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Background: The study assesses the decisional regret following Shared Decision-making (SDM) in patients selecting either early ureteroscopic lithotripsy (URSL) or medical expulsive therapy (MET) for ureteric stones ≤ 1 cm, with the aim to evaluate their decisional Conflict, satisfaction, and regret regarding their opted treatment choices., Methods: Adults aged more than 18 years with one stone up to 1 cm in either ureter were included. After SDM, the patients were allocated into their opted group viz. URSL or MET. Patients in each group were reassessed at "treatment completion". Cambridge Ureteric Stone PROM (CUSP) questionnaire for HRQoL, Decision Regret Scale and the OPTION scale (SDM) were filled at treatment completion., Findings: 111 patients opted for MET, while 396 patients opted for early URSL. Mean stone size was larger in URSL group (7.16 ± 1.63 mm vs. 5.50 ± 1.89; p < 0.001). Decisional conflict was higher in patients opting for URSL (77.3% vs. 57.7%; p < 0.001). Stone-free rate at four weeks was higher in URSL group (87.1%vs68.5%, p < 0.001). Decisional regret was higher in patients opting for MET (33.24 ± 30.89 vs. 17.26 ± 12.92; p = 0.002). Anxiety, was higher in patients opting for MET (6.94 ± 1.89 vs. 5.85 ± 1.54; p < 0.001). Urinary symptoms and interference in patients' travel plans and work-related activities were more in URSL group (6.21 ± 1.57 vs. 5.59 ± 1.46; p < 0.001 and 6.56 ± 1.59 vs. 6.05 ± 1.72; p < 0.001 respectively)., Interpretation: After SDM, decisional regret is higher in patients opting for MET mainly due protracted treatment duration with increased pain and anxiety during the treatment course and the need for additional procedure for attaining stone clearance and the. Despite higher decisional conflict, a larger proportion of patients opt for early URSL with the aim of avoiding anxiety and achieving early stone clearance., (© 2024. The Author(s).)

In this article, we detail a comprehensive laboratory evaluation of an immunoassay for the rapid detection of ricin using the Meso Scale Diagnostics Sector PR2 Model 1800. For the assay evaluation, we used inclusivity, exclusivity, and informational panels comprised of extracts of 35 near-neighbor plant cultivar-extracts, 66 lectins, 26 white powders, 16 closely related toxins and proteins/toxoids, and a pool of 30 BioWatch filter extracts. The results show that the Meso Scale Diagnostics ricin detection assay exhibits good sensitivity and specificity with a limit of detection of 1.2 ng/mL. However, the dynamic range of the assay for the quantitation of ricin was limited. We observed a hook effect at higher ricin concentrations, which can lead to potential false negative results. A modification of the assay protocol that incorporates extra wash steps can decrease the hook effect and the potential for false negative results.

The maternal-fetal interaction has been hypothesized to involve the human leucocyte antigen (HLA). It has been suggested that excessive HLA antigen sharing between spouses is a mechanism causing maternal hyporesponsiveness to paternal antigens encountered during pregnancy and thus leading to a miscarriage. Participants in this retrospective study are RIF and RPL couples who visited Gunasheela Surgical and Maternity Hospital, Bangalore, India from November 2019 to September 2022. A total of 40 couples with RIF and 195 couples with RPL are included in the study. We observed that the DQB1*02:01:01 allele is associated with an increase in risk of both RIF and RPL, while the C*12:02:01 allele increases risk of only RPL. On the contrary, DQB1*02:02:01 and DQB1*06:03 alleles appear to be protective against both RPL and RIF. In addition, the C*07:02:01 allele was observed to be protective against RPL. In conclusion, C*12:02:01 and DQB1*02:01:01 could play a major role in RPL which is consistent with other studies, while DQB1*02:01:01 is the risk allele in our RIF group. The protective alleles C*07:02:01 in the RPL group, DQB1*02:02:01, and DQB1*06:03 in both RIF and RPL, were discovered for the first time. Allele frequencies will vary in population-based studies depending on the ethnicities of the cohort. Meta-analysis and antibody testing will provide additional insights on whether and how this data can be adopted into clinical practices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The work investigates the implementation of personalized radiotherapy boluses by means of additive manufacturing technologies. Boluses materials that are currently used need an excessive amount of human intervention which leads to reduced repeatability in terms of dosimetry. Additive manufacturing can solve this problem by eliminating the human factor in the process of fabrication. Planar boluses with fixed geometry and personalized boluses printed starting from a computed tomography scan of a radiotherapy phantom were produced. First, a dosimetric characterization study on planar bolus designs to quantify the effects of print parameters such as infill density and geometry on the radiation beam was made. Secondly, a volumetric quantification of air gap between the bolus and the skin of the patient as well as dosimetric analyses were performed. The optimization process according to the obtained dosimetric and airgap results allowed us to find a combination of parameters to have the 3D-printed bolus performing similarly to that in conventional use. These preliminary results confirm those in the relevant literature, with 3D-printed boluses showing a dosimetric performance similar to conventional boluses with the additional advantage of being perfectly conformed to the patient geometry., (© 2024. The Author(s).)

The role of Real-Time PCR assays for surveillance and rapid screening for pathogens is garnering more and more attention because of its versatility and ease of adoption. The goal of this study was to design, test, and evaluate Real-Time TaqMan PCR assays for the detection of botulinum neurotoxin ( bont /A-G) genes from currently recognized BoNT subtypes. Assays were computationally designed and then laboratory tested for sensitivity and specificity using DNA preparations containing bont genes from 82 target toxin subtypes, including nine bivalent toxin types; 31 strains representing other clostridial species; and an extensive panel that consisted of DNA from a diverse set of prokaryotic (bacterial) and eukaryotic (fungal, protozoan, plant, and animal) species. In addition to laboratory testing, the assays were computationally evaluated using in silico analysis for their ability to detect bont gene sequences from recently identified toxin subtypes. Seventeen specific assays (two for each of the bont /C, bont /D, bont /E, and bont /G subtypes and three for each of the bont /A, bont /B, and bont /F subtypes) were designed and evaluated for their ability to detect bont genes encoding multiple subtypes from all seven serotypes. These assays could provide an additional tool for the detection of botulinum neurotoxins in clinical, environmental and food samples that can complement other existing methods used in clinical diagnostics, regulatory, public health, and research laboratories., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pillai, Hill, Gans and Smith.)

