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Limits to Sustained Energy Intake XXXI: Effect of Graded Levels of Dietary Fat on Lactation Performance in Swiss Mice [RESEARCH ARTICLE]

Yi Huang, Jazmin Osorio Mendoza, Catherine Hambly, Baoguo Li, Zengguang Jin, Li Li, Moshen Madizi, Sumei Hu, and John R. Speakman

The heat dissipation limit theory predicts lactating female mice consuming diets with lower specific dynamic action (SDA) should have enhanced lactation performance. Dietary fat has lower SDA than other macronutrients. Here we tested the effects of graded dietary fat levels on lactating Swiss mice. We fed females five diets varying in fat content from 8.3 to 66.6%. Offspring of mothers fed diets of 41.7% fat and above were heavier and fatter at weaning compared to those of 8.3% and 25% fat diets. Mice on dietary fat contents of 41.7% and above had greater metabolizable energy intake at peak lactation (8.3%: 229.4±39.6, 25%: 278.8±25.8, 41.7%: 359.6±51.5, 58.3%: 353.7±43.6, 66.6%: 346±44.7 kJ day–1), lower daily energy expenditure (8.3%: 128.5±16, 25%: 131.6±8.4, 41.7%: 124.4±10.8, 58.3%: 115.1±10.5, 66.6%: 111.2±11.5 kJ day–1) and thus delivered more milk energy to their offspring (8.3%: 100.8±27.3, 25%: 147.2±25.1, 41.7%: 225.1±49.6, 58.3%: 238.6±40.1, 66.6%: 234.8±41.1 kJ day–1). Milk fat content (%) was unrelated to dietary fat content, indicating females on higher fat diets (> 41.7%) produced more rather than richer milk. Mothers consuming diets with 41.7% fat or above enhanced their lactation performance compared to those on 25% or less, probably by diverting dietary fat directly into the milk, thereby avoiding the costs of lipogenesis. At dietary fat contents above 41.7% they were either unable to transfer more dietary fat to the milk, or they chose not to do so, potentially because of a lack of benefit to the offspring that were increasingly fatter as maternal dietary fat increased.




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Genetic lineage tracing with multiple DNA recombinases: A user's guide for conducting more precise cell fate mapping studies [Methods and Resources]

Site-specific recombinases, such as Cre, are a widely used tool for genetic lineage tracing in the fields of developmental biology, neural science, stem cell biology, and regenerative medicine. However, nonspecific cell labeling by some genetic Cre tools remains a technical limitation of this recombination system, which has resulted in data misinterpretation and led to many controversies in the scientific community. In the past decade, to enhance the specificity and precision of genetic targeting, researchers have used two or more orthogonal recombinases simultaneously for labeling cell lineages. Here, we review the history of cell-tracing strategies and then elaborate on the working principle and application of a recently developed dual genetic lineage-tracing approach for cell fate studies. We place an emphasis on discussing the technical strengths and caveats of different methods, with the goal to develop more specific and efficient tracing technologies for cell fate mapping. Our review also provides several examples for how to use different types of DNA recombinase–mediated lineage-tracing strategies to improve the resolution of the cell fate mapping in order to probe and explore cell fate–related biological phenomena in the life sciences.




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Recent Approaches To Optimize Laboratory Assessment of Antinuclear Antibodies [Minireviews]

The presence of antinuclear antibodies (ANAs) is a hallmark of a number of systemic autoimmune rheumatic diseases, and testing is usually performed as part of the initial diagnostic workup when suspicion of an underlying autoimmune disorder is high. The indirect immunofluorescence antibody (IFA) technique is the preferred method for detecting ANAs, as it demonstrates binding to specific intracellular structures within the cells, resulting in a number of staining patterns that are usually categorized based on the cellular components recognized and the degree of binding, as reflected by the fluorescence intensity or titer. As a screening tool, the ANA patterns can guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. However, routine use of ANA IFA testing as a global screening test is hampered by its labor-intensiveness, subjectivity, and limited diagnostic specificity, among other factors. This review focuses on current efforts to standardize the nomenclature of ANA patterns and on alternative methods for ANA determination, as well as on recent advances in image-based computer algorithms to automate IFA testing in clinical laboratories.




