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The effect of plasma-activated water (PAW) generated with a dielectric barrier discharge diffusor (DBDD) system on microbial load and organoleptic quality of cucamelons was investigated and compared to the established sanitizer, sodium hypochlorite (NaOCl). Pathogenic serotypes of Escherichia coli, Salmonella enterica, and Listeria monocytogenes were inoculated onto the surface of cucamelons (6.5 log CFU g-1) and into the wash water (6 log CFU mL-1). PAW treatment involved 2 min in situ with water activated at 1,500 Hz and 120 V and air as the feed gas; NaOCl treatment was a wash with 100 ppm total chlorine; control treatment was a wash with tap water. PAW treatment produced a 3-log CFU g-1 reduction of pathogens on the cucamelon surface without negatively impacting quality or shelf life. NaOCl treatment reduced the pathogenic bacteria on the cucamelon surface by 3 to 4 log CFU g-1; however, this treatment also reduced fruit shelf life and quality. Both systems reduced 6-log CFU mL-1 pathogens in the wash water to below detectable limits. The critical role of superoxide anion radical (·O2-) in the antimicrobial power of DBDD-PAW was demonstrated through a Tiron scavenger assay, and chemistry modeling confirmed that ·O2- generation readily occurs in DBDD-PAW generated with the employed settings. Modeling of the physical forces produced during plasma treatment showed that bacteria likely experience strong local electric fields and polarization. We hypothesize that these physical effects synergize with reactive chemical species to produce the acute antimicrobial activity seen with the in situ PAW system. IMPORTANCE Plasma-activated water (PAW) is an emerging sanitizer in the fresh food industry, where food safety must be achieved without a thermal kill step. Here, we demonstrate PAW generated in situ to be a competitive sanitizer technology, providing a significant reduction of pathogenic and spoilage microorganisms while maintaining the quality and shelf life of the produce item. Our experimental results are supported by modeling of the plasma chemistry and applied physical forces, which show that the system can generate highly reactive ·O2- and strong electric fields that combine to produce potent antimicrobial power. In situ PAW has promise in industrial applications as it requires only low power (12 W), tap water, and air. Moreover, it does not produce toxic by-products or hazardous effluent waste, making it a sustainable solution for fresh food safety.

California Leafy Green Products Handler Marketing Agreement (LGMA) established food safety metrics with guidance recommendations of 366 m (1,200 feet) and 1,609 m (1 mile) distances between production fields of leafy greens and a concentrated animal feeding operation (CAFO) containing >1,000 and >80,000 head of cattle, respectively. This study evaluated the effect of these distance metrics and environmental factors on the occurrence of airborneEscherichia coliin proximity to seven commercial beef cattle feedlots located in Imperial Valley, California. A total of 168 air samples were collected from seven beef cattle feedlots during March and April 2020, which were the months implicated in the 2018 Yuma Arizona lettuce outbreak of E. coli O157:H7. The distance between air sampling sites and the edge of the feedlot ranged from ∼0 to ∼2,200 m (∼1.3 mile), with each sample comprised of 1,000 L of processed air taken at a 1.2 m elevation over a 10-minute duration. E. colicolonies were enumerated on CHROMagar ECC selective agar and confirmed with conventional PCR. Meteorological data (air temperature, wind speed, wind direction, relative humidity) were collectedin situ. The prevalence and mean concentration ofE. coliwere 6.55% (11/168) and 0.09 CFU per 1,000 L of air, with positive samples limited to within 37 m (120 ft) of the feedlot.Based on logistic regression, the odds of airborne E. coli detection were associated with little to no wind and close proximity to a feedlot. This pilot study found limited dispersal of airborne E. coli in proximity to commercial feedlots in Imperial Valley, with light-to-no wind and proximity within 37 m of a feedlot significant factor-associated airborne E. coli in this produce-growing region of California.

Climate change may impact human health through the influence of weather on environmental transmission of diarrhea. Previous studies have found that high temperatures and heavy precipitation are associated with increased diarrhea prevalence, but the underlying causal mechanisms have not been tested and validated. We linked measurements of Escherichia coli in source water (n = 1673), stored drinking water (n = 9692), and hand rinses from children

An increased understanding of the interaction between manure management and public and environmental health has led to the development of Alternative Dairy Effluent Management Strategies (ADEMS). The efficiency of such ADEMS can be increased using mechanical solid-liquid-separator (SLS) or gravitational Weeping-Wall (WW) solid separation systems. In this research, using pilot study data from 96 samples, the chemical, physical, biological, seasonal, and structural parameters between SLS and WW of ADEM systems were compared. Parameters including sodium, potassium, total salts, volatile solids, pH, and E. coli levels were significantly different between the SLS and WW of ADEMS. The separated solid fraction of the dairy effluents had the lowest E. coli levels, which could have beneficial downstream implications in terms of microbial pollution control. To predict effluent quality and microbial pollution risk, we used Escherichia coli as the indicator organism, and a versatile machine learning, ensemble, stacked, super-learner model called E-C-MAN (Escherichia coli-Manure) was developed. Using pilot data, the E-C-MAN model was trained, and the trained model was validated with the test dataset. These results demonstrate that the heuristic E-C-MAN ensemble model can provide a pilot framework toward predicting Escherichia coli levels in manure treated by SLS or WW systems.

