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Novel ionophores active against La Crosse virus identified through rapid antiviral screening [Antiviral Agents]

Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (Coxsackievirus, rhinovirus), flavirivuses (Zika), and coronaviruses (HCoV-229E and MERS-CoV). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.

Importance No antivirals are approved for the treatment of bunyavirus infection. The ability to rapidly screen compounds and identify novel antivirals is one means to accelerate drug discovery for viruses with no approved treatments. We used this approach to screen hundreds of compounds against La Crosse virus, an emerging bunyavirus that causes significant disease, including encephalitis. We identified several known and previously unidentified antivirals. We focused on a potassium ionophore, valinomycin, due to its promising in vitro antiviral activity. We demonstrate that valinomycin, as well as a selection of other ionophores, exhibits activity against La Crosse virus as well as several other distantly related bunyaviruses. We finally observe that valinomycin has activity against a wide array of human viral pathogens, suggesting that disrupting potassium ion homeostasis with valinomycin may be a potent host pathway to target to quell virus infection.




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A genotype-phenotype correlation study of SHV {beta}-lactamases - new insight into SHV resistance profiles [Mechanisms of Resistance]

The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.




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Efficacy of neuraminidase inhibitors against H5N6 highly pathogenic avian influenza virus in a non-human primate model [Antiviral Agents]

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.




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Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials [Antiviral Agents]

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.




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Genetic Mutations Associated with Isoniazid Resistance in Mycobacterium tuberculosis in Mongolia [Epidemiology and Surveillance]

Globally, mutations in the katG gene account for the majority of isoniazid-resistant strains of Mycobacterium tuberculosis. Buyankhishig et al analyzed a limited number of Mycobacterium tuberculosis strains in Mongolia and found that isoniazid resistance was mainly attributable to inhA mutations. The GenoType® MTBDRplus assay was performed for isolates collected in the First National Tuberculosis Prevalence Survey and the Third Anti-Tuberculosis Drug Resistance Survey to investigate genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis in Mongolia. Of the 409 isoniazid-resistant isolates detected by the GenoType® MTBDRplus assay, 127 (31.1%) were resistant to rifampicin, 294 (71.9%) had inhA mutations without katG mutations, 113 (27.6%) had katG mutations without inhA mutations, and two (0.5%) strains had mutations in both the inhA and katG genes. Of the 115 strains with any katG mutation, 114 (99.1%) had mutations in codon 315 (S315T). Of the 296 trains with any inhA mutation, 290 (98.0%) had a C–15T mutation. The proportion of isoniazid-resistant strains with katG mutations was 25.3% among new cases and 36.2% among retreatment cases (p=0.03), as well as 17.0% among rifampicin-susceptible strains and 52.8% among rifampicin-resistant strains (p<0.01). Rifampicin resistance was significantly associated with the katG mutation (adjusted odds ratio 5.36, 95% CI 3.3–8.67, p<0.001). Mutations in inhA predominated in isoniazid-resistant tuberculosis in Mongolia. However, the proportion of katG mutations in isolates from previously treated cases was higher than that among new cases, and that in cases with rifampicin resistance was higher than that in cases without rifampicin resistance.




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Emergence of Mycobacterium leprae rifampicin resistance evaluated by whole-genome sequencing after 48 years of irregular treatment [Epidemiology and Surveillance]

A case of M. leprae rifampicin resistance after irregular anti-leprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampicin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.




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A novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery [Antiviral Agents]

Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVBres) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVBres was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.




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The emergence of fexA in mediating resistance to florfenicols in Campylobacter [Mechanisms of Resistance]

Florfenicol belongs to a class of phenicol antimicrobials widely used as feed additives and for the treatment of respiratory infections. In recent years, increasing resistance to florfenicol has been reported in Campylobacter spp., the leading foodborne enteric pathogen causing diarrheal diseases worldwide. Here, we reported the identification of fexA, a novel mobile florfenicol resistance gene in Campylobacter. Of the 100 Campylobacter jejuni strains isolated from poultry in Zhejiang, China, nine of them were shown to be fexA positive, and their whole genome sequences were further determined by integration of Illumina short-read and MinION long-read sequencing. The fexA gene was found in the plasmid of one strain and chromosomes of eight strains, and its location was verified by S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting. Based on comparative analysis, the fexA gene was located within a region with the tet(L)-fexA-catA-tet(O) gene arrangement, demonstrated to be successfully transferrable among C. jejuni strains. Functional cloning indicated that acquisition of the single fexA gene significantly increased resistance to florfenicol, whereas its inactivation resulted in increased susceptibility to florfenicol in Campylobacter. Taken together, these results indicated that the emerging fexA resistance is horizontally transferable, which might greatly facilitate the adaptation of Campylobacter in food producing environments where florfenicols are frequently used.