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Development of an Extended-Specificity Multiplex Immunoassay for Detection of Streptococcus pneumoniae Serotype-Specific Antigen in Urine by Use of Human Monoclonal Antibodies [Diagnostic Laboratory Immunology]

Current pneumococcal vaccines cover the 10 to 23 most common serotypes of the 92 presently described. However, with the increased usage of pneumococcal-serotype-based vaccines, the risk of serotype replacement and an increase in disease caused by nonvaccine serotypes remains. Serotype surveillance of pneumococcal infections relies heavily on culture techniques, which are known to be insensitive, particularly in cases of noninvasive disease. Pneumococcal-serotype-specific urine assays offer an alternative method of serotyping for both invasive and noninvasive disease. However, the assays described previously cover mainly conjugate vaccine serotypes, give little information about circulating nonvaccine serotypes, and are currently available only in one or two specialist laboratories. Our laboratory has developed a Luminex-based extended-range antigen capture assay to detect pneumococcal-serotype-specific antigens in urine samples. The assay targets 24 distinct serotypes/serogroups plus the cell wall polysaccharide (CWP) and some cross-reactive serotypes. We report that the assay is capable of detecting all the targeted serotypes and the CWP at 0.1 ng/ml, while some serotypes are detected at concentrations as low as 0.3 pg/ml. The analytical serotype specificity was determined to be 98.4% using a panel of polysaccharide-negative urine specimens spiked with nonpneumococcal bacterial antigens. We also report clinical sensitivities of 96.2% and specificities of 89.9% established using a panel of urine specimens from patients diagnosed with community-acquired pneumonia or pneumococcal disease. This assay can be extended for testing other clinical samples and has the potential to greatly improve serotype-specific surveillance in the many cases of pneumococcal disease in which a culture is never obtained.




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Identification of Novel Antigens Recognized by Serum Antibodies in Bovine Tuberculosis [Diagnostic Laboratory Immunology]

Bovine tuberculosis (TB), caused by Mycobacterium bovis, remains an important zoonotic disease posing a serious threat to livestock and wildlife. The current TB tests relying on cell-mediated and humoral immune responses in cattle have performance limitations. To identify new serodiagnostic markers of bovine TB, we screened a panel of 101 recombinant proteins, including 10 polyepitope fusions, by a multiantigen print immunoassay (MAPIA) with well-characterized serum samples serially collected from cattle with experimental or naturally acquired M. bovis infection. A novel set of 12 seroreactive antigens was established. Evaluation of selected proteins in the dual-path platform (DPP) assay showed that the highest diagnostic accuracy (~95%) was achieved with a cocktail of five best-performing antigens, thus demonstrating the potential for development of an improved and more practical serodiagnostic test for bovine TB.




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High-Resolution Epitope Positioning of a Large Collection of Neutralizing and Nonneutralizing Single-Domain Antibodies on the Enzymatic and Binding Subunits of Ricin Toxin [Clinical Immunology]

We previously produced a heavy-chain-only antibody (Ab) VH domain (VHH)-displayed phage library from two alpacas that had been immunized with ricin toxoid and nontoxic mixtures of the enzymatic ricin toxin A subunit (RTA) and binding ricin toxin B subunit (RTB) (D. J. Vance, J. M. Tremblay, N. J. Mantis, and C. B. Shoemaker, J Biol Chem 288:36538–36547, 2013, https://doi.org/10.1074/jbc.M113.519207). Initial and subsequent screens of that library by direct enzyme-linked immunosorbent assay (ELISA) yielded more than two dozen unique RTA- and RTB-specific VHHs, including 10 whose structures were subsequently solved in complex with RTA. To generate a more complete antigenic map of ricin toxin and to define the epitopes associated with toxin-neutralizing activity, we subjected the VHH-displayed phage library to additional "pannings" on both receptor-bound ricin and antibody-captured ricin. We now report the full-length DNA sequences, binding affinities, and neutralizing activities of 68 unique VHHs: 31 against RTA, 33 against RTB, and 4 against ricin holotoxin. Epitope positioning was achieved through cross-competition ELISAs performed with a panel of monoclonal antibodies (MAbs) and verified, in some instances, with hydrogen-deuterium exchange mass spectrometry. The 68 VHHs grouped into more than 20 different competition bins. The RTA-specific VHHs with strong toxin-neutralizing activities were confined to bins that overlapped two previously identified neutralizing hot spots, termed clusters I and II. The four RTB-specific VHHs with potent toxin-neutralizing activity grouped within three adjacent bins situated at the RTA-RTB interface near cluster II. These results provide important insights into epitope interrelationships on the surface of ricin and delineate regions of vulnerability that can be exploited for the purpose of vaccine and therapeutic development.




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Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies

Objective

To describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs).

Methods

Identification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry.