Protein N-glycosylation is a common post-translational modification that plays significant roles on the structure, property, and function of glycoproteins. Due to N-glycan heterogeneity of naturally occurring glycoproteins, the functions of specific N-glycans on a particular glycoprotein are not always clear. Glycoprotein in vitro N-glycan engineering using purified recombinant enzymes is an attractive strategy to produce glycoproteins with homogeneous N-glycoforms to elucidate the specific functions of N-glycans and develop better glycoprotein therapeutics. Toward this goal, we have successfully expressed in E. coli glycoside hydrolases and glycosyltransferases from bacterial and human origins and developed a robust enzymatic platform for in vitro processing glycoprotein N-glycans from high-mannose-type to α2-6- or α2-3-disialylated biantennary complex type. The recombinant enzymes are highly efficient in step-wise or one-pot reactions. The platform can find broad applications in N-glycan engineering of therapeutic glycoproteins.

This study characterized the effect of distance from beef cattle feedlots, environmental factors, and climate on the occurrence of airborne bacterial indicators and pathogens. Three hundred air samples were collected over 6 months from five feedlots, with each air sample comprising 6000 L of air. Air samples were processed onto TSB-enriched air filters, qPCR-screened, and then qPCR-confirmed for suspect positive colonies of E. coli O157, non-O157-Shiga-toxin-producing E. coli (STEC), Salmonella, and E. coli. Direct enumeration of E. coli was also collected. Although no bacterial pathogens were qPCR-confirmed for the 300 samples, E. coli was detected in 16.7% (50/300) of samples, with an overall mean concentration of 0.17 CFU/6000 L air. Logistic regression analyses revealed a higher odds of E. coli for samples in close proximity compared to >610 m (2000 ft) distance from feedlots, along with significant associations with meteorological factors, sampling hour of day, and the presence of a dust-generating activity such as plowing a field or nearby vehicular traffic. The lack of bacterial pathogen detection suggests airborne deposition from nearby feedlots may not be a significant mechanism of leafy green bacterial pathogen contamination; the result of our study provides data to inform future revisions of produce-safety guidance.

The probiotic bacterium Escherichia coli Nissle 1917 (EcN) holds significant promise for use in clinical and biological industries. However, the reliance on antibiotics to maintain plasmid-borne genes has overshadowed its benefits. In this study, we addressed this issue by engineering the endogenous cryptic plasmids pMUT1 and pMUT2. The non-essential elements were removed to create more stable derivatives pMUT1NR△ and pMUT2HBC△. Synthetic promoters by integrating binding motifs on sigma factors were further constructed and applied for expression of Bacteroides thetaiotaomicron heparinase III and the biosynthesis of ectoine. Compared to traditional antibiotic-dependent expression systems, our newly constructed antibiotic-free expression systems offer considerable advantages for clinical and synthetic biology applications. [ABSTRACT FROM AUTHOR]

A sequential chlorination and electrochemical reduction process is demonstrated to convert Na–doped iridium oxide nanoparticles into useful IrIIICl 6 3− (aq) serving as the precursor for the fabrication of bio–stimulating electrode. The Na–doped iridium oxide nanoparticles are treated in 35 wt% hydrochloric acid at 70 °C for 18 h to form IrIVCl 6 2− (aq) with pH of 0.3, so the latter could be readily reduced to IrIIICl 6 3− (aq) at a potentiostatic mode of 0.6 V (vs. SCE). The oxidation state and the nature of complexing ligands for the regenerated IrIIICl 6 3− and IrIVCl 6 2−, as well as commercially available IrIIICl 6 3− are validated by X–ray Absorption Spectroscopy. UV–Vis profiles of regenerated IrIVCl 6 2− (aq) are recorded and the absorbance at 487 nm signal is benchmarked against that of standard IrIVCl 6 2− (aq) to obtain the effective regeneration ratio of 68.6%. X–ray diffraction patterns of Na–doped iridium oxide nanoparticles before and after the annealing treatment indicate the amorphous structure facilitates the chlorination step. The regenerated IrIIICl 6 3− is reused to synthesize Na–doped iridium oxide thin film serving as a bio–stimulating electrode for implantable bio–electronics. The regenerated Na–doped iridium oxide thin film reveals a charge-storage capacity of 0.32 mC/cm2-nm and impressive stability that are comparable to those of fresh Na–doped iridium oxide thin film derived from commercially available IrIIICl 6 3−. [ABSTRACT FROM AUTHOR]