Purpose: To assess the safety and efficacy of super-mini PCNL (SMP, 14 Fr) when compared to standard PCNL (sPCNL, 24-30 Fr) in the management of renal calculi of size ranging from 1.5 to 3 cm., Methods: From February 2021 to January 2022, a total of 100 patients were randomized to either SMP group or sPCNL group in a 1:1 ratio (50 in each group) using computer-generated simple randomization. Demographic data, stone characteristics, operative times, perioperative complications, blood transfusions, postoperative drop in haemoglobin, postoperative pain, duration of hospital stay and stone-free rates were compared between the two groups., Results: Mean stone volume (2.41 cm 2 vs 2.61 cm 2 ) and stone-free rates (98% vs 94%, p = 0.14) were similar in both the SMP and sPCNL groups, respectively. The SMP group had significantly longer mean operative times (51.62 ± 10.17 min vs 35.6 ± 6.8 min, p = 0.03). Intraoperative calyceal injury (1/50 vs 7/50, p = 0.42) and mean postoperative drop in haemoglobin (0.8 ± 0.7 g/dl vs 1.2 ± 0.81, p = 0.21) were lower in the SMP group, but not statistically significant. SMP group showed significantly lower mean postoperative pain VAS scores (5.4 ± 0.7 vs 5.9 ± 0.9, p = 0.03) and mean duration of hospital stay (28.38 ± 3.6 h vs 39.84 ± 3.7 h, p = 0.0001). Complications up to Clavien grade 2 were comparable, with grade ≥ 3 complications higher in the standard group, but not statistically significant., Conclusion: Super-mini PCNL is equally effective as standard PCNL in treating renal calculi up to 3 cm, with significantly reduced postoperative pain and duration of hospital stay and lower risk of Clavien grade ≥ 3 complications, although with higher operative times., (© 2024. The Author(s).)

The continued emergence and spread of antimicrobial resistance among pathogenic bacteria are ever-growing threats to health and economy. Here, we report the draft genomes for 45 Enterobacterales clinical isolates, including historical and contemporary drug-resistant organisms, obtained in Pakistan between 1998 and 2016: 5 Serratia , 3 Salmonella , 3 Enterobacter , and 34 Klebsiella ., Competing Interests: The authors declare no conflict of interest.

The United States Department of Agriculture (USDA) Division of Agricultural Select Agents and Toxins (DASAT) established a list of biological agents (Select Agents List) that threaten crops of economic importance to the United States and regulates the procedures governing containment, incident response, and the security of entities working with them. Every 2 years the USDA DASAT reviews their select agent list, utilizing assessments by subject matter experts (SMEs) to rank the agents. We explored the applicability of multi-criteria decision analysis (MCDA) techniques and a decision support framework (DSF) to support the USDA DASAT biennial review process. The evaluation includes both current and non-select agents to provide a robust assessment. We initially conducted a literature review of 16 pathogens against 9 criteria for assessing plant health and bioterrorism risk and documented the findings to support this analysis. Technical review of published data and associated scoring recommendations by pathogen-specific SMEs was found to be critical for ensuring accuracy. Scoring criteria were adopted to ensure consistency. The MCDA supported the expectation that select agents would rank high on the relative risk scale when considering the agricultural consequences of a bioterrorism attack; however, application of analytical thresholds as a basis for designating select agents led to some exceptions to current designations. A second analytical approach used agent-specific data to designate key criteria in a DSF logic tree format to identify pathogens of low concern that can be ruled out for further consideration as select agents. Both the MCDA and DSF approaches arrived at similar conclusions, suggesting the value of employing the two analytical approaches to add robustness for decision making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pillai, Fruetel, West, Anderson, Hernandez, Ball, McNeil, Beck and Morse.)

Objectives: The study aim was to investigate multidrug-resistant (MDR) plasmids from a collection of 10 carbapenemase-producing Klebsiella pneumoniae clinical isolates identified within the same healthcare institution in Pakistan. Full characterization of the MDR plasmids including structure, typing characteristics, and AMR content as well as determination of their plasmid-based antimicrobial susceptibility profiles were carried out., Methods: Plasmids were isolated from 10 clinical isolates of Klebsiella pneumoniae , and from a corresponding set of Escherichia coli transconjugants, then sequenced using Nanopore/Illumina technology to generate plasmid hybrid assemblies. Full characterization of MDR plasmids, including determination of next generation sequencing (NGS)-based AMR profiles, plasmid incompatibility groups, and types, was carried out. The structure of MDR plasmids was analyzed using the Galileo AMR platform. For E. coli transconjugants, the NGS-based AMR profiles were compared to NGS-predicted AMR phenotypes and conventional broth microdilution (BMD) antimicrobial susceptibility testing (AST) results., Results: All carbapenemase-producing K. pneumoniae isolates (carrying either bla NDM-1 , or/and bla OXA-48 ) carried multiple AMR plasmids encoding 34 antimicrobial resistance genes (ARGs) conferring resistance to antimicrobials from 6 different classes. The plasmid incompatibility groups and types identified were: IncC (types 1 and 3), IncFIA (type 26) IncFIB, IncFII (types K1, K2, K7, and K9), IncHI1B, and IncL. None of the bla NDM-1 and bla ESBL -plasmids identified in this study were previously described. Most bla NDM-1- plasmids shared identical AMR regions suggesting potential genetic material/plasmid exchange between K. pneumoniae isolates of this collection. The majority of NGS-based AMR profiles from the E. coli transconjugants correlated well with both NGS-based predicted and conventional AST results., Conclusion: This study highlights the complexity and diversity of the plasmid-based genetic background of carbapenemase-producing clinical isolates from Pakistan. This study emphasizes the need for characterization of MDR plasmids to determine their complete molecular background and monitor AMR through plasmid transmission between multi-resistant bacterial pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lascols, Cherney, Conley, Rishishwar, Crawford, Morse, Fisher, Anderson, Hodge, Pillai, Hughes, Khan and Sue.)