Results

Ten children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4–16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/μL, range: 21–256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320–1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis.

Discussion

AE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE.




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Recombinase Polymerase Amplification and Lateral Flow Assay for Ultrasensitive Detection of Low-Density Plasmodium falciparum Infection from Controlled Human Malaria Infection Studies and Naturally Acquired Infections [Parasitology]

Microscopy and rapid diagnostic tests (RDTs) are the main diagnostic tools for malaria but fail to detect low-density parasitemias that are important for maintaining malaria transmission. To complement existing diagnostic methods, an isothermal reverse transcription-recombinase polymerase amplification and lateral flow assay (RT-RPA) was developed. We compared the performance with that of ultrasensitive reverse transcription-quantitative PCR (uRT-qPCR) using nucleic acid extracts from blood samples (n = 114) obtained after standardized controlled human malaria infection (CHMI) with Plasmodium falciparum sporozoites. As a preliminary investigation, we also sampled asymptomatic individuals (n = 28) in an area of malaria endemicity (Lambaréné, Gabon) to validate RT-RPA and assess its performance with unprocessed blood samples (dbRT-RPA). In 114 samples analyzed from CHMI trials, the positive percent agreement to uRT-qPCR was 90% (95% confidence interval [CI], 80 to 96). The negative percent agreement was 100% (95% CI, 92 to 100). The lower limit of detection was 64 parasites/ml. In Gabon, RT-RPA was 100% accurate with asymptomatic volunteers (n = 28), while simplified dbRT-RPA showed 89% accuracy. In a subgroup analysis, RT-RPA detected 9/10 RT-qPCR-positive samples, while loop-mediated isothermal amplification (LAMP) detected 2/10. RT-RPA is a reliable diagnostic test for asymptomatic low-density infections. It is particularly useful in settings where uRT-qPCR is difficult to implement.




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Subtle Variations in Dietary-Fiber Fine Structure Differentially Influence the Composition and Metabolic Function of Gut Microbiota

ABSTRACT

The chemical structures of soluble fiber carbohydrates vary from source to source due to numerous possible linkage configurations among monomers. However, it has not been elucidated whether subtle structural variations might impact soluble fiber fermentation by colonic microbiota. In this study, we tested the hypothesis that subtle structural variations in a soluble polysaccharide govern the community structure and metabolic output of fermenting microbiota. We performed in vitro fecal fermentation studies using arabinoxylans (AXs) from different classes of wheat (hard red spring [AXHRS], hard red winter [AXHRW], and spring red winter [AXSRW]) with identical initial microbiota. Carbohydrate analyses revealed that AXSRW was characterized by a significantly shorter backbone and increased branching compared with those of the hard varieties. Amplicon sequencing demonstrated that fermentation of AXSRW resulted in a distinct community structure of significantly higher richness and evenness than those of hard-AX-fermenting cultures. AXSRW favored OTUs within Bacteroides, whereas AXHRW and AXHRS favored Prevotella. Accordingly, metabolic output varied between hard and soft varieties; higher propionate production was observed with AXSRW and higher butyrate and acetate with AXHRW and AXHRS. This study showed that subtle changes in the structure of a dietary fiber may strongly influence the composition and function of colonic microbiota, further suggesting that physiological functions of dietary fibers are highly structure dependent. Thus, studies focusing on interactions among dietary fiber, gut microbiota, and health outcomes should better characterize the structures of the carbohydrates employed.

IMPORTANCE Diet, especially with respect to consumption of dietary fibers, is well recognized as one of the most important factors shaping the colonic microbiota composition. Accordingly, many studies have been conducted to explore dietary fiber types that could predictably manipulate the colonic microbiota for improved health. However, the majority of these studies underappreciate the vastness of fiber structures in terms of their microbial utilization and omit detailed carbohydrate structural analysis. In some cases, this causes conflicting results to arise between studies using (theoretically) the same fibers. In this investigation, by performing in vitro fecal fermentation studies using bran arabinoxylans obtained from different classes of wheat, we showed that even subtle changes in the structure of a dietary fiber result in divergent microbial communities and metabolic outputs. This underscores the need for much higher structural resolution in studies investigating interactions of dietary fibers with gut microbiota, both in vitro and in vivo.