Copyright of Cuadernos del Centro de Estudios de Diseño y Comunicación is the property of Cuadernos del Centro de Estudios de Diseno y Comunicacion and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Coastal pollution is of public health concern due to the possibility of bacterial contamination in aquaculture affecting health risk and seafood safety. This study determined the concentrations of total coliforms, fecal coliforms, E. coli, and V. parahaemolyticus and the presence of V. cholerae and Salmonella in water and measured water quality and meteorological factors from the major oyster cultivation areas in Thailand. The water samples (n = 363) were collected from Surat Thani (n = 60), Chanthaburi (n = 60), Trat (n = 60), Phetchaburi (n = 60), Chonburi (n = 63), and Phang Nga (n = 60) from February 2021 to January 2022. The prevalence of total coliforms (96.7%), fecal coliforms (60.6%), E. coli (22.9%), along with the prevalence of Salmonella (2.5%), Vibrio parahaemolyticus (74.9%), and V. cholerae (11.3%) were determined. Common Salmonella serovars were Othmarschen and Lamberhurst. The concentration of E. coli was significantly associated with dissolved oxygen and precipitation (p < 0.0001). Therefore, continuing microbiological monitoring and surveillance of water for coastal aquaculture is important to produce safe aquatic products. Furthermore, raising awareness of coastal pollution and seafood safety will help enhance sustainable coastal fisheries in Thailand.

Bioactive edible films have received more attention in recent years as a method for food preservation with value-added functions. The aim of this study was to develop a bioactive edible film containing mucilage of cactus (Opuntia ficus-indica) and incorporating the probiotic strain Enterococcus faecium FM11-2 as an active component to promote consumer health benefits. Opuntia ficus-indica is rich in nutritional and bioactive compounds and the abundance of this cactus makes it attractive for food applications. Mucilage of Opuntia ficus-indica contained 0.47 ± 0.06 mg/g total sugar, 0.33 ± 0.06 mg AGE/mL phenolic content, 0.14 mg/ mL vitamin C, and possessed 35.51 ± 1.88% DPPH scavenging activity. The edible film that was developed exhibited the following characteristics: thickness of 0.02-0.11 mm, percent moisture content 0.19-0.24%, water solubility 30.66-59.41% and water vapor permeability of 0.15-1.5 g·mm/m2·min·kpa, while the range of the variation depended on the type of plasticizer used (either sorbitol or glycerol). The addition of sorbitol in the film provided the maximum mechanical strength based on the evaluation of tensile strength, Young's modulus and elongation at break (44.71 ± 0.78 MPa, 113.22 ± 0.23 MPa and 39.47 ± 0.61%, respectively). The optimal formulation of the edible film, according to the physicochemical, physical and maintenance of fresh-cut apple slices, contained cactus mucilage, gelatin, glycerol and a probiotic. The incorporation of a probiotic into the cactus film created a bioactive edible film that could provide a health benefit. While improvement is needed to maintain the survival rate of the probiotic, this work presents an exciting method for furthering the study of food preservation with edible films.

The prevalence of carbapenem-resistant Enterobacterales (CRE) has been increasing since the year 2000 and is considered a serious public health threat according to the Centers for Disease Control and Prevention. Limited studies have genotyped Carbapenem-resistant Escherichia coli using whole genome sequencing to characterize the most common lineages and resistance and virulence genes. The aim of this study was to characterize sequence data from carbapenem-resistant E. coli isolates (n = 82) collected longitudinally by the Alameda County Public Health Laboratory (ACPHL) between 2017 and 2019. E. coli genomes were screened for antibiotic resistance genes (ARGs) and extraintestinal pathogenic E. coli virulence factor genes (VFGs). The carbapenem-resistant E. coli lineages were diverse, with 24 distinct sequence types (STs) represented, including clinically important STs: ST131, ST69, ST95, and ST73. All Ambler classes of Carbapenemases were present, with NDM-5 being most the frequently detected. Nearly all isolates (90%) contained genes encoding resistance to third-generation cephalosporins; blaCTX-M genes were most common. The number of virulence genes present within pandemic STs was significantly higher than the number in non-pandemic lineages (p = 0.035). Virulence genes fimA (92%), trat (71%), kpsM (54%), and iutA (46%) were the most prevalent within the isolates. Considering the public health risk associated with CRE, these data enhance our understanding of the diversity of clinically important E. coli that are circulating in Alameda County, California.

The mitochondrial AAA (ATPase Associated with diverse cellular Activities) protein ATAD1 (in humans; Msp1 in yeast) removes mislocalized membrane proteins, as well as stuck import substrates from the mitochondrial outer membrane, facilitating their re-insertion into their cognate organelles and maintaining mitochondria's protein import capacity. In doing so, it helps to maintain proteostasis in mitochondria. How ATAD1 tackles the energetic challenge to extract hydrophobic membrane proteins from the lipid bilayer and what structural features adapt ATAD1 for its particular function has remained a mystery. Previously, we determined the structure of Msp1 in complex with a peptide substrate (Wang et al., 2020). The structure showed that Msp1's mechanism follows the general principle established for AAA proteins while adopting several structural features that specialize it for its function. Among these features in Msp1 was the utilization of multiple aromatic amino acids to firmly grip the substrate in the central pore. However, it was not clear whether the aromatic nature of these amino acids were required, or if they could be functionally replaced by aliphatic amino acids. In this work, we determined the cryo-EM structures of the human ATAD1 in complex with a peptide substrate at near atomic resolution. The structures show that phylogenetically conserved structural elements adapt ATAD1 for its function while generally adopting a conserved mechanism shared by many AAA proteins. We developed a microscopy-based assay reporting on protein mislocalization, with which we directly assessed ATAD1's activity in live cells and showed that both aromatic amino acids in pore-loop 1 are required for ATAD1's function and cannot be substituted by aliphatic amino acids. A short α-helix at the C-terminus strongly facilitates ATAD1's oligomerization, a structural feature that distinguishes ATAD1 from its closely related proteins.

Alteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (m8A2503). Acquisition of cfr results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how m8A2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant that achieves near-stoichiometric methylation of rRNA, we determined a 2.2 Å cryo-electron microscopy structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr.

The advent of whole genome sequencing has revealed that common laboratory strains of human cytomegalovirus (HCMV) have major genetic deficiencies resulting from serial passage in fibroblasts. In particular, tropism for epithelial and endothelial cells is lost due to mutations disrupting genes UL128, UL130, or UL131A, which encode subunits of a virion-associated pentameric complex (PC) important for viral entry into these cells but not for entry into fibroblasts. The endothelial cell-adapted strain TB40/E has a relatively intact genome and has emerged as a laboratory strain that closely resembles wild-type virus. However, several heterogeneous TB40/E stocks and cloned variants exist that display a range of sequence and tropism properties. Here, we report the use of PacBio sequencing to elucidate the genetic changes that occurred, both at the consensus level and within subpopulations, upon passaging a TB40/E stock on ARPE-19 epithelial cells. The long-read data also facilitated examination of the linkage between mutations. Consistent with inefficient ARPE-19 cell entry, at least 83% of viral genomes present before adaptation contained changes impacting PC subunits. In contrast, and consistent with the importance of the PC for entry into endothelial and epithelial cells, genomes after adaptation lacked these or additional mutations impacting PC subunits. The sequence data also revealed six single noncoding substitutions in the inverted repeat regions, single nonsynonymous substitutions in genes UL26, UL69, US28, and UL122, and a frameshift truncating gene UL141. Among the changes affecting protein-coding regions, only the one in UL122 was strongly selected. This change, resulting in a D390H substitution in the encoded protein IE2, has been previously implicated in rendering another viral protein, UL84, essential for viral replication in fibroblasts. This finding suggests that IE2, and perhaps its interactions with UL84, have important functions unique to HCMV replication in epithelial cells.

Copyright of Cuadernos del Centro de Estudios de Diseño y Comunicación is the property of Cuadernos del Centro de Estudios de Diseno y Comunicacion and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cerebral palsy (CP) is a group of neuromotor diseases that develops as a result of damage to the developing central nervous system during the perinatal period. The condition is usually accompanied by musculoskeletal problems resulting in movement disorders. Gait improvement therefore, is an important part of its treatment. Roboticassisted gait training (RAGT) is a new potential rehabilitation tool for CP patients, however there is no clear evidence for the effectiveness of this method. Can robotic-assisted gait training improve walking function in children with CP? A systematic search was performed in five databases: MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Scopus, and Web of Science. Eligible studies were randomized controlled trials (RCT) with CP patients under the age of 18. Gross motor function and kinematic gait parameters of patients were the main outcomes. Two authors determined the risk of bias of the RCTs independently using the revised Risk of Bias 2 (ROB 2) tool. Mean Differences (MDs) along with their 95% Confidence Interval (CI) were calculated when at least three studies were present for an outcome, subgroup analysis was performed based on the treatment of the control group. Of the 7363 screened articles, 13 papers met our inclusion criteria and among them, 7 studies could be used in our meta-analyses. The results related to RAGT suggest nonsignificant improvement in standing and walking function (Gross Motor Function Measure D, E), moreover changes in gait speed, step length, and in cadence were also only comparable to controls. The results indicate that there is a trend in some gait parameters where the improvement was higher in the intervention group than in control group. The therapeutic effect of RAGT was probably not superior to physiotherapy combined with treadmill training. • Robotic-assisted gait training is a promising new treatment in cerebral palsy. • Effects and significance are not proven yet. • This review found a tendency for gait improvement after robotic training. • Straightforward evidence for effectiveness is still missing. [ABSTRACT FROM AUTHOR]