The United States Department of Agriculture (USDA), Division of Agricultural Select Agents and Toxins (DASAT) established a list of biological agents and toxins (Select Agent List) that potentially threaten agricultural health and safety, the procedures governing the transfer of those agents, and training requirements for entities working with them. Every 2 years the USDA DASAT reviews the Select Agent List, using subject matter experts (SMEs) to perform an assessment and rank the agents. To assist the USDA DASAT biennial review process, we explored the applicability of multi-criteria decision analysis (MCDA) techniques and a Decision Support Framework (DSF) in a logic tree format to identify pathogens for consideration as select agents, applying the approach broadly to include non-select agents to evaluate its robustness and generality. We conducted a literature review of 41 pathogens against 21 criteria for assessing agricultural threat, economic impact, and bioterrorism risk and documented the findings to support this assessment. The most prominent data gaps were those for aerosol stability and animal infectious dose by inhalation and ingestion routes. Technical review of published data and associated scoring recommendations by pathogen-specific SMEs was found to be critical for accuracy, particularly for pathogens with very few known cases, or where proxy data (e.g., from animal models or similar organisms) were used to address data gaps. The MCDA analysis supported the intuitive sense that select agents should rank high on the relative risk scale when considering agricultural health consequences of a bioterrorism attack. However, comparing select agents with non-select agents indicated that there was not a clean break in scores to suggest thresholds for designating select agents, requiring subject matter expertise collectively to establish which analytical results were in good agreement to support the intended purpose in designating select agents. The DSF utilized a logic tree approach to identify pathogens that are of sufficiently low concern that they can be ruled out from consideration as a select agent. In contrast to the MCDA approach, the DSF rules out a pathogen if it fails to meet even one criteria threshold. Both the MCDA and DSF approaches arrived at similar conclusions, suggesting the value of employing the two analytical approaches to add robustness for decision making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pillai, West, Anderson, Fruetel, McNeil, Hernandez, Ball, Beck and Morse.)

The landscape of aortic valve replacement (AVR) has evolved dramatically over the years, but time-varying outcomes have yet to be comprehensively explored. This study aimed to compare the all-cause mortality among 3 AVR techniques: transcatheter (TAVI), minimally invasive (MIAVR), and conventional AVR (CAVR). An electronic literature search was performed for randomized controlled trials (RCTs) comparing TAVI with CAVR and RCTs or propensity score-matched (PSM) studies comparing MIAVR with CAVR or MIAVR to TAVI. Individual patient data for all-cause mortality were derived from graphical reconstruction of Kaplan-Meier curves. Pairwise comparisons and network meta-analysis were conducted. Sensitivity analyses were performed in the TAVI arm for high risk and low/intermediate risk, as well as patients who underwent transfemoral (TF) TAVI. A total of 27 studies with 16,554 patients were included. In the pairwise comparisons, TAVI showed superior mortality to CAVR until 37.5 months, beyond which there was no significant difference. When restricted to TF TAVI versus CAVR, a consistent mortality benefit favoring TF TAVI was seen (shared frailty hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.76 to 0.98, p = 0.024). In the network meta-analysis involving majority PSM data, MIAVR demonstrated significantly lower mortality than TAVI (HR = 0.70, 95% CI = 0.59 to 0.82) and CAVR (HR = 0.69, 95% CI = 0.59 to 0.80); this association remained compared with TF TAVI but with a lower extent of benefit (HR = 0.80, 95% CI = 0.65 to 0.99). In conclusion, the initial short- to medium-term mortality benefit for TAVI over CAVR was attenuated over the longer term. In the subset of patients who underwent TF TAVI, a consistent benefit was found. Among majority PSM data, MIAVR showed improved mortality compared with TAVI and CAVR but less than the TF TAVI subset, which requires validation by robust RCTs., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inhalational anthrax is a fatal infectious disease. Rapid and effective treatment is critically dependent on early and accurate diagnosis. Blood culture followed by identification and confirmation may take days to provide clinically relevant information. In contrast, immunoassay for a shed antigen, the capsular polypeptide gamma-d-polyglutamate (γDPGA), can provide rapid results at the point of care. In this study, a lateral flow immunoassay for γDPGA was evaluated in a robust nonhuman primate model of inhalational anthrax. The results showed that the time to a positive result with the rapid test using either serum or blood as a clinical specimen was similar to the time after infection when a blood culture became positive. In vitro testing showed that the test was equally sensitive with cultures of the three major clades of Bacillus anthracis. Cultures from other Bacillus spp. that are known to produce γDPGA also produced positive results. The test was negative with human sera from 200 normal subjects and 45 subjects with culture-confirmed nonanthrax bacterial or fungal sepsis. Taken together, the results showed that immunoassay for γDPGA is an effective surrogate for blood culture in a relevant cynomolgus monkey model of inhalational anthrax. The test would be a valuable aid in early diagnosis of anthrax, which is critical for rapid intervention and a positive outcome. Use of the test could facilitate triage of patients with signs and symptoms of anthrax in a mass-exposure incident and in low-resource settings where laboratory resources are not readily available. IMPORTANCE Patient outcome in anthrax is critically dependent on early diagnosis followed by effective treatment. We describe a rapid lateral flow immunoassay that detects capsular antigen of Bacillus anthracis that is shed into blood during infection. The test was evaluated in a robust cynomolgus monkey model of inhalational anthrax. Rapid detection of capsular antigen is an effective surrogate for the time-consuming and laboratory-intensive diagnosis by blood culture, direct fluorescent antibody staining, or other molecular testing. The test can be performed at the point of patient contact, is rapid and inexpensive, and can be used by individuals with minimal training.