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Disinfectant Efficacy: Understanding the Expectations and How to Design Effective Studies That Include Leveraging Multi-Site Data to Drive an Efficient Program

For manufacturers of both sterile and nonsterile pharmaceuticals, there is an expectation that the manufacturing process is performed in a manner that prevents extraneous contamination so that the products are provided in a safe, integral, pure, and unadulterated form. As part of that process, cleaning and disinfection are an absolute necessity. Although cleaning and disinfection support control of microbial contamination through preventive and corrective action, specific compendia methods do not currently exist. The intent of this paper is to provide a general guidance on how to perform disinfectant efficacy validation and implementation. This includes how to make sure the concepts are understood, how to interpret facility data and utilize it to demonstrate control awareness for your facilities, and how to leverage the data to reduce redundancies in validation or verification. This paper represents the thoughts and best practices of the authoring team and their respective companies and provides an efficient way to qualify disinfectants without impacting the quality of the study. If you choose to follow the recommendations in this paper, you must ensure that the appropriate rationale is sound and the scientific data is documented. It is the belief of the authoring team that only then will this approach meet regulatory requirements.




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Intrahepatic Fat and Postprandial Glycemia Increase After Consumption of a Diet Enriched in Saturated Fat Compared With Free Sugars

OBJECTIVE

Debate continues regarding the influence of dietary fats and sugars on the risk of developing metabolic diseases, including insulin resistance and nonalcoholic fatty liver disease (NAFLD). We investigated the effect of two eucaloric diets, one enriched with saturated fat (SFA) and the other enriched with free sugars (SUGAR), on intrahepatic triacylglycerol (IHTAG) content, hepatic de novo lipogenesis (DNL), and whole-body postprandial metabolism in overweight males.

RESEARCH DESIGN AND METHODS

Sixteen overweight males were randomized to consume the SFA or SUGAR diet for 4 weeks before consuming the alternate diet after a 7-week washout period. The metabolic effects of the respective diets on IHTAG content, hepatic DNL, and whole-body metabolism were investigated using imaging techniques and metabolic substrates labeled with stable-isotope tracers.

RESULTS

Consumption of the SFA diet significantly increased IHTAG by mean ± SEM 39.0 ± 10.0%, while after the SUGAR diet IHTAG was virtually unchanged. Consumption of the SFA diet induced an exaggerated postprandial glucose and insulin response to a standardized test meal compared with SUGAR. Although whole-body fat oxidation, lipolysis, and DNL were similar following the two diets, consumption of the SUGAR diet resulted in significant (P < 0.05) decreases in plasma total, HDL, and non-HDL cholesterol and fasting β-hydroxybutyrate plasma concentrations.

CONCLUSIONS

Consumption of an SFA diet had a potent effect, increasing IHTAG together with exaggerating postprandial glycemia. The SUGAR diet did not influence IHTAG and induced minor metabolic changes. Our findings indicate that a diet enriched in SFA is more harmful to metabolic health than a diet enriched in free sugars.




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Books: Pain and Prejudice: a Call to Arms for Women and Their Bodies




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As the profession soldiers on, all members hear the call to arms




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Single-Cell Immune Competency Signatures Associate with Survival in Phase II GVAX and CRS-207 Randomized Studies in Patients with Metastatic Pancreatic Cancer

The identification of biomarkers for patient stratification is fundamental to precision medicine efforts in oncology. Here, we identified two baseline, circulating immune cell subsets associated with overall survival in patients with metastatic pancreatic cancer who were enrolled in two phase II randomized studies of GVAX pancreas and CRS-207 immunotherapy. Single-cell mass cytometry was used to simultaneously measure 38 cell surface or intracellular markers in peripheral blood mononuclear cells obtained from a phase IIa patient subcohort (N = 38). CITRUS, an algorithm for identification of stratifying subpopulations in multidimensional cytometry datasets, was used to identify single-cell signatures associated with clinical outcome. Patients with a higher abundance of CD8+CD45ROCCR7CD57+ cells and a lower abundance of CD14+CD33+CD85j+ cells had improved overall survival [median overall survival, range (days) 271, 43–1,247] compared with patients with a lower abundance of CD8+CD45ROCCR7CD57+ cells and higher abundance of CD14+CD33+CD85j+ cells (77, 24–1,247 days; P = 0.0442). The results from this prospective–retrospective biomarker analysis were validated by flow cytometry in 200 patients with pancreatic cancer enrolled in a phase IIb study (P = 0.0047). The identified immune correlates provide potential prognostic or predictive signatures that could be employed for patient stratification.