The research aimed to know the effect of an Designing E-brochures with augmented reality technology to developing awareness of the Egyptian tourist and heritage places and some of their aesthetic values among fourth grade primary pupils in the light of the new curriculum 2.0, The researcher followed the experimental method of designing the two groups (experimental-control), and the research sample consisted of (60) pupils from the fourth grade primary pupils, and the research tools and materials included: a list of the dimensions of awareness of Egyptian tourist and heritage places, a list of aesthetic values, a list of criteria for designing E-brochures with augmented reality technology, experimental unit (objectives-enhanced Ebrochures-activities-student guide-The teacher's guide), achievement test of awareness of Egyptian tourist and heritage places, the scale of awareness behaviors of Egyptian tourist and heritage places, the aesthetic values test, and the research results indicated: The existence of a statistically significant effect among the average scores of the experimental group members in the tribal and dimensional application of research tools in favor of the dimensional application, which indicates the effectiveness of Ebrochures with augmented reality technology in developing awareness of Egyptian tourist and heritage places and some aesthetic values associated with them. The research recommended the need to encourage and train social studies teachers to use, design and produce educational E-brochures enhanced by Visual Media and use in teaching and teaching social studies, attention to the development of awareness of Egyptian tourist and heritage places and aesthetic values in the subject of social studies for students at all educational stages. [ABSTRACT FROM AUTHOR]

We report an outbreak of confirmed Mycoplasma pneumoniae community-acquired pneumonia (CAP) in Nord Franche-Comté Hospital, France, from 14 November 2023 to 31 January 2024. All 13 inpatients (11 adults with a mean age of 45.5 years and 2 children) were diagnosed with positive serology and/or positive reverse transcription polymerase chain reaction (RT-PCR) on respiratory specimens. All patients were immunocompetent and required oxygen support with a mean duration of oxygen support of 6.2 days. Two patients were transferred to the intensive care unit (ICU) but were not mechanically ventilated. Patients were treated with macrolides (n = 12, 92.3%) with recovery in all cases. No significant epidemiological link was reported in these patients. [ABSTRACT FROM AUTHOR]

The primary objective of this paper is to examine the impact of innovation and economic globalization on economic growth and the transition from the middle-income trap. The study analyses the impact of innovation and economic globalization on economic growth using the Bayesian model averaging (BMA) and the generalized method of moments (GMM). For the first time, this paper employs Cox regressions to estimate the transition speed from the middle-income trap. With the help of the extended Cox regression analysis, the study shows that mean years of education, life-insurance and non-life insurance premiums significantly increased the transition speed to high-income and thus reduced the transition duration. The important innovation variables like labour productivity, internet usage and scientific journal articles count also increased the transition speed and reduced the transition duration. The time-dependent covariates of trade openness, foreign direct investment, high-technology exports, health spending, urbanization, and life insurance premiums also increased the transition speed and thus reduced the transition duration. The research indicates that breaking free from the middle-income trap may not require a surge in patent numbers. The present paper provides some directions to achieve better economic growth and escape the middle-income trap. [ABSTRACT FROM AUTHOR]

Introduction: In 2018, gastric cancer (GC) was estimated to account for over 1.03 million new cases globally, making it one of the most frequently diagnosed malignancies. In Spain, about 6,913 new cases were diagnosed in 2022. GC is an aggressive cancer originating in the stomach and ranks fifth in cancer incidence and third in cancer-related deaths worldwide. Despite treatment, only 25% of patients survive more than 5 years after diagnosis. Methods: To estimate the economic impact of premature mortality due to GC, the human capital method was employed. This approach involved collecting data on mortality rates, average salaries, and unemployment rates. The study spanned a 10-year period, from 2013 to 2022, to integrate the latest and most pertinent data for analysis. The goal was to quantify the economic consequences GC-related deaths, providing valuable information for policy makers and healthcare professionals. Results: GC caused 51,814 deaths over the study period with a slight annual decline, predominantly affecting men. Approximately 23% of deaths occurred among people of working age, amounting to a total of 122,632 YPLL. In economic terms, GC deaths accounted for costs of €1,239.34 million in 2013, rising to €1,242.04 million by 2021, for a total of €11,469.07 million over the study period. Conclusions: The incidence of gastrointestinal cancers has decline in some types, but they remain a substantial public health challenge. These findings underline the significant health and economic challenges posed by GC, highlighting the need for targeted interventions to mitigate its impact on both individuals and healthcare systems. [ABSTRACT FROM AUTHOR]

Aims: Economic studies have found that public support of basic medical research provides important long-term benefits. In response to suggestions that private pharmaceutical research and development (R&D) funding could be totally replaced by public funding, we investigate the economic implications of such a substitution in funding roles that maintain the recent pace of pharmaceutical innovation. Materials and methods: Total lifecycle R&D costs were estimated using the latest available R&D expenditures per novel molecule entering clinical trials, likelihood of approval, pre-clinical and post-approval expenditures, using a published survey and a review of publicly available financial accounts from US-listed multinational developers. This estimate was then stratified by the average number of annual FDA approvals to estimate total costs of R&D funding born by the private sector. Results: We find total lifecycle R&D costs were US$2.83 billion per approved medicine. Estimated uncapitalized costs to replace private R&D funding for one year of FDA approvals were $139.6 billion. These additional costs are equivalent to 302% of the entire National Institute for Health 2022 budget of $46.2 billion, and around 25 times NIH's estimated annual $5.6 billion currently dedicated to clinical research trials for pharmaceuticals. Further assessing the policy proposition through a literature review, we found little evidence for improvements in economic efficiency via public funding substitution, while there may be additional challenges including asymmetric information, adverse selection, yardstick competition, hold-up, under-rewarding of incremental innovation and political rent-seeking. Limitations: Our calculations may undervalue full replacement costs, by excluding non-R&D expenses for manufacturing, distribution, or financing. Conclusions: The bulk of investment in R&D is underwritten by the private sector. Political discourse portraying the NIH as the central force in bringing a new drug to market may underappreciate the pivotal role of private at-risk capital. Replacing such investment while maintaining the current innovation output in terms of approved therapies would necessitate substantial increases in taxpayer financing. [ABSTRACT FROM AUTHOR]