The Centers for Disease Control and Prevention (CDC) Select Agent Program establishes a list of biological agents and toxins that potentially threaten public health and safety, the procedures governing the possession, utilization, and transfer of those agents, and training requirements for entities working with them. Every 2 years the Program reviews the select agent list, utilizing subject matter expert (SME) assessments to rank the agents. In this study, we explore the applicability of multi-criteria decision analysis (MCDA) techniques and logic tree analysis to support the CDC Select Agent Program biennial review process, applying the approach broadly to include non-select agents to evaluate its generality. We conducted a literature search for over 70 pathogens against 15 criteria for assessing public health and bioterrorism risk and documented the findings for archiving. The most prominent data gaps were found for aerosol stability and human infectious dose by inhalation and ingestion routes. Technical review of published data and associated scoring recommendations by pathogen-specific SMEs was found to be critical for accuracy, particularly for pathogens with very few known cases, or where proxy data (e.g., from animal models or similar organisms) were used to address data gaps. Analysis of results obtained from a two-dimensional plot of weighted scores for difficulty of attack (i.e., exposure and production criteria) vs. consequences of an attack (i.e., consequence and mitigation criteria) provided greater fidelity for understanding agent placement compared to a 1-to-n ranking and was used to define a region in the upper right-hand quadrant for identifying pathogens for consideration as select agents. A sensitivity analysis varied the numerical weights attributed to various properties of the pathogens to identify potential quantitative (x and y) thresholds for classifying select agents. The results indicate while there is some clustering of agent scores to suggest thresholds, there are still pathogens that score close to any threshold, suggesting that thresholding "by eye" may not be sufficient. The sensitivity analysis indicates quantitative thresholds are plausible, and there is good agreement of the analytical results with select agent designations. A second analytical approach that applied the data using a logic tree format to rule out pathogens for consideration as select agents arrived at similar conclusions., Competing Interests: SM was a CDC employee when this study was conducted. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pillai, Fruetel, Anderson, Levinson, Hernandez, Heimer and Morse.)

We conducted a comprehensive, multiphase laboratory evaluation of InBios Active Melioidosis Detect (AMD) rapid test, a lateral flow immunoassay designed to detect capsular polysaccharides produced by Burkholderia mallei or Burkholderia pseudomallei , used in conjunction with the Omni Array Reader (OAR) for the rapid detection of B mallei or B pseudomallei in environmental (nonclinical) samples at 2 sites. The limit of detection, using reference strains B mallei strain ATCC 23344 and B pseudomallei strain ATCC 11668, was determined to be 10 3 to 10 4 CFU/mL. In different phases of the evaluation, inclusivity strains that included geographically diverse strains of B mallei (N = 13) and B pseudomallei (N = 22), geographically diverse phylogenetic near neighbor strains (N = 66), environmental background strains (N = 64), white powder samples (N = 26), and environmental filter extracts (N = 1 pooled sample from 10 filter extracts) were also tested. A total of 1,753 tests were performed, which included positive and negative controls. Visual and OAR results showed that the AMD test detected 92.3% of B mallei and 95.5% of B pseudomalle i strains. Of the 66 near-neighbor strains tested, cross-reactivity was observed with only B stabilis 2008724195 and B thailandensis 2003015869. Overall, the specificity and sensitivity were 98.8% and 98.7%, respectively. The results of this evaluation support the use of the AMD test as a rapid, qualitative assay for the presumptive detection of B mallei and B pseudomallei in suspicious environmental samples such as white powders and aerosol samples by first responders and laboratory personnel.

We conducted a comprehensive, multiphase laboratory evaluation of the InBios Active Melioidosis Detect (AMD) rapid test, a lateral flow immunoassay designed to detect capsular polysaccharides produced by Burkholderia mallei or Burkholderia pseudomallei , used in conjunction with the Omni Array Reader for the rapid identification of culture isolates of B mallei or B pseudomallei to support clinical diagnosis for response and triage during a mass casualty event, such as a biological attack. The study was conducted at 2 sites to assess the performance of the AMD test. The sensitivity, specificity, and reproducibility of the assay was determined using 5 replicates of 35 inclusivity strains and 64 clinical background strains. A total of 520 tests were performed, which included both positive and negative controls. Results obtained visually and with the Omni Array Reader showed a sensitivity of 92.3% for B mallei and 95.6% for B pseudomallei ; no cross-reactivity was observed with any of the 64 clinical background organisms. The results from this study indicate that the AMD test for the presumptive identification of B mallei and B pseudomallei isolates to support clinical diagnosis is highly robust, specific, and sensitive. This evaluation supports the use of this test as a rapid, qualitative assay for the presumptive identification of B mallei and B pseudomallei in a clinical setting.