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Prebiotics Inhibit Proteolysis by Gut Bacteria in a Host Diet-Dependent Manner: a Three-Stage Continuous In Vitro Gut Model Experiment [Food Microbiology]

Dietary protein residue can result in microbial generation of various toxic metabolites in the gut, such as ammonia. A prebiotic is "a substrate that is selectively utilised by host microorganisms conferring a health benefit" (G. R. Gibson, R. Hutkins, M. E. Sanders, S. L. Prescott, et al., Nat Rev Gastroenterol Hepatol 14:491–502, 2017, https://doi.org/10.1038/nrgastro.2017.75). Prebiotics are carbohydrates that may have the potential to reverse the harmful effects of gut bacterial protein fermentation. Three-stage continuous colonic model systems were inoculated with fecal samples from omnivore and vegetarian volunteers. Casein (equivalent to 105 g protein consumption per day) was used within the systems as a protein source. Two different doses of inulin-type fructans (Synergy1) were later added (equivalent to 10 g per day in vivo and 15 g per day) to assess whether this influenced protein fermentation. Bacteria were enumerated by fluorescence in situ hybridization with flow cytometry. Metabolites from bacterial fermentation (short-chain fatty acid [SCFA], ammonia, phenol, indole, and p-cresol) were monitored to further analyze proteolysis and the prebiotic effect. A significantly higher number of bifidobacteria was observed with the addition of inulin together with reduction of Desulfovibrio spp. Furthermore, metabolites from protein fermentation, such as branched-chain fatty acids (BCFA) and ammonia, were significantly lowered with Synergy1. Production of p-cresol varied among donors, as we recognized four high producing models and two low producing models. Prebiotic addition reduced its production only in vegetarian high p-cresol producers.

IMPORTANCE Dietary protein levels are generally higher in Western populations than in the world average. We challenged three-stage continuous colonic model systems containing high protein levels and confirmed the production of potentially harmful metabolites from proteolysis, especially replicates of the transverse and distal colon. Fermentations of proteins with a prebiotic supplementation resulted in a change in the human gut microbiota and inhibited the production of some proteolytic metabolites. Moreover, we observed both bacterial and metabolic differences between fecal bacteria from omnivore donors and vegetarian donors. Proteins with prebiotic supplementation showed higher Bacteroides spp. and inhibited Clostridium cluster IX in omnivore models, while in vegetarian modes, Clostridium cluster IX was higher and Bacteroides spp. lower with high protein plus prebiotic supplementation. Synergy1 addition inhibited p-cresol production in vegetarian high p-cresol-producing models while the inhibitory effect was not seen in omnivore models.




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Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Part 2: Potential Alternatives to the Use of Animals in Preclinical Trials

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.




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Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379 [Antiviral Agents]

Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC50) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC50 of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC50 of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.




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Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function [Experimental Therapeutics]

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.




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A Case of Euglycemic Diabetic Ketoacidosis Triggered by a Ketogenic Diet in a Patient With Type 2 Diabetes Using a Sodium-Glucose Cotransporter 2 Inhibitor




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Objectively-Measured Light-Intensity Physical Activity and Risk of Cancer Mortality: A Meta-analysis of Prospective Cohort Studies

Background:

The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality.

Methods:

We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose–response analysis was used to plot their relationship.

Results:

Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79–0.95; I2 < 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (Pnonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, Pinteraction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, Pinteraction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%.

Conclusions:

Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality.

Impact:

LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.




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The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.




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A Systematic Review on Cost-effectiveness Studies Evaluating Ovarian Cancer Early Detection and Prevention Strategies

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.




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Duy nhất 1 căn Shophouse 90m2 GĐ1 của CĐT mặt tiền đường Xa Lộ Hà Nội Q9, đối diện ga Metro số 10

- Chủ đầu tư mở bán giai đoạn 1 duy nhất còn 1 căn diện tích 90m2 Shophouse Metro Star góc 2 mặt tiền tiện kinh doanh hoặc cho thuê sau này. - Shophouse Metro Star nằm đối diện trạm metro số 10 tuyến số 1 có cầu bộ hành kết nối trực tiếp vào tầng 2 của trung tâm thương mại của dự án. - Hiện tại tuyến Metro số 1 đã hoàn thiện hơn 70% tiến độ, dự kiến sẽ đi vào vận hành vào cuối ...




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Nhanh tay sở hữu căn hộ Bcons Green View cực đẹp, giá gốc CĐT, đối diện Big C Dĩ An TT chỉ 10%

Liên hệ: 0933 686 500.Hiện đang nhận booking ưu tiên Giai đoạn 2.Căn đẹp tầng đẹp.Giá gốc từ chủ đầu tư.Chỉ từ 1 tỷ 3 ~ 1 tỷ 5/ căn 2 PN (thanh toán chỉ 130tr~140tr).Thông tin:Tên dự án: Căn hộ Bcons Green View.Nối tiếp hàng loạt dự án hot vượt tiến độ tại Dĩ An. Bcons Suối Tiên ...




