The Difficulties Of South American Football

Aboriginal Australians -- Land tenure.

London : Cassell, 1901.

London : Cassell, 1894.

Paris : G. Steinheil, 1888.

Blending marshmallows with scientific rigor, the contest offers levity during a difficult time

Last March, analysts and tech bloggers dumped out arrogant contempt over Apple's latest product introduction. This year, those new offerings helped save Apple's Q2 earnings and are projected to bolster its June quarter performance despite the pandemic.

Behind the glow of city lights, a group of people easily go unnoticed—lost sheep in desperate need of the hope of the gospel.

Balboa, Panama :: Logos Hope's volunteers make an uplifting visit to a shelter for migrant men, testing their eyesight and handing out reading glasses.

Children with special health care needs present clinically with varied functional difficulties across an array of health conditions. Little attention has been given to the interaction of these descriptors at a population level, thereby not addressing the complexity of functional difficulties and their impact on the health of CSHCN.

The data demonstrate the relationships among functional difficulties and health conditions, which then improve our understanding of CSHCN and their needs. Functional difficulties contribute significantly to outcomes, such as emergency room visits, parental work patterns, and limitations in daily activities, and have implications for practice, training, policy, and research. (Read the full article)

Cross-sectional studies have shown an increased risk of mental health difficulties in children with developmental coordination disorder. However, there has been limited longitudinal research in this area controlling for confounding factors and assessing the role of potential mediators.

Children with "probable" developmental coordination disorder at 7 years had a significantly increased risk mental health difficulties at 10 years. Protective factors for self-reported depression included high IQ, high self-esteem, good social communication skills, and the absence of bullying. (Read the full article)

Validated questionnaires can improve the identification of psychosocial problems among children. The Strengths and Difficulties Questionnaire (SDQ) 3-4 is a promising option. However, no studies are available that examine the psychometric properties of the SDQ parent form 3-4.

The results of this study show that the SDQ 3-4 is a valid tool for the identification of psychosocial problems in preschool-aged children. (Read the full article)

Caregiver behavioral symptom ratings are frequently used to assist in diagnosing childhood behavioral disorders. Although behavioral disorders are highly comorbid with learning disabilities (LDs), little work has examined the utility of caregiver ratings of learning concerns for screening of comorbid LD.

The validity of a time- and cost-efficient caregiver rating of academic concerns (Colorado Learning Difficulties Questionnaire) was examined. The screening measure accurately predicted children without LD, suggesting that the absence of parent-reported difficulties may be adequate to rule out overt LD. (Read the full article)

Links between clinically diagnosed sleep problems and adverse behavioral outcomes are well documented. However, in nonclinical populations, causal links between disrupted sleep and the development of behavioral difficulties are far from clear.

Seven-year-old children with nonregular bedtimes had more behavioral difficulties than children who had regular bedtimes. There were clear dose–response relationships, and the effects of not having regular bedtimes appeared to be reversible. (Read the full article)

Little is known about the epidemiology and pathogenicity of Clostridium difficile infection among children, particularly those aged ≤3 years in whom colonization is common and pathogenicity uncertain.

Young children, 1 to 3 years of age, had the highest Clostridium difficile infection incidence. Considering that clinical presentation, outcomes, and disease severity were similar across age groups, C difficile infection in the youngest age group likely represents true disease and not asymptomatic colonization. (Read the full article)

Although the psychometric properties of the school-age Strengths and Difficulties Questionnaire (SDQ) have been extensively examined by using longitudinal data, the preschool version of the SDQ has only been explored in a limited number of cross-sectional studies.

This is the first psychometric study of the preschool SDQ using longitudinal data. We report measurement invariance over time, satisfactory reliability, construct and criterion validity, and predictive utility for subsequent behavioral problems (4 years) and clinical disorders (2 years). (Read the full article)

Students with dyslexia often struggle with math fluency as well, and scholars at a recent conference put a spotlight on some of the possible connections.

The biologic Griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs) including human immunodeficiency virus (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) fibers, that incorporate GRFT, in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via ELISA, and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavages were evaluated for histology and cytokine expression, 24 and 72 hr after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavages treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue.