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Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs [Susceptibility]

Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here we extended this study and included isolates with acquired fluconazole resistance.

Isolates (n=835) were identified using CHROMagar, MALDI-TOF and, when needed, ITS-sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole and voriconazole. Manogepix wildtype-upper-limit (WT-UL) values were established following EUCAST-principles for ECOFF setting allowing wildtype/non-wildtype classification. Drug-specific MIC correlations were investigated using Pearson's correlation.

Manogepix modal MICs were low (range 0.004-0.06 mg/L against 16/20 included species). Exceptions were C. krusei and C. inconspicua, and to a lesser extent C. kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot-spot alterations (n=17). Adopting the WT-UL established for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis, 14/724 (1.9%) isolates were non-wildtype for manogepix. Twelve of these (85.7%) were also non-wildtype for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis (Pearson r=0.401-0.575), but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r=0.519 for manogepix versus micafungin).

Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1-4 two-fold-dilution increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.




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Quercetin blocks Ebola Virus infection by counteracting the VP24 Interferon inhibitory function [Antiviral Agents]

Ebola Virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The 2013–2016 epidemics resulted in over 11000 deaths, while another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type-I Interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort of finding novel EBOV inhibitors, a screening of a small set of flavonoids was performed, showing that Quercetin and Wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, Quercetin, showing an IC50 value of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN genes transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, Quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.




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Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs [Antiviral Agents]

Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects.




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Influence of CYP2C8, CYP3A4 and CYP3A5 host genotypes on early recurrence of Plasmodium vivax [Mechanisms of Resistance]

CYP450 enzymes are involved in biotransformation of chloroquine (CQ), but the role of the different metabolism profiles of this drug has not been properly investigated in relation to P. vivax recurrences. To investigate the influence of CYPs genotypes associated with CQ-metabolism on early recurrence rates of P. vivax, a case-control study was carried out. Cases included patients presenting an early recurrence (CQ-recurrent), defined as recurrence during the first 28 days after initial infection, plasma concentrations of CQ plus desethylchloroquine (DCQ, the major CQ metabolite) higher than 100 ng/mL. A control (CQ-responsive) with no parasite recurrence over the follow-up was also included. CQ and DCQ plasma levels were measured on Day 28. CQ CYPs (CYP2C8, CYP3A4 and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify CQ and DCQ efficacy in P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and controls for CYP2C8 (OR=1.45, 95% CI=0.51-4.14, p=0.570), CYP3A4 (OR=2.38, 95% CI=0.92-6.19, p=0.105) and CYP3A5 (OR=4.17, 95% CI=0.79-22.04, p=1.038) genes. DCQ levels were higher than CQ, regardless of the genotype. Regarding the DCQ/CQ rate, there was no difference between groups or between those patients who had a normal or mutant genotype. DCQ and CQ showed similar efficacy ex vivo. CYPs genotypes had no influence on early recurrence rates. Similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite presence of alleles associated with slow metabolism.




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Comparative Genomic Analysis of Third Generation Cephalosporin-Resistant Escherichia coli Harboring blaCMY-2-Positive IncI1 group, IncB/O/K/Z, and IncC Plasmids Isolated from Healthy Broilers in Japan. [Epidemiology and Surveillance]

The off-label use of third generation cephalosporin (3GC) during in ovo vaccination or vaccination of newly hatched chicks, was a common practice worldwide. CMY-2-producing Escherichia coli have been disseminated among broiler production. The objectives of this study were to determine the epidemiological linkage of blaCMY-2-positive plasmids among broilers both within and outside Japan because grandparent stock and parent stock were imported in Japan. We examined the whole genome sequences of 132 3GC-resistant E. coli isolates collected from healthy broilers during 2002-2014. The predominant 3GC-resistance gene was blaCMY-2, which was detected in the plasmids of 87 (65.9%) isolates. The main plasmid replicon types were IncI1-I (n=21; 24.1%), IncI (n=12; 13.8%), IncB/O/K/Z (n=28; 32.2%), and IncC (n=22; 25.3%). Those plasmids were subjected to gene clustering and network analyses and plasmid multi-locus sequence typing (pMLST). The chromosomal DNA of isolates was subjected to MLST and single nucleotide variant (SNV)-based phylogenetic analysis.