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Đất phân lô cách Trôi 1km, sát khu đô thị diện tích 54m2, vỉa hè thoáng, giá 2.43 tỷ

Đất phân lô cách Trôi 1km, sát khu đô thị diện tích 54m2, vỉa hè thoáng, giá 2.43 tỷ. Đường trước đất rộng rãi, chia ô bàn cờ đi lại thuận tiện. Kết nối dễ dàng với Quốc Lộ 32. Trong khu đô thị Tân Tây Đô rất nhiều tiện ích. Kích thước đất xây nhà rất đẹp, mặt tiền 4.5m. Giá bán ...




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Đất ngay Nguyễn Cửu Phú Bình Tân, đối diện Bách Hóa Xanh, cách UBND P Tân Tạo 500m. LH: 0914814032

- Vị trí: Nằm trên đường Số 7 liền kề khu Tên Lửa Bình Tân. Cách UBND Quận Bình Tân 500m, cách trung tâm y tế Kỹ Thuật Cao Quận Bình Tân 1km. Thuận tiện di chuyển về Quốc lộ 1A, Võ Văn Kiệt, Nguyễn Văn Linh.- Dịch vụ tiện ích cận kề: + Chỉ 5 phút đến Aeon Bình Tân, bệnh viện Quốc...




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Diện tích tối thiểu cấp sổ hồng tại Tp.HCM

Theo tôi được biết thì ở Tp.HCM có chia làm 3 khu vực với quy định về diện tích tối thiểu cấp sổ hồng khác nhau. Theo đó thì các quận huyện như Hóc Môn, Củ Chi, Quận 12 phải có diện tích trên 80m2 đối với đất đã có nhà. Tuy nhiên khi tìm mua nhà thì có nơi cam kết có sổ hồng cho nhà đất tại Hóc Môn với diện tích chỉ 60m2. Theo người bán thì đây là nhà trong khu quy hoạch dân cư nhà phố nên được phép tách như vậy. Xin hỏi việc này có đúng không? Văn bản nào quy định điều này? Xin cám ơn luật sư!




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5 mẫu phòng ngủ tiện nghi bất chấp diện tích nhỏ hẹp

Sở hữu một phòng ngủ nhỏ không đồng nghĩa với việc bạn phải hy sinh sự tiện nghi và phong cách thiết kế. Trên thực tế, với những không gian nhỏ, chỉ cần lên kế hoạch thiết kế kỹ lưỡng ngay từ đầu là bạn vừa có thể tận dụng tối đa diện tích căn phòng, vừa thể hiện được cá tính của bản thân trong lối bài trí.




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Nợ ngập đầu chỉ vì “sĩ diện” muốn xây nhà hoành tráng

“Các cụ vẫn bảo, đàn ông có ba việc lớn nhất định phải hoàn thành trong đời mới xứng phận nam nhi, đó là tậu trâu, cưới vợ, làm nhà. Nhưng cũng bởi hai chữ “sĩ diện” muốn xây ngôi nhà hoành tráng mà tôi đã đẩy gia đình lâm vào cảnh nợ nần chồng chất”, anh Tấn chia sẻ.




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Diễn biến thị trường BĐS 2019

Chủ đề cập nhật thông tin nhanh và chính xác nhất về diễn biến của thị trường bất động sản trong cả nước do đội ngũ phóng viên, Ban nghiên cứu thị trường Batdongsan.com.vn thực hiện.




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Diễn biến thị trường BĐS năm 2020

Tập hợp những bài viết, nhận định của chuyên gia, nhóm PV, biên tập, NCTT của Batdongsan.com.vn về diễn biến thị trường bất động sản năm 2020.




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HOUSE FOR RENT IN THAO DIEN, DISTRICT D2

HOUSE FOR RENT IN THAO DIEN, DISTRICT D2 ...A simple home with Zen ambiance enhances your good vibe.- Located in Thao Dien, a green and classified ex-pat village. - Fully furnished - 2 bedrooms/ 3 bathrooms/ living room/ bar/ lounge for meditation or working/ attic/ balcony/ smal...