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at the concentrations of 0.5 μg/mL and 2 μg/mL, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3-log₁₀ within six hours. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.

One father in Bangladesh struggles to find believing husbands for his two daughters, after all three have come to faith in Jesus.

Virat Kohli feels that it would be difficult to create the magic of playing in front of thousands of fans if games are held behind closed doors.

BCCI treasurer Arun Dhumal has expressed his concerns over the possibility of hosting the T20 World Cup in October as per scheduled.

Two weeks ago we looked at the first two steps in effecting forecasting process change: Justify your suspicions with data Communicate your findings That was the easy part. So why is it that so many organization realize they have a forecasting problem, yet are unable to do anything about it? [...]

The post The difficult step in effecting forecasting process change (1 of 2) appeared first on The Business Forecasting Deal.

Fildes and Goodwin (F&G) observed the subject (the regional subsidiary of a pharmaceutical company) was using a statistical forecasting system, but not fully trusting its output. Forecasters were making overrides to the system generated forecast to make it look like what they believed it should (e.g., following a life-cycle curve [...]

The post The difficult step in effecting forecasting process change (2 of 2) appeared first on The Business Forecasting Deal.

The 38-year-old Gambhir picked KL Rahul, who has been keeping in ODIs, as an "apt replacement" for Dhoni.

The ocean has deep secrets. It is a world as vibrant as the one outside. There is a unique ecology that defies common knowledge and often perplexes scientists. This barely-explored territory is also believed to hold vast quantities of precious metals and minerals that can sustain the modern world for centuries. So it is not […]

Winds are from the West at 27.6 gusting to 35.7 MPH (24 gusting to 31 KT). The pressure is 1010.6 mb and the humidity is 50%. The wind chill is 25. Last Updated on May 9 2020, 11:53 am EDT.

Differentiating good IP from mediocre or bad IP is getting more difficult, in part because it depends upon how and where it is used and in part, because even the best IP may work better in one system than another—even in chips developed by the same vendor.  

So, how do you measure IP quality and why it is so complicated?

The answer depends on who is asking. Most of the time, the definition of IP quality depends on your vantage point.  If you are an R&D manager, IP quality means something. If you are a global supply manager, IP quality means something else. If you are an SoC start-up, your measure of quality is quite different from that of an established fabless company. If you are designing IP in-house, then your considerations are very different than being a commercial IP vendor. If you are designing an automotive SoC, then we are in a totally different category. How about as an IP vendor? How do you articulate IP quality metrics to your customers?

This varies greatly by the type of IP, as well. When it comes to interface (hard) IP and controllers, if you are an R&D manager, your goal is to design IP that meets the IP specifications and PPA (power, performance, and area) targets. You need to validate your design via silicon test chips. This applies to all hard PHYs, which must be mapped to a particular foundry process. For controllers that are in RTL form—we called these soft IP—you have to synthesize them into a particular target library in a particular foundry process in order to realize them in a physical form suitable for SoC integration. Of course, your design will need to go through a series of design validation steps via simulation, design verification and passing the necessary DRC checks, etc. In addition, you want to see the test silicon in various process corners to ensure the IP is robust and will perform well under normal process variations in the production wafers.

For someone in IP procurement, the measure of quality will be based on the maturity of the IP. This involves the number of designs that have been taped out using this IP and the history of bug reports and subsequent fixes. You will be looking for quality of the documentation and the technical deliverables. You will also benchmark the supplier’s standard operating procedures for bug reporting and technical support, as well as meeting delivery performance in prior programs. This is in addition to the technical teams doing their technical diligence.

An in-house team that is likely to design IP for a particular SoC project will be using an established design flow and will have legacy knowledge of last generation’s IP. They may be required to design the IP with some reusability in mind for future programs. However, such reusability requirements will not need to be as stringent and as broad as those of commercial IP vendors because there are likely to be established metrics and procedures in place to follow as part of the design team’s standard operating procedures. Many times, new development based on a prior design that has been proven in use will be started, given this stable starting point. All of these criteria help the team achieve a quality outcome more easily.