MLST and SNV-based phylogenetic analysis revealed high diversity of E. coli isolates. ST429 harboring blaCMY-2-positive IncB/O/K/Z was closely related to isolates from broiler in Germany harboring blaCMY-2-positive IncB/O/K/Z. pST55-IncI and pST12-IncI1-I and pST3-IncC were prevalent in western Japan. pST12-IncI1-I and pST3-IncC were closely related to those detected in E. coli isolates from chicken in American continent, whereas 26 IncB/O/K/Z were related to those in Europe. These data will be useful to reveal the whole picture of transmission of CMY-2-producing bacteria in and out of Japan.




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Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages. [Susceptibility]

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.




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Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor Alisporivir (Debio 025) [Antiviral Agents]

Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC50 of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection.




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Antibiotic Use and Outcomes in Children in the Emergency Department With Suspected Pneumonia

BACKGROUND AND OBJECTIVES:

Antibiotic therapy is often prescribed for suspected community-acquired pneumonia (CAP) in children despite a lack of knowledge of causative pathogen. Our objective in this study was to investigate the association between antibiotic prescription and treatment failure in children with suspected CAP who are discharged from the hospital emergency department (ED).

METHODS:

We performed a prospective cohort study of children (ages 3 months–18 years) who were discharged from the ED with suspected CAP. The primary exposure was antibiotic receipt or prescription. The primary outcome was treatment failure (ie, hospitalization after being discharged from the ED, return visit with antibiotic initiation or change, or antibiotic change within 7–15 days from the ED visit). The secondary outcomes included parent-reported quality-of-life measures. Propensity score matching was used to limit potential bias attributable to treatment selection between children who did and did not receive an antibiotic prescription.

RESULTS:

Of 337 eligible children, 294 were matched on the basis of propensity score. There was no statistical difference in treatment failure between children who received antibiotics and those who did not (odds ratio 1.0; 95% confidence interval 0.45–2.2). There was no difference in the proportion of children with return visits with hospitalization (3.4% with antibiotics versus 3.4% without), initiation and/or change of antibiotics (4.8% vs 6.1%), or parent-reported quality-of-life measures.

CONCLUSIONS:

Among children with suspected CAP, the outcomes were not statistically different between those who did and did not receive an antibiotic prescription.




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Body Dissatisfaction and Mental Health Outcomes of Youth on Gender-Affirming Hormone Therapy

OBJECTIVES:

Our first aim was to examine baseline differences in body dissatisfaction, depression, and anxiety symptoms by gender, age, and Tanner (ie, pubertal) stage. Our second aim was to test for changes in youth symptoms over the first year of receiving gender-affirming hormone therapy. Our third aim was to examine potential differences in change over time by demographic and treatment characteristics. Youth experiences of suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) are also reported.

METHODS:

Participants (n = 148; ages 9–18 years; mean age 14.9 years) were receiving gender-affirming hormone therapy at a multidisciplinary program in Dallas, Texas (n = 25 puberty suppression only; n = 123 feminizing or masculinizing hormone therapy). Participants completed surveys assessing body dissatisfaction (Body Image Scale), depression (Quick Inventory of Depressive Symptoms), and anxiety (Screen for Child Anxiety Related Emotional Disorders) at initial presentation to the clinic and at follow-up. Clinicians completed the Quick Inventory of Depressive Symptoms and collected information on youth experiences of suicidal ideation, suicide attempt, and NSSI.

RESULTS:

Affirmed males reported greater depression and anxiety at baseline, but these differences were small (P < .01). Youth reported large improvements in body dissatisfaction (P < .001), small to moderate improvements in self-report of depressive symptoms (P < .001), and small improvements in total anxiety symptoms (P < .01). No demographic or treatment-related characteristics were associated with change over time. Lifetime and follow-up rates were 81% and 39% for suicidal ideation, 16% and 4% for suicide attempt, and 52% and 18% for NSSI, respectively.

CONCLUSIONS:

Results provide further evidence of the critical role of gender-affirming hormone therapy in reducing body dissatisfaction. Modest initial improvements in mental health were also evident.