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Bán gấp đất làm nhà vườn nghỉ dưỡng, tại Lương Sơn, Hòa Bình, diện tích 6296m2

Tổng diện tích 6296m2 đất, trong đó có 400m2 đất ở, còn lại là đất vườn, sổ đỏ chính chủ sang tên nhanh gọn. - Lô đất có vị trí đẹp thế đất cao thoáng thoai thoải nhẹ phía tựa vào núi đường đẹp ô tô vào tận nơi. + Hiện trên đất có 01 nhà cấp 4, xung quanh vườn đang trồng nhiều lo...




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Chính chủ cần bán 1500m2 full bưởi đỏ, bưởi diễn, đất thoải, hướng ĐN, view hồ cực đẹp, cách HN35km

- Chính chủ cần bán 1500m2 có 100m2 đất thổ cư, còn lại là đất trồng cây lâu năm tại Hòa Sơn, Lương Sơn Hòa Bình. - Thế đất thoải sườn đồi, đã trồng toàn bộ bưởi đỏ Tân Lạc, bưởi Diễn và một số cây ăn trái khác đang cho thu hoạch, tường bao vây xung quanh, hướng Đông Nam, view hồ...




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Cho thuê nhà mặt đường Tam Trinh diện tích 180m2 làm cửa hàng, trụ sở công ty. LH : 0906246169.

Cho thuê nhà 807 Tam Trinh, nhà mặt đường diện tích 180m2, có cửa hàng 60m2 kinh doanh, phía trong có nhà 4 tầng đầy đủ tiện nghi. Có thể kinh doanh hoặc làm trụ sở công ty. Giá thuê : 18 triệu/tháng. Liên hệ : chị Nguyệt - ĐT : 0906246169...




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Chính chủ cần cho thuê 2 mặt bằng diện tích lớn 2500m2 và 900m2 mặt tiền đường Hậu Giang, Quận 6

Cần cho thuê 2 mặt bằng mặt bằng mặt tiền đường Hậu Giang khu kinh doanh sầm uất bậc nhất Quận 6. Mặt bằng thứ 1: Địa chỉ: 947 - 949 đường Hậu Giang Phường 11, Quận 6 TP. HCM. Diện tích: 2500m2. Giá cho thuê: 350 triệu/tháng. Liên hệ: 0909127979 gặp Anh Hải (Chủ mặt bằng). Thuận ...




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Cho thuê phòng trọ cao cấp tại Đồng Diều, Quận 8

Cho CBCNV & SV thuê phòng trọ. Nhà mới 100% chưa sử dụng. Nội thất cao cấp, tiện nghi đầy đủ, có tivi mới máy lạnh máy nước nóng năng lượng mặt trời, trên sân thượng phơi đồ có sẵn máy giặt phục vụ theo nhu cầu. Mỗi phòng đều có toilet riêng. Giờ giấc tự do ra vào bằng máy giám s...




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Bán khách sạn góc 2MT P. Bến Nghé, Q1 diện tích 1000m2, 2 hầm 20 tầng. Giá: 1300 tỷ

Bán gấp siêu phẩm khách sạn góc 2 mặt tiền, phường Bến Nghé, Quận 1.Diện tích: 25m x 40m.Kết cấu: 2 hầm 20 tầng.Vị trí: Tọa lạc tại vị trí vô cùng đắc địa, ngay phố đi bộ Nguyễn Huệ, gần các khách sạn nổi tiếng như: Times Square, Caravelle, Sheraton,...Giá bán chỉ: 1300 tỷ.Liên h...




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Bán nhà 5 tầng bãi tắm Sơn Thủy, đối diện công viên, đang cho thuê 50 triệu/tháng

Bán nhà mới 100%, full nội thất cao cấp, đang cho người nước ngoài thuê ổn định 50 tr/tháng. Hợp đồng 2 năm cam kết. Kích thước: 5 x 20m. Hướng: Bắc. Đường: 5,5m, vỉa hè 4m. Nhà mới xây 100%, full nội thất cao cấp, 7 phòng ngủ khép kín (40m2). Các phòng đều có ban công, có thể vậ...




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Cho thuê mặt bằng kinh doanh MT Trần Quang Diệu, Quận 3, lầu 1: 11 tr/tháng, lầu 2: 9 triệu/tháng

Cho thuê mặt bằng lầu 1 + lầu 2 để kinh doanh, diện tích 33m2. Lầu 1: 11 triệu/tháng. Lầu 2: 9 triệu/tháng. Vị trí tòa nhà mặt tiền đường Trần Quang Diệu, góc ngã tư Lê Văn Sỹ, Trần Quang Diệu, đối diện cây xăng. Tọa lạc tại khu mua sắm sắm đông đúc, phù hợp kinh doanh mọi ngành ...