Then, if designing for an automotive SoC, additional heavy lifting is required.  Aside from ensuring that the IP meets the specifications of the protocol standards and passes the compliance testing, you also must pay attention to meeting functional safety requirements. This means adherence to ISO 26262 requirements and subsequently achieving ASIL certification. Oftentimes, even for IP, you must perform some AEC-Q100-related tests that are relevant to IP, such as ESD, LU, and HTOL.

To read more, please visit: https://semiengineering.com/why-ip-quality-is-so-difficult-to-determine/

On 1 May, the FCA issued two sets of draft guidance which will be important reading for all firms involved in insurance arrangements and particularly insurers, intermediaries and premium finance lenders. As it considers that the delay involved in co...

Opinion on the way forward regarding the fate of the PSL campaign is still divided and the Amakhosi legend has weighed in with his views ......

Companies are facing difficult times with reporting, audits and meetings in view of the COVID-19  outbreak. In this update we take a look at the measures that have been announced this week to assist companies. Whilst we are seeing some creative...

CHENNAI: As if land grab bids and ‘double documents’ are not menace enough for property owners/buyers, the state registration department shocked the Madras high court on Monday, saying it is difficult to issue encumbrance certificates without any fault. An encumbrance certificate (EC) is the basic document which reveals the current status of an immovable property. It is supposed to contain correct ownership details of a piece of property and inform the applicant whether it is encumbered or mortgaged in favour of a bank or any individual. However, responding to an anticipatory bail petition of a landowner who ended up purchasing another person’s property as the EC did not reflect latest […]

ABSTRACT

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils.

IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

ABSTRACT

Clostridioides difficile is an important nosocomial pathogen that causes approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths annually in the United States. Antibiotic use is a major risk factor for CDI because broad-spectrum antimicrobials disrupt the indigenous gut microbiota, decreasing colonization resistance against C. difficile. Vancomycin is the standard of care for the treatment of CDI, likely contributing to the high recurrence rates due to the continued disruption of the gut microbiota. Thus, there is an urgent need for the development of novel therapeutics that can prevent and treat CDI and precisely target the pathogen without disrupting the gut microbiota. Here, we show that the endogenous type I-B CRISPR-Cas system in C. difficile can be repurposed as an antimicrobial agent by the expression of a self-targeting CRISPR that redirects endogenous CRISPR-Cas3 activity against the bacterial chromosome. We demonstrate that a recombinant bacteriophage expressing bacterial genome-targeting CRISPR RNAs is significantly more effective than its wild-type parent bacteriophage at killing C. difficile both in vitro and in a mouse model of CDI. We also report that conversion of the phage from temperate to obligately lytic is feasible and contributes to the therapeutic suitability of intrinsic C. difficile phages, despite the specific challenges encountered in the disease phenotypes of phage-treated animals. Our findings suggest that phage-delivered programmable CRISPR therapeutics have the potential to leverage the specificity and apparent safety of phage therapies and improve their potency and reliability for eradicating specific bacterial species within complex communities, offering a novel mechanism to treat pathogenic and/or multidrug-resistant organisms.

IMPORTANCE Clostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with type I CRISPR-Cas systems and modified to reduce lysogeny and to enable the specific and efficient targeting and killing of C. difficile in vitro and in vivo. Additional genetic engineering to disrupt phage modulation of toxin expression by lysogeny or other mechanisms would be required to advance a CRISPR-enhanced phage antimicrobial for C. difficile toward clinical application. These findings provide evidence into how phage can be combined with CRISPR-based targeting to develop novel therapies and modulate microbiomes associated with health and disease.