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Trends in Regionalization of Emergency Care for Common Pediatric Conditions

BACKGROUND:

For children who cannot be discharged from the emergency department, definitive care has become less frequent at most hospitals. It is uncertain whether this is true for common conditions that do not require specialty care. We sought to determine how the likelihood of definitive care has changed for 3 common pediatric conditions: asthma, croup, and gastroenteritis.

METHODS:

We used the Nationwide Emergency Department Sample database to study children <18 years old presenting to emergency departments in the United States from 2008 to 2016 with a primary diagnosis of asthma, croup, or gastroenteritis, excluding critically ill patients. The primary outcome was referral rate: the number of patients transferred among all patients who could not be discharged. Analyses were stratified by quartile of annual pediatric volume. We used logistic regression to determine if changes over time in demographics or comorbidities could account for referral rate changes.

RESULTS:

Referral rates increased for each condition in all volume quartiles. Referral rates were greatest in the lowest pediatric volume quartile. Referral rates in the lowest pediatric volume quartile increased for asthma (13.6% per year; 95% confidence interval [CI] 5.6%–22.2%), croup (14.8% per year; 95% CI 2.6%–28.3%), and gastroenteritis (16.4% per year; 95% CI 3.5%–31.0%). Changes over time in patient age, sex, comorbidities, weekend presentation, payer mix, urban-rural location of presentation, or area income did not account for these findings.

CONCLUSIONS:

Increasing referral rates over time suggest decreasing provision of definitive care and regionalization of inpatient care for 3 common, generally straightforward conditions.




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Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia

BACKGROUND:

Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ~27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables.

METHODS:

We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule (n = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 (n = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots.

RESULTS:

With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities.

CONCLUSIONS:

In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model’s ability to predict mortality in a population of patients with prenatally diagnosed CDH.




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Transgender Youth Experiences and Perspectives Related to HIV Preventive Services

BACKGROUND:

In the United States, transgender youth are at especially high risk for HIV infection. Literature regarding HIV prevention strategies for this vulnerable, often-hidden population is scant. Before effective, population-based HIV prevention strategies may be adequately developed, it is necessary to first enhance the contextual understanding of transgender youth HIV risk and experiences with HIV preventive services.

METHODS:

Two 3-day, online, asynchronous focus groups were conducted with transgender youth from across the United States to better understand participant HIV risk and experiences with HIV preventive services. Participants were recruited by using online advertisements posted via youth organizations. Qualitative data were analyzed by using content analysis.

RESULTS:

A total of 30 transgender youth participated. The average age was 18.6 years, and youth reported a wide range of gender identities (eg, 27% were transgender male, 17% were transgender female, and 27% used ≥1 term) and sexual orientations. Four themes emerged: (1) barriers to self-efficacy in sexual decision-making; (2) safety concerns, fear, and other challenges in forming romantic and/or sexual relationships; (3) need for support and education; and (4) desire for affirmative and culturally competent experiences and interactions (eg, home, school, and health care).

CONCLUSIONS:

Youth discussed experiences and perspectives related to their gender identities, sexual health education, and HIV preventive services. Findings should inform intervention development to improve support and/or services, including the following: (1) increasing provider knowledge and skills to provide gender-affirming care, (2) addressing barriers to services (eg, accessibility and affordability as well as stigma and discrimination), and (3) expanding sexual health education to be inclusive of all gender identities, sexual orientations, and definitions of sex and sexual activity.




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Could Artificial Intelligence Automate Student Note-Taking?

An AI-powered digital assistant to take notes for you? It’s already happening in the workplace, but classroom note taking could prove harder to automate.




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Hintzes commit $100,000 for emergency aid to students

Two of Penn State’s most generous supporters and prominent alumni leaders have made a new commitment to support students impacted by the COVID-19 crisis. Helen S. Hintz, 1960, and Edward “Ed” R. Hintz, 1959, have directed $100,000 to the Student Care and Advocacy Emergency Fund.




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Fossil Gen 5 Smartwatch

The Fossil Gen 5 Smartwatch features an attractive design and smooth performance, but its size isn't suitable for all wrists.




