollution in Chinese cities? The mediating role of green technology innovation.

To achieve the win-win goal of fostering economic development and inhibiting haze pollution in China, environmental information disclosure has been given more and more attention for its role of promoting green technology innovation. Utilizing a panel data of 113 prefecture and above cities from 2008 to 2018, this thesis first provides an empirical evidence for the strategic interaction of environmental information disclosure in China, verifies the coexistence of "race to the bottom" and "race to the top", and finds that the intensity of "race to the bottom" is stronger than that of "race to the top". Then, this thesis employs an empirical analysis on the mediating role of green technology innovation between environmental information disclosure and economic development and haze pollution from the perspective of static, dynamic, and even dynamic spatial perspectives. The results show that green technology innovation partly mediates the promotion effect of environmental information disclosure on economic development and the inhibition effect of environmental information disclosure on haze pollution under the static situation. In addition, green technology innovation fully mediates the promotion effect of environmental information disclosure on economic development but partly mediates the inhibition effect of environmental information disclosure on haze pollution under the dynamic situation. Furthermore, with the consideration of dynamic and spatial spillover effects of dependent variables such as economic development and haze pollution simultaneously, the mediation roles of green technology innovation between environmental information disclosure and economic development and haze pollution are both not supported, while the inhibition effect of green technology innovation on haze pollution is still established. The results not only identify the strategic interaction of environmental information disclosure and reveal the effectiveness of the mediating role of green technology innovation between environmental information disclosure and economic development and environmental pollution under the static and dynamic situations, but also provide a theoretical framework for green, sustainable, and high-quality development in China.

Quantitative Imaging of pN Intercellular Force and Energetic Costs during Collective Cell Migration in Epithelial Wound Healing.

Collective cell migration plays a key role in tissue repair, metastasis, and development. Cellular tension is a vital mechanical regulator during the force-driven cell movements. However, the contribution and mechanism of cell-cell force interaction and energetic costs during cell migration are yet to be understood. Here, we attempted to unfold the mechanism of collective cell movement through quantification of the intercellular tension and energetic costs. The measurement of pN intercellular force is based on a "spring-like" DNA-probe and a molecular tension fluorescence microscopy. During the process of wound healing, the intercellular force along with the cell monolayer mainly originates from actin polymerization, which is strongly related to the cellular energy metabolism level. Intracellular force at different spatial regions of wound and the energetic costs of leader and follower cells were measured. The maximum force and energy consumption are mainly concentrated at the wound edge and dynamically changed along with different stages of wound healing. These results indicated the domination of leader cells other than follower cells during the collective cell migration.

Incorporation of in vitro techniques for botanicals dietary supplement safety assessment - Towards evaluation of developmental and reproductive toxicity (DART).

As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Here we explore in vitro gene expression as well receptor binding and enzyme activity as alternative assays to inform on developmental and reproductive toxicity (DART) relevant modes of action, since DART data gaps are common for botanicals. Specifically, botanicals suspected to have DART effects, in addition to those with a significant history of use, were tested in these assays. Gene expression changes in a number of different cell types were analysed using the connectivity mapping approach (CMap) to identify modes of action through a functional read across approach. Taken together with ligand affinity data obtained using a set of molecular targets customised towards known DART relevant modes of action, it was possible to inform DART risk using functional analogues, potency comparisons and a margin of internal exposure approach.

High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction.