Introduction: Our model was conducted from Kuwaiti payer's perspective to provide evidence on the cost-effectiveness of Sodium zirconium cyclosilicate (SZC) versus patiromer to correct and maintain serum potassium (K+) in combination with renin‐angiotensin‐aldosterone system inhibitors (RAASis) with different dose titration in patients with chronic kidney disease/heart failure (CKD/HF) with/without renal replacement therapy (RRT). Methodology: The model was developed as a patient-level, fixed-time increment stochastic simulation to simulate the complexity of disease, including multiple coexisting and competing conditional risks. This model was established to compare SZC versus patiromer as a treatment for hyperkalemia (HK) among adult populations with underlying conditions of advanced CKD stages 3a–5 or HF to correct and maintain serum K + over a lifetime horizon. The clinical outcomes of SZC and patiromer were demonstrated through arm-specific K + trajectories extracted from the HARMONIZE trial and OPAL-HK trial, respectively. The utility data was captured from different studies. Direct medical cost was captured from local data from Kuwaiti hospitals. Sensitivity analyses were conducted to assess the uncertainty in the model. Results: Within different scenarios of CKD/HF, SZC was a cost-saving option, with/without RRT, whether one-off administration or repeated administration, except for one-off treatment administration among the HF cohort, which generated an incremental cost effectiveness ratio of KWD 331/quality adjusted life year (QALY). The incremental QALY of SZC ranged from 0.007 to 0.202. In addition, the savings observed with SZC fall within a range of KWD −60 to KWD −1,235 at serum K+ ≥ 5.1 mmol/L. Conclusion: The evidence generated by our model recommends the inclusion of SZC as a treatment option to correct HK and maintain normal serum K + level for CKD/HF patients within the Kuwaiti healthcare system. The costs saved from reducing frequent HK episodes, RAASis discontinuation/down titration, major cardiovascular events, and hospitalization offset the drug acquisition cost of SZC. [ABSTRACT FROM AUTHOR]

The objectives of this study were to characterize overall genomic antibiotic resistance profiles of fecal Escherichia coli and Enterococcus spp. from dairy cattle at different production stages using whole-genome sequencing and to determine the association between antimicrobial resistance (AMR) phenotypes and their corresponding genotypes. The Comprehensive Antibiotic Resistance Database (CARD) and ResFinder, two publicly available databases of antimicrobial resistance genes, were used to annotate isolates. Based on the ResFinder database, 27.5% and 20.0% of tested E. coli isolates (n = 40) harbored single and ≥3 antimicrobial resistance genes, respectively; for Enterococcus spp., we observed 87.8% and 8.2%, respectively. The highest prevalence of AMR genes in E. coli was for resistance to tetracycline (27.5%), followed by sulphonamide (22.5%) and aminoglycoside (20.0%); the predominant antimicrobial resistance genes in Enterococcus spp. targeted macrolide drugs (77.6%). Based on the CARD database, resistance to ≥3 antimicrobial classes was observed in all E. coli and 77.6% in Enterococcus spp. isolates. A high degree of agreement existed between the resistance phenotype and the presence of resistance genes for various antimicrobial classes for E. coli but much less so for isolates of Enterococcus. Consistent with prior work, fecal E. coli and Enterococcus spp. isolates from calves harbored a wide spectrum of resistance genes, compared to those from cattle at other production stages, based on the cross-sectional samples from the studied farm.

There is substantial evidence that both N-methyl-D-aspartate receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. Although models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR coagonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.NEW & NOTEWORTHY Recently, disruption of excitation/inhibition (E/I) balance has become an area of considerable interest for psychiatric research. Here, we report a reduction in inhibition in the serine racemase knockout mouse model of schizophrenia that increases E/I balance and enhances synaptically driven neuronal excitability. This reduced inhibition was driven cell-autonomously in pyramidal cells lacking serine racemase, suggesting a novel mechanism for how chronic NMDA receptor hypofunction can disrupt information processing in schizophrenia.