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Cần cho thuê mặt bằng diện tích lớn thuận tiện kinh doanh mặt tiền đường Hậu Giang, Q 6

Tôi cần cho thuê 2 mặt bằng mặt bằng mặt tiền đường Hậu Giang khu kinh doanh sầm uất bậc nhất Quận 6. Mặt bằng thứ 1: Địa chỉ: 947 - 949 đường Hậu Giang Phường 11, Quận 6 TP. HCM. Diện tích: 2500m2. Giá cho thuê: 350 triệu/tháng. Liên hệ: 0909127979 gặp Anh Hải (Chủ mặt bằng). Th...




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Cho thuê mặt bằng mặt đường trung tâm làm trường khu vực Đống Đa diện tích 1280m2 siêu đẹp

Cho thuê mặt bằng làm trường tại khu vực Đống Đa. - Vị trí: Nằm tại trung tâm quận Đống Đa, đông dân, dân trí cao, gần các bệnh viện lớn, nhiều công ty quy mô, giao thông thuận tiện. * Mô tả: - Diện tích khuôn viên riêng biệt là 1280m2, xây dựng 690m2 x 2 tầng. - Hiện tại ngăn tư...




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Cận cảnh chiếc đèn chùm vi diệu biết "nở hoa"

Những chiếc đèn chùm đa năng có tên Shylight này được thiết kế kiểu dáng đẹp mắt như những bông hoa đang bung nở, với khung đèn và kỹ thuật chiếu sáng bởi đèn led từ bên trong, mang lại vẻ đẹp sang trọng và bắt mắt cho bất kỳ căn phòng nào.




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Tủ quần áo mở - thiết kế phù hợp với mọi không gian diện tích

Kiểu tủ quần áo mở ngày càng được nhiều người ưa chuộng bởi ưu điểm dễ dàng lưu trữ, đồng thời còn giúp tủ đồ trông gọn gàng và thẩm mỹ hơn.




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Chọn bàn nước vừa đẹp vừa tiết kiệm diện tích cho nhà nhỏ

Những mẫu bàn nước dưới đây có thiết kế vô cùng sáng tạo khi có thể lồng ghép với nhau để không chiếm quá nhiều diện tích trong phòng khách.




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Villa for sale in compound Thao Dien, 4 bedrooms, 7 bathrooms

Thao Dien compound villa complex consists of 2 layers of protection, land area of 780m2, 100% residential land, swimming pool and garden, 4 bedrooms, 7 bathrooms + 2 kitchens (dry kitchen and kitchen convention) modern design, designed by American architects, around the villa are...




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Tăng diện tích khu đô thị Long Vân (Bình Định) lên gần 1.400ha

Tổng diện tích khu đô thị Long Vân, TP. Quy Nhơn sẽ là gần 1.400ha, tăng thêm 14,55ha so với diện tích được phê duyệt năm 2013.




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Thao Dien D2 - Brand new studio apartment for rent

Thao Dien D2 - Brand new studio apartment for rent- Locarion: No. 30, 60 street, Thao Dien ward, Dist. 2 Guaranteed pictures are the same as reality (Status: Available NOW)SPECIAL PROMOTION THIS MONTH: DISCOUNT 50$ for 6 months contractsApartment Description:Modern design Full fu...




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Thao Dien D2 - Brand new studio apartment for rent

Thao Dien D2 - Brand new studio apartment for rent No. 30, 60 street, Thao Dien ward, Dist. 2 GUARANTEED PICTURES ARE THE SAME AS REALITY (Status: Available NOW)SPECIAL PROMOTION THIS MONTH: DISCOUNT 50$ for 6 months contractsApartment Description:Modern design Full furniture 40 ...




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Cho thuê kho, bãi tại Quận 7 nằm trên đường Huỳnh Tấn Phát, diện tích đa dạng, LH 0909.511.320

Cho thuê kho, bãi Quận 7(giáp Q4) diện tích cụ thể: - Bãi: 20.000m2, 30.000m2. - Kho lẻ: 200m2, 150m2, 100m2, 50m2, kho lẻ có thủ kho quản lý nhập xuất hàng hóa. Kho đẹp, cao ráo, xe container ra vào nhập hàng thuận tiện, đường vành đai ưu tiên, không cấm tải. Có đội ngủ bốc xếp,...