Mitochondrial dysfunction is a prevalent molecular event that can result in multiple adverse outcomes. Recently, a novel high throughput method to assess metabolic capacity in fish embryos following exposure to chemicals has been adapted for environmental toxicology. Assessments of oxygen consumption rates using the Seahorse XF(e) 24/96 Extracellular Flux Analyzer (Agilent Technologies) can be used to garner insight into toxicant effects at early stages of development. Here we synthesize the current state of the science using high throughput metabolic profiling in zebrafish embryos, and present considerations for those wishing to adopt high throughput methods for mitochondrial bioenergetics into their research. Chemicals that have been investigated in zebrafish using this metabolic platform include herbicides (e.g. paraquat, diquat), industrial compounds (e.g. benzo-[a]-pyrene, tributyltin), natural products (e.g. quercetin), and anti-bacterial chemicals (i.e. triclosan). Some of these chemicals inhibit mitochondrial endpoints in the µM-mM range, and reduce basal respiration, maximum respiration, and spare capacity. We present a theoretical framework for how one can use mitochondrial performance data in zebrafish to categorize chemicals of concern and prioritize mitochondrial toxicants. Noteworthy is that our studies demonstrate that there can be considerable variation in basal respiration of untreated zebrafish embryos due to clutch-specific effects as well as individual variability, and basal oxygen consumption rates (OCR) can vary on average between 100 and 300 pmol/min/embryo. We also compare OCR between chorionated and dechorionated embryos, as both models are employed to test chemicals. After 24 h, dechorionated embryos remain responsive to mitochondrial toxicants, although they show a blunted response to the uncoupling agent carbonylcyanide-4-trifluoromethoxyphenylhydrazone (FCCP); dechorionated embryos are therefore a viable option for investigations into mitochondrial bioenergetics. We present an adverse outcome pathway framework that incorporates endpoints related to mitochondrial bioenergetics. High throughput bioenergetics assays conducted using whole embryos are expected to support adverse outcome pathways for mitochondrial dysfunction.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R2 = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R2 = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment.

Simple and cost-effective methods for precise analysis of trace element abundances in geological materials with ICP-MS.

Inductively coupled plasma mass spectrometry (ICP-MS) is the most commonly used technique to determine the abundances of trace elements in a wide range of geological materials. However, incomplete sample digestion, isobaric interferences and instrumental drift remain obvious problems that must be overcome in order to obtain precise and accurate results. For this reason, we have done many experiments and developed a set of simple, cost-effective and practical methods widely applicable for precise and rapid determination of trace element abundances in geological materials using ICP-MS. Commonly used high-pressure digestion technique is indeed effective in decomposing refractory phases, but this inevitably produces fluoride complexes that create new problems. We demonstrate that the fluoride complexes formed during high-pressure digestion can be readily re-dissolved using high-pressure vessel at 190°C for only 2h for 50mg sample. In the case of isobaric interferences, although oxide (e.g., MO+/M+) and hydroxide (e.g., MOH+/M+) productivity is variable between runs, the (MO+/M+)/(CeO+/Ce+) and (MOH+/M+)/(CeO+/Ce+) ratios remain constant, making isobaric interference correction for all other elements of interest straightforward, for which we provide an easy-to-use off-line procedure. We also show that mass-time-intensity drift curve is smooth as recognized previously, for which the correction can be readily done by analyzing a quality-control (QC) solution and using off-line Excel VBA procedure without internal standards. With these methods, we can produce data in reasonable agreement with recommended values of international rock reference standards with a relative error of <8% and precision generally better than 5%. Importantly, compared to the widely used analytical practice, we can effectively save >60% of time (e.g., <24h vs. >60h).

Principles of biofouling protection in marine sponges: a model for the design of novel biomimetic and bio-inspired coatings in the marine environment?