Bone biomineralization is a complex process in which type I collagen and associated non-collagenous proteins (NCPs), including glycoproteins and proteoglycans, interact closely with inorganic calcium and phosphate ions to control the precipitation of nanosized, non-stoichiometric hydroxyapatite (HAP, idealized stoichiometry Ca10(PO4)6(OH)2) within the organic matrix of a tissue. The ability of certain vertebrate tissues to mineralize is critically related to several aspects of their function. The goal of this study was to identify specific NCPs in mineralizing and non-mineralizing tissues of two animal models, rat and turkey, and to determine whether some NCPs are unique to each type of tissue. The tissues investigated were rat femur (mineralizing) and tail tendon (non-mineralizing) and turkey leg tendon (having both mineralizing and non-mineralizing regions in the same individual specimen). An experimental approach ex vivo was designed for this investigation by combining sequential protein extraction with comprehensive protein mapping using proteomics and Western blotting. The extraction method enabled separation of various NCPs based on their association with either the extracellular organic collagenous matrix phases or the inorganic mineral phases of the tissues. The proteomics work generated a complete picture of NCPs in different tissues and animal species. Subsequently, Western blotting provided validation for some of the proteomics findings. The survey then yielded generalized results relevant to various protein families, rather than only individual NCPs. This study focused primarily on the NCPs belonging to the small leucine-rich proteoglycan (SLRP) family and the small integrin-binding ligand N-linked glycoproteins (SIBLINGs). SLRPs were found to be associated only with the collagenous matrix, a result suggesting that they are mainly involved in structural matrix organization and not in mineralization. SIBLINGs as well as matrix Gla (γ-carboxyglutamate) protein were strictly localized within the inorganic mineral phase of mineralizing tissues, a finding suggesting that their roles are limited to mineralization. The results from this study indicated that osteocalcin was closely involved in mineralization but did not preclude possible additional roles as a hormone. This report provides for the first time a spatial survey and comparison of NCPs from mineralizing and non-mineralizing tissues ex vivo and defines the proteome of turkey leg tendons as a model for vertebrate mineralization.

Biocide use is essential and ubiquitous, exposing microbes to sub-inhibitory concentrations of antiseptics, disinfectants, and preservatives. This can lead to the emergence of biocide resistance, and more importantly, potential cross-resistance to antibiotics, although the degree, frequency, and mechanisms that give rise to this phenomenon are still unclear. Here, we systematically performed adaptive laboratory evolution of the gut bacteria Escherichia coli in the presence of sub-inhibitory, constant concentrations of ten widespread biocides. Our results show that 17 out of 40 evolved strains (43%) also decreased the susceptibility to medically relevant antibiotics. Through whole-genome sequencing, we identified mutations related to multidrug efflux proteins (mdfA and acrR), porins (envZ and ompR), and RNA polymerase (rpoA and rpoBC), as mechanisms behind the resulting (cross)resistance. We also report an association of several genes (yeaW, pyrE, yqhC, aes, pgpA, and yeeP-isrC) and specific mutations that induce cross-resistance, verified through mutation repairs. A greater capacity for biofilm formation with respect to the parent strain was also a common feature in 11 out of 17 (65%) cross-resistant strains. Evolution in the biocides chlorophene, benzalkonium chloride, glutaraldehyde, and chlorhexidine had the most impact in antibiotic susceptibility, while hydrogen peroxide and povidone-iodine the least. No cross-resistance to antibiotics was observed for isopropanol, ethanol, sodium hypochlorite, and peracetic acid. This work reinforces the link between exposure to biocides and the potential for cross-resistance to antibiotics, presents evidence on the underlying mechanisms of action, and provides a prioritized list of biocides that are of greater concern for public safety from the perspective of antibiotic resistance.Significance statementBacterial resistance and decreased susceptibility to antimicrobials is of utmost concern. There is evidence that improper biocide (antiseptic and disinfectant) use and discard may select for bacteria cross-resistant to antibiotics. Understanding the cross-resistance emergence and the risks associated with each of those chemicals is relevant for proper applications and recommendations. Our work establishes that not all biocides are equal when it comes to their risk of inducing antibiotic resistance; it provides evidence on the mechanisms of cross-resistance and a risk assessment of the biocides concerning antibiotic resistance under residual sub-inhibitory concentrations.

High mobility group box-1 (HMGB1) and the toll-like receptor 4 (TLR4) axis is a key mediator of inflammation. Platelet-derived high mobility group box-1 (HMGB1) may also play a critical role in sepsis-mediated thrombosis resulting in complications like disseminated intravascular coagulation and multiple organ failure. While elevated levels of HMGB1 have been documented in humans and dogs with systemic inflammatory response syndrome and sepsis, a better understanding of how platelet agonists and lipopolysaccharide (LPS) mediate platelet HMGB1 expression would open doors to novel therapies for sepsis-mediated thrombosis. Herein, we sought to determine if canine platelets express HMGB1 in the presence or absence of LPS and agonists (ADP or thrombin) and if surface expression of HMGB1 is dependent on platelet TLR4. Canine platelets were unstimulated (resting) or activated with thrombin or adenosine diphosphate (ADP) in the presence or absence of Escherichia coli LPS prior to flow cytometric and western blot analyses for HMGB1 expression. We also treated canine platelets with or without TLR4 function blocking antibody or its isotype control. We discovered that while thrombin upregulated both surface and cellular HMGB1 expression, LPS-mediated activation in the presence of ADP priming led to upregulation of surface HMGB1 expression. This expression was found to be most prominent in platelets that had undergone alpha-granule secretion. Inhibition of TLR4 attenuated LPS-induced HMGB1 expression indicating that exteriorization of HMGB1 may be dependent on the non-genomic pathway of platelet TLR4. Our findings indicate that upregulation of platelet-derived HMGB1 occurs as a result of thrombin or TLR4-mediated activation in dogs. Future studies should explore the translational implication of platelet-derived HMGB1 as novel therapeutic targets in humans and dogs with sepsis.