Introduction: Emphysematous pyelonephritis (EPN), an acute necrotizing infection of the kidney and surrounding tissues, is associated with considerable mortality. We evaluated how existing critical care scoring systems could predict the need for intensive care unit (ICU) management for these patients. We also analyzed if CT-imaging further enhances these predictive systems., Patients and Methods: A retrospective analysis of 90 consecutive patients diagnosed clinico-radiologically with EPN from January 2011 to September 2020. Five scoring systems were evaluated for their predictive ability for the need for ICU management and mortality risk: National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), 'quick' Sequential Organ Failure Assessment score (qSOFA), Systemic Inflammatory Response Syndrome score (SIRS), and Sequential Organ Failure Assessment score (SOFA). CT images were classified as per Huang & Tseng and evaluated as stand-alone or added to the different predictive models. Receiver operating characteristic (ROC) curves were plotted for each critical care score and CT-Class using logistic regression, to obtain the area under curve (AUC) value for comparison of ICU admission predictability. Patients were analyzed up till discharge., Results: Ninety patients were diagnosed with EPN. Twenty-six patients required ICU management and nine patients died. The best scoring system to predict the need of early ICU management is NEWS (AUC 0.884). CT Class had no independent predictive power, nor did it add significantly to improvement in most of the early warning scoring systems, but rather guided us to the need for radiological, endourological or surgical intervention., Conclusion: In patients with EPN, the NEWS scoring system predicts best the requirement of ICU care. It aids in triage of patients with EPN to appropriate early management and reduce mortality risk., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Clopidogrel is a prodrug chiefly metabolized by the hepatic isoenzyme CYP2C19 to its active metabolite that inhibits the platelet aggregation. It has been proven in many populations that the genetic polymorphism of CYP2C19 has influence on the pharmacokinetic and or pharmacodynamics of this drug and resulting in high inter-individual variability in the treatment outcomes. As CYP2C19 genetic polymorphism is highly prevalent among the Asian population, the influence of the same on the pharmacokinetics and; thereby, the pharmacodynamics of clopidogrel needs more attention. Using the pharmacogenetic information for drug therapy could help overcome these issues and to optimize the dosage regimen of clopidogrel, this review advocates the precision medicine approach for reducing the clopidogrel resistance and adverse cardiovascular events.

In this article, we detail a comprehensive laboratory evaluation of an immunoassay for the rapid detection of abrin using the Meso Scale Diagnostics Sector PR2 Model 1800. For the assay evaluation, we used inclusivity and exclusivity panels comprised of extracts of 11 Abrus precatorius cultivars and 35 near-neighbor plants, 65 lectins, 26 white powders, 11 closely related toxins and proteins, and a pool of 30 BioWatch filter extracts. The results show that the Meso Scale Diagnostics abrin detection assay exhibits good sensitivity and specificity with a limit of detection of 4 ng/mL. However, the dynamic range of the assay for the quantitation of abrin was limited. We observed a hook effect at higher abrin concentrations, which can lead to potential false negative results. A modification of the assay protocol that incorporates extra wash steps can decrease the hook effect and the potential for false negative results.

The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. Fcγ receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability. Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. Dengue infection can lead to the generation of autoantibodies against DENV NS1antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. This review article highlights the various factors responsible for the pathogenesis of dengue and also highlights the recent advances in the field related to biomarkers which can be used in future for predicting severe disease outcome.

The 143 low- and middle-income countries (LMICs) of the world constitute 80% of the world's population or roughly 5.86 billion people with much variation in geography, culture, literacy, financial resources, access to health care, insurance penetration, and healthcare regulation. Unfortunately, their burden of cardiovascular disease in general and acute ST-segment-elevation myocardial infarction (STEMI) in particular is increasing at an unprecedented rate. Compounding the problem, outcomes remain suboptimal because of a lack of awareness and a severe paucity of resources. Guideline-based treatment has dramatically improved the outcomes of STEMI in high-income countries. However, no such focused recommendations exist for LMICs, and the unique challenges in LMICs make directly implementing Western guidelines unfeasible. Thus, structured solutions tailored to their individual, local needs, and resources are a vital need. With this in mind, a multicountry collaboration of investigators interested in LMIC STEMI care have tried to create a consensus document that extracts transferable elements from Western guidelines and couples them with local realities gathered from expert experience. It outlines general operating principles for LMICs focused best practices and is intended to create the broad outlines of implementable, resource-appropriate paradigms for management of STEMI in LMICs. Although this document is focused primarily on governments and organizations involved with improvement in STEMI care in LMICs, it also provides some specific targeted information for the frontline clinicians to allow standardized care pathways and improved outcomes.

Infections in immunocompromised patients that are caused by extensively drug-resistant (XDR) Acinetobacter baumannii strains have been increasingly reported worldwide. In particular, carbapenem-resistant A. baumannii strains are a prominent cause of health care-associated infections. Here, we report draft genome assemblies for two clinical XDR A. baumannii isolates obtained from hospitalized patients in Pakistan.

We conducted a comprehensive, multi-phase laboratory evaluation of the Tularemia BioThreat Alert ® (BTA) test, a lateral flow assay (LFA) for the rapid detection of Francisella tularensis . The study, conducted at 2 sites, evaluated the limit of detection (LOD) of this assay using the virulent SchuS4 strain and the avirulent LVS strain of F. tularensis . In 6-phase evaluation (linear dynamic range and reproducibility, inclusivity, near-neighbor, environmental background, white powder, and environmental filter extract), 13 diverse strains of F. tularensis , 8 Francisella near neighbors, 61 environmental background organisms, 26 white powders, and a pooled aerosol extract were tested. In the 937 tests performed, the Tularemia BTA demonstrated an LOD of 10 7 to 10 8 cfu/mL, with a sensitivity of 100.00%, specificity of 98.08%, and accuracy of 98.84%. These performance data are important for accurate interpretation of qualitative results arising from screening suspicious white powders in the field.