The process of biofouling of marine structures and substrates, such as platforms or ship hulls, proceeds in multiple steps. Soon after the formation of an initial conditioning film, formed via the adsorption of organic particles to natural or man-made substrates, a population of different bacterial taxa associates under the formation of a biofilm. These microorganisms communicate through a complex quorum sensing network. Macro-foulers, e.g., barnacles, then settle and form a fouling layer on the marine surfaces, a process that globally has severe impacts both on the economy and on the environment. Since the ban of tributyltin, an efficient replacement of this antifouling compound by next-generation antifouling coatings that are environmentally more acceptable and also showing longer half-lives has not yet been developed. The sponges, as sessile filter-feeder animals, have evolved antifouling strategies to protect themselves against micro- and subsequent macro-biofouling processes. Experimental data are summarized and suggest that coating of the sponge surface with bio-silica contributes to the inhibition of the formation of a conditioning film. A direct adsorption of the surfaces by microorganisms can be impaired through poisoning the organisms with direct-acting secondary metabolites or toxic peptides. In addition, first, compounds from sponges have been identified that interfere with the anti-quorum sensing network. Sponge secondary metabolites acting selectively on diatom colonization have not yet been identified. Finally, it is outlined that direct-acting secondary metabolites inhibiting the growth of macro-fouling animals and those that poison the multidrug resistance pump are available. It is concluded that rational screening programs for inhibitors of the complex and dynamic problem of biofilm production, based on multidisciplinary studies and using sponges as a model, are required in the future.

[Long-term assessment of relapse and associated risk factors in chronic hepatitis C patients treated with interferon and ribavirin].

OBJECTIVE: To investigate viral relapse and the associated risk factors during a long-term follow-up study of chronic hepatitis C (CHC) patients who achieved end-of-treatment response (ETR) after interferon and ribavirin therapy. METHODS: This retrospective study was conducted on 146 CHC patients treated with a combination of ribavirin and pegylated (PEG) interferon-alpha (IFNa) (n=126) or conventional IFNa (n=20) for 24 (hepatitis C virus (HCV) non-genotype 1b) or 48 (HCV genotype 1b) weeks. The main outcome measure was serum HCV RNA load. The risk factors analyzed included age, sex, HCV genotype, baseline HCV RNA load, and IFN type. RESULTS: The mean follow-up time for all patients was 33.45+/-16.41 months (range: 12-85 months). The cumulative relapse rate during follow-up was 14.80%. The relapse rate within six months (8.90%) was significantly higher than other periods during two years of follow-up, and no relapse occurred after 30 months. Of all relapsers (n=20), 65% occurred within six months, followed by 35% within 7-24 months after antiviral therapy. The relapse rates in patients with HCV genotype 1b and non-1b were not significantly different (20.37% vs. 12.12%, X2 =1.517, P=0.315). The mean baseline HCV RNA load was significantly higher in the relapsers than that in the non-relapsers (t=0.915, P=0.362). Relapse rates were similar in patients treated with PEG-IFNa-2b, PEG-IFNa-2a and IFNa (12.12% vs. 13.97% vs. 15.00%, respectively; X2=0.104, p=0.949). The mean age of relapsers was significantly higher than that of non-relapsers (P less than 0.005). CONCLUSION: The maximum probability of relapse for CHC patients exists within six months from when ETR is achieved by interferon and ribavirin therapy. A lower risk for relapse persists past this period. Thus, ETR CHC patients, especially older patients, should be carefully monitored during the two years after cessation of antiviral therapy. Standard antiviral therapy based on HCV genotype eliminates the influence of viral factors on treatment-response.

Modeling control strategies for concurrent epidemics of seasonal and pandemic H1N1 influenza.