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Transgender Adolescent Suicide Behavior

Russell B. Toomey
Oct 1, 2018; 142:e20174218-e20174218
ARTICLES




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Mental Health of Transgender Children Who Are Supported in Their Identities

Kristina R. Olson
Mar 1, 2016; 137:e20153223-e20153223
ARTICLES




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Antibiotic Use and Outcomes in Children in the Emergency Department With Suspected Pneumonia

Matthew J. Lipshaw
Apr 1, 2020; 145:e20193138-e20193138
ARTICLES




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Groups seek injunction to stop Idaho transgender sports ban




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Volkswagen gives UEFA Futsal EURO 2018 wheels

The 55-vehicle Volkswagen fleet which will transport players and officials at UEFA Futsal EURO 2018 has been handed over to the tournament organisers.




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A Conservative Agenda for School Board Members

School boards are well positioned to push back against so much of the influences of the "progressive" left on our schools and our society, write Michael J. Petrilli and Chester E. Finn Jr.




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Kids React to First-Gen Apple iPod

"It's like a cinderblock," one seven-year-old said of Apple's original MP3 player.




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Education Groups Seek Over $200 Billion in New Coronavirus Emergency Aid

The two national teachers' unions and other prominent groups are seeking $175 billion for state K-12 budgets, $13 billion in dedicated aid for special education, and more to help schools deal with the coronavirus.




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In full: Partick Thistle criticise SPFL in scathing letter and hit out at 'agenda' accusations

Partick Thistle have released, in full, a letter sent by the club to SPFL chiefs following the news that league reconstruction has been scrapped - confirming the Jags' relegation.




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Choice, Vouchers and the Trump Education Agenda

Marc Tucker looks at what the world's top performers tell us about the school choice agenda likely to be pursued by President Trump and his Education Secretary nominee Betsy DeVos.




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Variation in Care of the Febrile Young Infant <90 Days in US Pediatric Emergency Departments

Paul L. Aronson
Oct 1, 2014; 134:667-677
ARTICLES




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Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP), A Randomized, Controlled Trial. I: Primary Outcomes

The STOP-ROP Multicenter Study Group
Feb 1, 2000; 105:295-310
ARTICLES




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Abnormal Pulmonary Outcomes in Premature Infants: Prediction From Oxygen Requirement in the Neonatal Period

Andrew T. Shennan
Oct 1, 1988; 82:527-532
ARTICLES




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Here's What Gen Z Teachers Around the World Want in Their Jobs

"This is a very values-oriented generation—they seek to work with purpose and passion, and without that, they'll leave," an education leader at Microsoft said about Generation Z teachers.




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Response: Blended Learning Is 'the Next Generation of Education'

Angel Cintron Jr., Connie Parham, Catlin Tucker, Sheri Edwards, Cheryl Costello, William J. Tolley and George Station explore what blended learning is and how it can be made most effective.




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Argentine archbishop proposes measures to open country's churches amid coronavirus pandemic

Denver Newsroom, Apr 21, 2020 / 03:15 pm (CNA).- An Argentine archbishop has proposed 13 measures that would aim to allow churches to reopen churches during the coronavirus pandemic while reducing the risk of contagion.

The proposal is an effort to balance safety and the need for Catholics to receive the Eucharist, Archbishop Víctor Fernández of La Plata said this week.

In response to the pandemic, Argentina has been under lockdown since March 20. According to John Hopkins University, there are 3,031 confirmed cases of COVID-19 with 145 deaths in the country.

Fernández said that although the Church is providing material sustenance to those hardest hit by the pandemic “when we think about sustaining the interior life of the faithful and encouraging its growth, we find ourselves in the serious difficulty of seeing them deprived of the Eucharist for a long time, and we can also foresee that this situation could last for several months.”

In a letter dated April 19 and addressed to the conference’s executive committee, the bishop said the Second Vatican Council teaches that “no Christian community is built up if it is not rooted and centered on the celebration of the Holy Eucharist,” and that Saint John Paul II emphasized that the Mass “rather than an obligation, should be felt as a requisite deeply inscribed in Christian existence.”

Fernández said the letter he sent puts together the suggestions of several bishops and that it is understandable “that many of the faithful are calling on us to find some way to make the Eucharist accessible again.”

“We tell them that they can experience other forms of prayer, and they do, but as Saint John Chrysostom has said “’You can also pray in your home, however, you cannot pray the same way you do in church where the brethren are gathered together.’”