We conducted a comprehensive, multiphase laboratory evaluation of the Plague BioThreat Alert ® (BTA) test, a lateral flow immunoassay (LFA), for the rapid detection of Yersinia pestis . The study was conducted in 7 phases at 2 sites to assess the performance of the LFA. The limit of detection (LOD) was determined using both a virulent and avirulent strain of Y. pestis , CO99-3015 (10 5 CFU/ml) and A1122 (10 4 CFU/ml), respectively. In the other phases, 18 Y. pestis strains, 20 phylogenetic near-neighbor strains, 61 environmental background microorganisms, 26 white powders, and a pooled aerosol sample were also tested. A total of 1,110 LFA test results were obtained, and their analysis indicates that this LFA had a sensitivity of 97.65% and specificity of 96.57%. These performance data are important for accurate interpretation of qualitative results arising from testing suspicious white powders and aerosol samples in the field. Any positive specimen in this assay is considered presumptive positive and should be referred to the Centers for Disease Control and Prevention Laboratory Response Network for additional testing, confirmation, and characterization for an appropriate public health response.

Purpose: This study examined the effects of combined cooling and lower body heat maintenance during half-time on second-half intermittent sprint performances., Methods: In a repeated measures design, nine males completed four intermittent cycling trials (32.1 ± 0.3 °C and 55.3 ± 3.7% relative humidity), with either one of the following half-time recovery interventions; mixed-method cooling (ice vest, ice slushy and hand cooling; COOL), lower body passive heating (HEAT), combined HEAT and COOL (COMB) and control (CON). Peak and mean power output (PPO and MPO), rectal (T re ), estimated muscle (T es-Mus ) and skin (T SK ) temperatures were monitored throughout exercise., Results: During half-time, the decrease in T re was substantially greater in COOL and COMB compared with CON and HEAT, whereas declines in T es-Mus within HEAT and COMB were substantially attenuated compared with CON and COOL. The decrease in T SK was most pronounced in COOL compared with CON, HEAT and COMB. During second-half, COMB and HEAT resulted in a larger decrease in PPO and MPO during the initial stages of the second-half when compared to CON. In addition, COOL resulted in an attenuated decrease in PPO and MPO compared to COMB in the latter stages of second-half., Conclusion: The maintenance of T es-Mus following half-time was detrimental to prolonged intermittent sprint performance in the heat, even when used together with cooling.

Shigella spp. are the most common cause of dysentery in developing countries and the second leading cause of diarrheal deaths worldwide. Multidrug-resistant (MDR) Shigella spp. are a serious threat to global health. Herein, we report draft genome sequences for three MDR Shigella isolates from Pakistan, two Shigella flexneri isolates and one Shigella sonnei isolate.

A comprehensive laboratory evaluation of the Tetracore RedLine Alert test, a lateral flow immunoassay (LFA) for the rapid presumptive identification of Bacillus anthracis, was conducted at 2 different test sites. The study evaluated the sensitivity of this assay using 16 diverse strains of B. anthracis grown on sheep blood agar (SBA) plates. In addition, 83 clinically relevant microorganisms were tested to assess the specificity of the RedLine Alert test. The results indicated that the RedLine Alert test for the presumptive identification of B. anthracis is highly robust, specific, and sensitive. RedLine Alert is a rapid test that has applicability for use in a clinical setting for ruling-in or ruling-out nonhemolytic colonies of Bacillus spp. grown on SBA medium as presumptive isolates of B. anthracis .

Background & Objectives: Dengue virus infection is endemic in India with all the four serotypes of dengue virus in circulation. This study was aimed to determine the geographic distribution of the primary and secondary dengue cases in India., Methods: A multicentre cross-sectional study was conducted at Department of Health Research / Indian Council of Medical Research (DHR)/(ICMR) viral research and diagnostic laboratories (VRDLs) and selected ICMR institutes located in India. Only laboratory-confirmed dengue cases with date of onset of illness less than or equal to seven days were included between September and October 2017. Dengue NS1 antigen ELISA and anti-dengue IgM capture ELISA were used to diagnose dengue cases while anti-dengue IgG capture ELISA was used for identifying the secondary dengue cases., Results: Of the 1372 dengue cases, 897 (65%) were classified as primary dengue and 475 (35%) as secondary dengue cases. However, the proportion varied widely geographically, with Theni, Tamil Nadu; Tirupati, Andhra Pradesh and Udupi-Manipal, Karnataka reporting more than 65 per cent secondary dengue cases while Srinagar, Jammu and Kashmir reporting as low as 10 per cent of the same. The median age of primary dengue cases was 25 yr [interquartile range (IQR 17-35] while that of secondary dengue cases was 23 yr (IQR 13.5-34). Secondary dengue was around 50 per cent among the children belonging to the age group 6-10 yr while it ranged between 20-43 per cent among other age groups., Interpretation & Conclusions: Our findings showed a wide geographical variation in the distribution of primary and secondary dengue cases in India. It would prove beneficial to include primary and secondary dengue differentiation protocol in the national dengue surveillance programme., Competing Interests: None

Clinical diagnostics is a challenge in resource poor areas. Accessibility to diagnostic laboratories is severely curtailed in areas where resources and infrastructure are limited. There is a need to develop low cost and portable devices to promote healthcare services in such places. The development of low cost paper-based microfluidic devices (μPADS) and thread-based devices have the potential to revolutionize point of care diagnostics in poverty-ridden areas. In this report, we describe how frugal technologies can be used for the detection of biological fluids, and the need for developing low cost wireless and wearable technologies to be deployed in resource poor settings.

Introduction: There is lack of information on the proportion of new smear-positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice-weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome., Objective: To estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined., Methodology: Adult (aged ≥ 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared "treatment success" at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years (with 95% confidence interval [95%CI]). Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence., Results: Of the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2-21.6] and TB recurrence rate per 100 person-years was 12.7 [95% CI: 0.4-25]. TB recurrence per 100 person-years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence., Conclusion: A substantial proportion of new smear positive PTB patients successfully treated with 6 -month thrice-weekly regimen have TB recurrence under program settings., Competing Interests: The authors have declared that no competing interests exist.