ABSTRACT

Insights into the interaction between phages and their bacterial hosts are crucial for the development of phage therapy. However, only one study has investigated global gene expression of Clostridioides (formerly Clostridium) difficile carrying prophage, and transcriptional reprogramming during lytic infection has not been studied. Here, we presented the isolation, propagation, and characterization of a newly discovered 35,109-bp phage, JD032, and investigated the global transcriptomes of both JD032 and C. difficile ribotype 078 (RT078) strain TW11 during JD032 infection. Transcriptome sequencing (RNA-seq) revealed the progressive replacement of bacterial host mRNA with phage transcripts. The expressed genes of JD032 were clustered into early, middle, and late temporal categories that were functionally similar. Specifically, a gene (JD032_orf016) involved in the lysis-lysogeny decision was identified as an early expression gene. Only 17.7% (668/3,781) of the host genes were differentially expressed, and more genes were downregulated than upregulated. The expression of genes involved in host macromolecular synthesis (DNA/RNA/proteins) was altered by JD032 at the level of transcription. In particular, the expression of the ropA operon was downregulated. Most noteworthy is that the gene expression of some antiphage systems, including CRISPR-Cas, restriction-modification, and toxin-antitoxin systems, was suppressed by JD032 during infection. In addition, bacterial sporulation, adhesion, and virulence factor genes were significantly downregulated. This study provides the first description of the interaction between anaerobic spore-forming bacteria and phages during lytic infection and highlights new aspects of C. difficile phage-host interactions.

IMPORTANCE C. difficile is one of the most clinically significant intestinal pathogens. Although phages have been shown to effectively control C. difficile infection, the host responses to phage predation have not been fully studied. In this study, we reported the isolation and characterization of a new phage, JD032, and analyzed the global transcriptomic changes in the hypervirulent RT078 C. difficile strain, TW11, during phage JD032 infection. We found that bacterial host mRNA was progressively replaced with phage transcripts, three temporal categories of JD032 gene expression, the extensive interplay between phage-bacterium, antiphage-like responses of the host and phage evasion, and decreased expression of sporulation- and virulence-related genes of the host after phage infection. These findings confirmed the complexity of interactions between C. difficile and phages and suggest that phages undergoing a lytic cycle may also cause different phenotypes in hosts, similar to prophages, which may inspire phage therapy for the control of C. difficile.

Clostridioides difficile infection (CDI) is one of the most common health care-associated infections that can cause significant morbidity and mortality. CDI diagnosis involves laboratory testing in conjunction with clinical assessment. The objective of this study was to assess the performance of various C. difficile tests and to compare clinical characteristics, Xpert C. difficile/Epi (PCR) cycle threshold (C_T), and Singulex Clarity C. diff toxins A/B (Clarity) concentrations between groups with discordant test results. Unformed stool specimens from 200 hospitalized adults (100 PCR positive and 100 negative) were tested by cell cytotoxicity neutralization assay (CCNA), C. diff Quik Chek Complete (Quik Chek), Premier Toxins A and B, and Clarity. Clinical data, including CDI severity and CDI risk factors, were compared between discordant test results. Compared to CCNA, PCR had the highest sensitivity at 100% and Quik Chek had the highest specificity at 100%. Among clinical and laboratory data studied, prevalences of leukocytosis, prior antibiotic use, and hospitalizations were consistently higher across all subgroups in comparisons of toxin-positive to toxin-negative patients. Among PCR-positive samples, the median C_T was lower in toxin-positive samples than in toxin-negative samples; however, C_T ranges overlapped. Among Clarity-positive samples, the quantitative toxin concentration was significantly higher in toxin-positive samples than in toxin-negative samples as determined by CCNA and Quik Chek Toxin A and B. Laboratory tests for CDI vary in sensitivity and specificity. The quantitative toxin concentration may offer value in guiding CDI diagnosis and treatment. The presence of leukocytosis, prior antibiotic use, and previous hospitalizations may assist with CDI diagnosis, while other clinical parameters may not be consistently reliable.

ABSTRACT

Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.

Clostridioides difficileDiagnosticsMetabolomicsMicrobiome

The COVID-19 pandemic has placed unprecedented pressure on societies worldwide, given the pandemic's rapid, often deadly spread. In health care, the pandemic has raised the pressing question of how society should allocate scarce resources during a crisis.

New research finds that sleep problems in a baby's first 12 months may not only precede an autism diagnosis, but also may be associated with altered growth trajectory in a key part of the brain, the hippocampus.

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