Biocide use is essential and ubiquitous, exposing microbes to sub-inhibitory concentrations of antiseptics, disinfectants, and preservatives. This can lead to the emergence of biocide resistance, and more importantly, potential cross-resistance to antibiotics, although the degree, frequency, and mechanisms that give rise to this phenomenon are still unclear. Here, we systematically performed adaptive laboratory evolution of the gut bacteria Escherichia coli in the presence of sub-inhibitory, constant concentrations of ten widespread biocides. Our results show that 17 out of 40 evolved strains (43%) also decreased the susceptibility to medically relevant antibiotics. Through whole-genome sequencing, we identified mutations related to multidrug efflux proteins (mdfA and acrR), porins (envZ and ompR), and RNA polymerase (rpoA and rpoBC), as mechanisms behind the resulting (cross)resistance. We also report an association of several genes (yeaW, pyrE, yqhC, aes, pgpA, and yeeP-isrC) and specific mutations that induce cross-resistance, verified through mutation repairs. A greater capacity for biofilm formation with respect to the parent strain was also a common feature in 11 out of 17 (65%) cross-resistant strains. Evolution in the biocides chlorophene, benzalkonium chloride, glutaraldehyde, and chlorhexidine had the most impact in antibiotic susceptibility, while hydrogen peroxide and povidone-iodine the least. No cross-resistance to antibiotics was observed for isopropanol, ethanol, sodium hypochlorite, and peracetic acid. This work reinforces the link between exposure to biocides and the potential for cross-resistance to antibiotics, presents evidence on the underlying mechanisms of action, and provides a prioritized list of biocides that are of greater concern for public safety from the perspective of antibiotic resistance.Significance statementBacterial resistance and decreased susceptibility to antimicrobials is of utmost concern. There is evidence that improper biocide (antiseptic and disinfectant) use and discard may select for bacteria cross-resistant to antibiotics. Understanding the cross-resistance emergence and the risks associated with each of those chemicals is relevant for proper applications and recommendations. Our work establishes that not all biocides are equal when it comes to their risk of inducing antibiotic resistance; it provides evidence on the mechanisms of cross-resistance and a risk assessment of the biocides concerning antibiotic resistance under residual sub-inhibitory concentrations.

The future Nobel laureates Robert Lucas and James Tobin debated the New Classical challenge to the microeconomic foundations and empirical validity of Keynesian economics, with Lucas singling Tobin out as an interlocutor among Keynesian economists who took the New Classical challenge seriously. Their intellectual exchanges began with Tobin, 'The Wage-Price Mechanism: Overview of the Conference' (1972), and Lucas, 'Econometric Testing of the Natural Rate Hypothesis' (1972), both in Otto Eckstein, ed., The Econometrics of Price Determination Conference (1972). That conference was a milestone in confronting alternative macroeconomic methodologies with each other, but has received relatively little attention in the literature, most notably from Stanley Fischer (in JMCB Supplement, 2007), who characterized 'that volume as representative of the best thinking of the time on the Phillips curve.' This paper examines the debate between Lucas and Tobin that began with their contributions to that conference and that reached a climax with Tobin's Yrjö Jahnsson Lectures (Asset Accumulation and Economic Activity, 1980) and Lucas's Journal of Economic Literature review article on those lectures. [ABSTRACT FROM AUTHOR]

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In the second half of the 1990's Christian Mauduit and András Sárközy introduced a new quantitative theory of pseudorandomness of binary sequences. Since then numerous papers have been written on this subject and the original theory was generalized in several directions. In this paper, I summarize some of the most notable results in the field. I compare four different constructions in the computational point of view. The first construction is the classic Legendre symbol construction, and the other three are construction based on digits of famous constants such as e, π, and v √2. I used SAGE, PYTHON, and MATLAB as programming languages. I run multiple tests and calculated the exact values of the pseudorandom measures for each construction in many cases and the runtime are also presented. [ABSTRACT FROM AUTHOR]

Public debt can be reduced in three ways: (1) repayment; (2) default; and (3) indirect default through monetary financing accompanied by debasement or followed by currency reform. In the course of history, repayment was more the exception than the rule, default often the only available way when a government had no control over the currency in which it borrowed, and indirect default more the rule than the exception. In this paper we review the three ways of debt reduction with exemplary references to historical events. We conclude that financial repression supplemented with debt repayment is likely to be the preferred way for public debt reduction today. The alternative would be currency reform. [ABSTRACT FROM AUTHOR]