The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria. In the current study, WGS data was used to characterize the genomic content of antimicrobial resistance genes, including those encoding carbapenemases, in 10 multidrug-resistant Klebsiella pneumoniae isolates from Pakistan. These clinical isolates represented five sequence types: ST11 (n = 3 isolates), ST14 (n = 3), ST15 (n = 1), ST101 (n = 2), and ST307 (n = 1). Resistance profiles against 25 clinically-relevant antimicrobials were determined by broth microdilution; resistant phenotypes were observed for at least 15 of the 25 antibiotics tested in all isolates except one. Specifically, 8/10 isolates were carbapenem-resistant and 7/10 isolates were colistin-resistant. The blaNDM-1 and blaOXA-48 carbapenemase genes were present in 7/10 and 5/10 isolates, respectively; including 2 isolates carrying both genes. No plasmid-mediated determinants for colistin resistance (e.g. mcr) were detected, but disruptions and mutations in chromosomal loci (i.e. mgrB and pmrB) previously reported to confer colistin resistance were observed. A blaOXA-48-carrying IncL/M-type plasmid was found in all blaOXA-48-positive isolates. The application of WGS to molecular epidemiology and surveillance studies, as exemplified here, will provide both a more complete understanding of the global distribution of MDR isolates and a robust surveillance tool useful for detecting emerging threats to public health., Competing Interests: Affiliation with IHRC does not alter our adherence to PLOS ONE policies on sharing data and materials.

Due to the multifactorial and multisystemic nature of diabetes mellitus, it is often treated with a combination of therapeutic agents having different mode of action. Earlier, we have synthesized several organozinc complexes and evaluated their safety and antidiabetic properties in experimental type 2 diabetes mellitus (T2DM). More recently, we have synthesized a metformin-3-hydroxyflavone complex and studied its antidiabetic efficacy in experimental rats. In the present study, a new zinc-mixed ligand (metformin-3-hydroxyflavone) was synthesized, characterized by spectral studies and its antidiabetic properties was evaluated in HFD fed-low dose streptozotocin induced T2DM in rats. The hypoglycemic efficacy of the complex was evaluated through oral glucose tolerance test, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index and by determining the status of important biochemical parameters. Oral administration of the complex at a concentration of 10 mg/kg body weight/rat/day for 30 days significantly improved the glucose homeostasis. The complex possesses significant antidiabetic properties relatively at a less concentration than metformin-3-hydroxyflavone complex in ameliorating hyperglycemia., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018 Korean Diabetes Association.)

Coxiella burnetii is a human pathogen that causes the serious zoonotic disease Q fever. It is ubiquitous in the environment and due to its wide host range, long-range dispersal potential and classification as a bioterrorism agent, this microorganism is considered an HHS Select Agent. In the event of an outbreak or intentional release, laboratory strain typing methods can contribute to epidemiological investigations, law enforcement investigation and the public health response by providing critical information about the relatedness between C. burnetii isolates collected from different sources. Laboratory cultivation of C. burnetii is both time-consuming and challenging. Availability of strain collections is often limited and while several strain typing methods have been described over the years, a true gold-standard method is still elusive. Building upon epidemiological knowledge from limited, historical strain collections and typing data is essential to more accurately infer C. burnetii phylogeny. Harmonization of auspicious high-resolution laboratory typing techniques is critical to support epidemiological and law enforcement investigation. The single nucleotide polymorphism (SNP) -based genotyping approach offers simplicity, rapidity and robustness. Herein, we demonstrate SNPs identified within 16S rRNA gene sequences can differentiate C. burnetii strains. Using this method, 55 isolates were assigned to six groups based on six polymorphisms. These 16S rRNA SNP-based genotyping results were largely congruent with those obtained by analyzing restriction-endonuclease (RE)-digested DNA separated by SDS-PAGE and by the high-resolution approach based on SNPs within multispacer sequence typing (MST) loci. The SNPs identified within the 16S rRNA gene can be used as targets for the development of additional SNP-based genotyping assays for C. burnetii.

Clostridial neurotoxins, including botulinum and tetanus neurotoxins, are among the deadliest known bacterial toxins. Until recently, the horizontal mobility of this toxin gene family appeared to be limited to the genus Clostridium We report here the closed genome sequence of Chryseobacterium piperi , a Gram-negative bacterium containing coding sequences with homology to clostridial neurotoxin family proteins., (Copyright © 2017 Wentz et al.)

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML ( n = 217) and MDS ( n = 42) randomized to receive either AZA monotherapy (75 mg/m 2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate ( P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A ( P = 0.0001), IDH1 ( P = 0.004), and TP53 ( P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430-40. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Rosmarinic acid (RA), a polyphenol, is known to improve hepatic insulin sensitivity in experimental type 2 diabetes. However, its effect on skeletal muscle insulin resistance is meagerly understood. The present study was aimed to investigate the up- and downstream mediators of the molecular targets of RA in attenuating insulin resistance in the skeletal muscle both in vivo and in vitro. We found that supplementation of RA increased the expression of key genes involved in the mitochondrial biogenesis like PGC-1α, SIRT-1, and TFAM via activation of AMPK in the skeletal muscle of insulin resistant rats as well as in L6 myotubes. Further, RA treatment increased the glucose uptake and decreased the phosphorylation of serine IRS-1 while increasing the translocation of GLUT 4. Together, our findings evidenced that RA treatment significantly inhibit insulin resistance in skeletal muscle cells by enhancing mitochondrial biogenesis. J. Cell. Biochem. 118: 1839-1848, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The emergence and spread of colistin resistance among multidrug-resistant (MDR) Klebsiella pneumoniae represent a critical threat to global health. Here, we report the complete genome sequences of 10 MDR, colistin-susceptible and -resistant K. pneumoniae clinical isolates obtained in Pakistan between 2010 and 2013., (Copyright © 2016 Crawford et al.)