The lessons learned from the 2009-2010 H1N1 influenza pandemic, as it moves out of the limelight, should not be under-estimated, particularly since the probability of novel influenza epidemics in the near future is not negligible and the potential consequences might be huge. Hence, as the world, particularly the industrialized world, responded to the potentially devastating effects of this novel A-H1N1 strain with substantial resources, reminders of the recurrent loss of life from a well established foe, seasonal influenza, could not be ignored. The uncertainties associated with the reported and expected levels of morbidity and mortality with this novel A-H1N1 live in a backdrop of deaths, over 200,000 hospitalizations, and millions of infections (20% of the population) attributed to seasonal influenza in the USA alone, each year. So, as the Northern Hemisphere braced for the possibility of a potentially "lethal" second wave of the novel A-H1N1 without a vaccine ready to mitigate its impact, questions of who should be vaccinated first if a vaccine became available, came to the forefront of the discussion. Uncertainty grew as we learned that the vaccine, once available, would be unevenly distributed around the world. Nations capable of acquiring large vaccine supplies soon became aware that those who could pay would have to compete for a limited vaccine stockpile. The challenges faced by nations dealing jointly with seasonal and novel A-H1N1 co-circulating strains under limited resources, that is, those with no access to novel A-H1N1 vaccine supplies, limited access to the seasonal influenza vaccine, and limited access to antivirals (like Tamiflu) are explored in this study. One- and two-strain models are introduced to mimic the influenza dynamics of a single and co-circulating strains, in the context of a single epidemic outbreak. Optimal control theory is used to identify and evaluate the "best" control policies. The controls account for the cost associated with social distancing and antiviral treatment policies. The optimal policies identified might have, if implemented, a substantial impact on the novel H1N1 and seasonal influenza co-circulating dynamics. Specifically, the implementation of antiviral treatment might reduce the number of influenza cases by up to 60% under a reasonable seasonal vaccination strategy, but only by up to 37% when the seasonal vaccine is not available. Optimal social distancing policies alone can be as effective as the combination of multiple policies, reducing the total number of influenza cases by more than 99% within a single outbreak, an unrealistic but theoretically possible outcome for isolated populations with limited resources.

[Value of dynamic contrast-enhanced MRI in assessment of early response to neoadjuvant chemotherapy in breast cancer].

OBJECTIVE: To assess the value of dynamic contrast-enhanced MRI (DMRI) in predicting early response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) and to assess the accuracy of MRI in evaluation of residual disease after NAC. METHODS: Forty-three women with LABC (44 lesions, all were invasive ductal carcinoma) underwent DMRI before, after the first and final cycles of NAC. For each patient, the tumor volume, early enhancement ratio (E1), maximum enhancement ratio (Emax), and maximum enhancement time (Tmax), dynamic signal intensity-time curve were obtained during treatment. The residual tumor volumes obtained by DMRI were compared with pathological findings to assess the accuracy of DMRI. RESULTS: After the first cycle of NAC, the mean volume of responders decreased insignificantly (P = 0.055), but after NAC, mean volume of residual tumor decreased significantly (P = 0.000). Morphological changes: 29 cases showed a concentric shrinkage pattern while 7 cases showed a dendritic shrinkage pattern. Significant differences were found in E1, Emax and Tmax between responders and non-responders (P < 0.05). After the first cycle of NAC, E1, Emax and Tmax of responders changed significantly (P < 0.001), while there was no significant change in non-responders (P > 0.05). After NAC, the dynamic signal intensity-time types were changed in responders, and tended to be significantly flattening, while no significant change was found in non-responders. The residual tumor volume correlation coefficient between MRI and pathology measurements was very high (r = 0.866, P < 0.01). CONCLUSION: DMRI is useful to evaluate the early response to NAC in LABC. The presence and volume of residual tumor in LABC patients treated with NAC can be accurately evaluated by DMRI.

Evaluation of cost-precision rations of different strategies for ELISA measurement of serum antibody levels.

Standardization and design of optimally reproducible strategies for the measurement of serum antibody levels by ELISA can present significant problems. In this article, we present a theoretical analysis of two common calculation methods in ELISA analysis (parallel line and reference line models), together with a new model, termed wPLL (a least squares-weighted modification of the parallel line model). The subject of required precision in relation to the marginal costs of increased precision has not been well explored. We compared the three different calculation methods of expressing ELISA results based on the relationship between the dose response curves obtained from the reference serum and the test samples in two viral antibody determination systems (human papillomavirus and measles). The three methods were evaluated for inter- and intraassay precision using the coefficient of variation in experiments with different numbers of dilutions and different numbers of replicates. Strategies with optimal cost-precision ratios were designed. The novel calculation method termed wPLL was preferable.