Fernández noted that Pope Francis “teaches that God ‘in the culmination of the mystery of the Incarnation, chose to reach our intimate depths through a fragment of matter.’ It’s good that our faithful have learned that and so it’s not the same thing for them,” he said, adding that Catholics are eager “the food of the love that is the source of supernatural life.”

“It won’t be easy to prove that this situation is lasting too long, nor can we simply wait till the pandemic is completely over,” the prelate noted.

“We know that exposing yourself to infection is irresponsible especially because it involves exposing others to infection and indirectly could lead to a public health crisis that we don’t want to see in our country,” he said.

Aiming to send “a clear message to our People of God to show that we’re truly concerned and that we intend to take some steps that would allow us to resolve this situation as soon as possible,” without neglecting “the health concerns of the authorities” Fernández proposed a series of obligatory measures to celebrate the Eucharist publicly:
1) Keep a distance of two meters between people to the side, front and back. This will require removing or closing off half the pews in the church.
2) No more than two people per pew.
3) Once the pews are occupied in that manner, no more people are to be allowed to enter the church.
4) In the churches where there is usually a lot of people in attendance, the number of Masses should be increased so the faithful can spread themselves out over Saturday and Sunday at different times. Given the prevalence and closeness of churches this will not involve using transportation.
5) Mass should not be celebrated publicly at the most frequently visited shrines due to the difficulty of establishing appropriate controls.
6) There should be no line for communion, instead the Eucharistic ministers should go to the people positioned at the ends of the pews and place the Eucharist in the hand.
7) Every Eucharistic minister should wash his hands with soap before and after and apply alcohol gel.
8) The sign of peace and any physical contact should be omitted.
9) Mass should last no more than 40 minutes.
10) People should leave the church progressively, not all at once, and avoid greeting each other.
11) No intentions should be taken at Mass time, only those previously received by phone, mail or messages.
12) Those people who because of their age are prevented from attending may receive Communion at home.
13) The dispensation from the Sunday obligation should be temporarily maintained so that people who prefer to exercise extreme caution don’t feel obliged to attend.

The archbishop also pointed out in his letter that “if the economic impact has to be foreseen, it’s also appropriate to place a value on those things that provide consolation and strength to people during hard times.”

 

A version of this story was first published by ACI Prensa, CNA's Spanish-language news partner. It has been translated and adapted by CNA.




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Coronavirus: Priests in Peru fund oxygen plant to meet shortage

Lima, Peru, May 7, 2020 / 06:00 am (CNA).- Two priests in a rural area of Peru aimed to fight the coronavirus pandemic by finding a way to supply oxygen tanks, much needed for medical treatment, to their region.

The recent death of two doctors from coronavirus in Iquitos, Peru, underscored the hard-hit region’s shortage of medical equipment and medications. Both doctors died because of the lack of oxygen to treat them.

The Medical Corps of Hospital III of Iquitos and the Medical College of Peru said in a joint statement last month that there is a shortage of medications in the Loreto region, and its capital Iquitos is "one of the cities hardest hit by the infection."

“We don’t have medications” to treat coronavirus patients and “not enough oxygen tanks, pressure gauges and refilled tanks,” they reported.

One doctor was in intensive care at Loreto Regional Hospital and the other at a hospital under the country’s universal health insurance program, both in Iquitos, the Medical College of Peru said on social media.

Fr. Raymond Portelli, a parish pastor in Iquitos, along with the diocesan administrator of the Apostolic Vicariate of Iquitos, Fr. Miguel Fuertes, decided to start a fundraising campaign to acquire an oxygen plant for the city.

Portelli himself is a doctor caring for COVID-19 patients.

To purchase the machinery, they needed to raise about $118,000.

The city does have an oxygen plant, but it only produces between 100 and 160 tanks a day. The dean of the Medical College of Peru, Miguel Palacios, told local media that quantity is not enough and that current production would need to be tripled.

The priests’ campaign was launched the morning of May 3 on social media, and in less than a day, they had raised about $300,000.

Both priests thanked contributors, and said that thanks to the amount collected, a “high capacity” plant could be purchased for Iquitos.

Portelli added that Fuentes is currently in Lima coordinating with a specialist for the acquisition of the plant.

“Pray a lot that this work can be accomplished quickly. May God bless all who have contributed. We hope to continue to cover all the expenses,” he added.

  This story was first published by CNA's Spanish-language news partner, ACI Prensa. It has been translated and adapted by CNA.



 




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