We report here the complete annotated genome sequence of the Burkholderia stabilis type strain ATCC BAA-67. There were three circular chromosomes with a combined size of 8,527,947 bp and G+C composition of 66.4%. These characteristics closely resemble the genomes of other sequenced members of the Burkholderia cepacia complex., (Copyright © 2016 Bugrysheva et al.)

Analysis of 16S rRNA genes is important for phylogenetic classification of known and novel bacterial genera and species and for detection of uncultivable bacteria. PCR amplification of 16S rRNA genes with universal primers produces a mixture of amplicons from all rRNA operons in the genome, and the sequence data generally yield a consensus sequence. Here we describe valuable data that are missing from consensus sequences, variable effects on sequence data generated from nonidentical 16S rRNA amplicons, and the appearance of data displayed by different software programs. These effects are illustrated by analysis of 16S rRNA genes from 50 strains of the Bacillus cereus group, i.e., Bacillus anthracis, Bacillus cereus, Bacillus mycoides, and Bacillus thuringiensis These species have 11 to 14 rRNA operons, and sequence variability occurs among the multiple 16S rRNA genes. A single nucleotide polymorphism (SNP) previously reported to be specific to B. anthracis was detected in some B. cereus strains. However, a different SNP, at position 1139, was identified as being specific to B. anthracis, which is a biothreat agent with high mortality rates. Compared with visual analysis of the electropherograms, basecaller software frequently missed gene sequence variations or could not identify variant bases due to overlapping basecalls. Accurate detection of 16S rRNA gene sequences that include intragenomic variations can improve discrimination among closely related species, improve the utility of 16S rRNA databases, and facilitate rapid bacterial identification by targeted DNA sequence analysis or by whole-genome sequencing performed by clinical or reference laboratories., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

We conducted a comprehensive, multiphase laboratory evaluation of the Anthrax BioThreat Alert(®) test strip, a lateral flow immunoassay (LFA) for the rapid detection of Bacillus anthracis spores. The study, conducted at 2 sites, evaluated this assay for the detection of spores from the Ames and Sterne strains of B. anthracis, as well as those from an additional 22 strains. Phylogenetic near neighbors, environmental background organisms, white powders, and environmental samples were also tested. The Anthrax LFA demonstrated a limit of detection of about 10(6) spores/mL (ca. 1.5 × 10(5) spores/assay). In this study, overall sensitivity of the LFA was 99.3%, and the specificity was 98.6%. The results indicated that the specificity, sensitivity, limit of detection, dynamic range, and repeatability of the assay support its use in the field for the purpose of qualitatively evaluating suspicious white powders and environmental samples for the presumptive presence of B. anthracis spores.

A β-diketiminate Al compound (1) with an exocyclic double bond reacts with two equivalents each of benzophenone and 2-benzoylpyridine in a [4+2] cycloaddition to generate bicyclic and tricyclic compounds 2 and 3, respectively. Compound 2 consists of six- and eight-membered aluminium rings, whereas 3 has two five- and one eight-membered ring. Compounds 2 and 3 were characterized by a number of analytical tools including single-crystal X-ray diffraction. The quantum mechanical calculations suggest that the dissociation of the solvent molecule from 1 would lead to an active species 1A having two 1,4-dipolar 4π electron moieties, in which the electrophilic site is the Al atom and the nucleophilic positions are polarized exocyclic and endocyclic C=C π bonds. The detailed mechanistic study shows that the dipolarophiles, benzophenone, and 2-benzoylpyridine undergo double cycloaddition with two 1,4-dipolar 4π electron moieties of 1A. Herein, the addition of one molecule of the dipolarophile promotes the addition of the second one., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Heart disease risk is elevated in South Asians possibly due to impaired postprandial metabolism. Running has been shown to induce greater reductions in postprandial lipaemia in South Asian than European men, but the effect of walking in South Asians is unknown., Methods: Fifteen South Asian and 14 white European men aged 19-30 years completed two, 2-day trials in a randomised crossover design. On day 1, participants rested (control) or walked for 60 min at approximately 50 % maximum oxygen uptake (exercise). On day 2, participants rested and consumed two high-fat meals over a 9-h period during which 14 venous blood samples were collected., Results: South Asians exhibited higher postprandial triacylglycerol [geometric mean (95 % confidence interval) 2.29 (1.82 to 2.89) vs. 1.54 (1.21 to 1.96) mmol L(-1) h(-1)], glucose [5.49 (5.21 to 5.79) vs. 5.05 (4.78 to 5.33) mmol L(-1) h(-1)], insulin [32.9 (25.7 to 42.1) vs. 18.3 (14.2 to 23.7) µU mL(-1) h(-1)] and interleukin-6 [2.44 (1.61 to 3.67) vs. 1.04 (0.68 to 1.59) pg mL(-1) h(-1)] than Europeans (all ES ≥ 0.72, P ≤ 0.03). Between-group differences in triacylglycerol, glucose and insulin were not significant after controlling for age and percentage body fat. Walking reduced postprandial triacylglycerol [1.79 (1.52 to 2.12) vs. 1.97 (1.67 to 2.33) mmol L(-1) h(-1)] and insulin [21.0 (17.0 to 26.0) vs. 28.7 (23.2 to 35.4) µU mL(-1) h(-1)] (all ES ≥ 0.23. P ≤ 0.01), but group differences were not significant., Conclusions: Healthy South Asians exhibited impaired postprandial metabolism compared with white Europeans, but these differences were diminished after controlling for potential confounders. The small-moderate reduction in postprandial triacylglycerol and insulin after brisk walking was not different between the ethnicities.

Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC., (© 2013 Blackwell Publishing Ltd.)