bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 spike protein binding selectively accelerates substrate-specific catalytic activity of ACE2
Authors: Kiseleva Anna A , Troisi Elizabeth M , Hensley Scott E , Kohli Rahul M , Epstein Jonathan A
Published: March 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that has given rise to the devastating global pandemic. In most cases, SARS-CoV-2 infection results in the development of viral pneumonia and acute respiratory distress syndrome, known as ‘coronavirus disease 2019’ or COVID-19. Intriguingly, besides the respiratory tract, COVID-19 affects other organs and systems of the human body. COVID-19 patients with pre-existing cardiovascular disease have a higher risk of death, and SARS-CoV-2 infection itself may cause myocardial inflammation and injury. One possible explanation of such phenomena is the fact that SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) as the receptor required for viral entry. ACE2 is expressed in the cells of many organs, including the heart. ACE2 functions as a carboxypeptidase that can cleave several endogenous substrates, including angiotensin II, thus regulating blood pressure and vascular tone. It remains largely unknown if the SARS-CoV-2 infection alters the enzymatic properties of ACE2, thereby contributing to cardiovascular complications in patients with COVID-19. Here, we demonstrate that ACE2 cleavage of des-Arg9-bradykinin substrate analogue is markedly accelerated, while cleavage of angiotensin II analogue is minimally affected by the binding of spike protein. These findings may have implications for a better understanding of COVID-19 pathogenesis.
Chemical Burns from Secondary Exposure to Paraquat Through Mishandling Urine of a Patient with Toxic Exposure
Authors: Denise Holley-Harrison H , Cunningham David , Velamuri Sai R , Hickerson William L , Hill David M
Published: March 2021

Paraquat is used throughout the world as an herbicide due to its efficacy and relative safety with proper handling. Accidents and misuse still occur, leading to countries banning its use or employing extra safeguards and special handling certifications. Severe toxicity is primarily associated with ingestion, but skin exposure leads to corrosive injury to the dermis, occurs rapidly, and progresses for up to 24 h. Prolonged skin exposure or the presence of open wounds can lead to systemic absorption. This is the first known report of burn injury and treatment due to secondary exposure to the urine of a patient who had accidental ingestion of paraquat. A 50-year-old Caucasian male presented to the emergency room after accidental ingestion of eight ounces of Gramoxone extra (Paraquat 30% concentration). During the initial care of the patient, the bedside registered nurse was placing an indwelling foley catheter when her forearms were contaminated with urine while wearing basic personal protective equipment (gloves). The registered nurse noticed bullae to bilateral forearms a short time after exposure to the urine. She presented to the burn center for evaluation and treatment. Poison Control was contacted but was unable to offer advise due to a lack of supportive literature. The risk and effects of primary exposure to Paraquat is described throughout the literature and documented in Material Safety Data Sheets (MSDS), but data regarding risk and treatment of secondary exposure is lacking. This case will aid outreach efforts for the prevention and treatment of burn injuries from secondary exposure to paraquat.
Digital Integrity
Authors: Fiorella Giancarlo , Godart Charlotte , Waters Nick
Published: March 2021

Researchers working with digital evidence must be aware of its vulnerabilities if they hope to maximize its value for justice and accountability. In this paper, we highlight two important vulnerabilities: the impermanent nature of digital evidence, and its susceptibility to attack from online dis/misinformation campaigns. We argue that to overcome the challenge that the impermanent nature of digital evidence presents, researchers can implement rapid response archiving techniques that, while not as rigorous as protocols set out for the collection of evidence in legal cases, could leave them with digital breadcrumbs to aid with the recovery of deleted digital evidence. We further propose that researchers consider implementing a stance of radical transparency in the collection, synthesis, and presentation of digital evidence with the goal of fortifying it against dis/misinformation campaigns.
Two New Alternatives to the Conventional Arm-in-Cage Test for Assessing Topical Repellents
Authors: Moreno-Gómez Mara , Bueno-Marí Rubén , Carr B Thomas , Bowman Gary R , Faherty Genevieve W , Gobbi Carlota , Palm Julie M , Van Sloun Petra , Miranda Miguel Ángel
Published: March 2021

European guidelines for testing attractant and repellent efficacy (i.e., Product type 19 [PT19]) have been in revision since 2017. A key topic of discussion is the current approach to evaluating topical repellents. The European Chemical Agency has stated field testing should be avoided because of mosquito-borne disease risks. However, the most common laboratory method, the arm-in-cage (AIC) test, may limit the reliable extrapolation of lab results to field conditions. This study’s main goal was to assess alternative laboratory methods for evaluating topical mosquito repellents that use mosquito landing rates more representative of those in the field. The study took place at three European testing labs using 30 study participants per test and the mosquito, Aedes albopictus (Skuse, 1894, Diptera: Culicidae). In phase 1, a conventional AIC test and a sleeved AIC test were performed. Respectively, the arm area exposed was 600 and 100 cm2, and cage volume was 0.040 and 0.064 m3. Mosquito density was the same for both: 1 female/840 cm3. In phase 2, room-based testing (40 ± 5 mosquitoes in 25–30 m3) was used as a proxy for field testing. The mosquito repellent employed was 15% N,N-diethyl-m-toluamide in ethanol at two doses: 1 and 0.5 g/600 cm2. The protection times measured at each laboratory were analyzed both separately and together using nonparametric (Kruskal–Wallis) test. The two alternatives methods showed to be potential alternatives to the current AIC method recreated field mosquito landing rates and achieved reproducible protection times across laboratories.
Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
Authors: Dahlgren Malin , George Anthony M , Brueffer Christian , Gladchuk Sergii , Chen Yilun , Vallon-Christersson Johan , Hegardt Cecilia , Häkkinen Jari , Rydén Lisa , Malmberg Martin , Larsson Christer , Gruvberger-Saal Sofia K , Ehinger Anna , Loman Niklas , Borg Åke , Saal Lao H
Published: March 2021

Background

More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET.

Methods

We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses.

Results

We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors.

Conclusions

These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
#28: Serum Posaconazole Concentrations Among Children, Adolescents, and Young Adults Receiving Delayed-Release Tablet And Intravenous Posaconazole
Authors: Bernardo Valeria , Liverman Rochelle , Tippett Ashley , Yildirimb Inci
Published: March 2021

Background

Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal infections. There are limited data on the optimal dosing, safety, and effectiveness of the delayed-released tablets (DRT) and intravenous (IV) formulations in immunocompromised pediatric and adolescent patients.

Methods

A retrospective chart review was performed to study all immunocompromised patients who received DRT or IV formulations of posaconazole at our institution from January 1, 2014, to July 31, 2019, and had at least one plasma trough concentration. Plasma concentrations ≥0.7 µg /mL were considered therapeutic for prophylaxis, and ≥1.0 µg/mL for treatment. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability.

Results

We identified 54 patients (28 males/26 females) who received DRT or IV formulations of posaconazole. The median age was 14 years (range 2–21 years). Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. The most common underlying condition was hematological malignancies (66%) and 19 patients (35%) had received an allogeneic HSCT and were receiving immunosuppressive therapy. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL, IQR 0.758–1.760 µg/mL) (Figure). The median daily dose among patients <13 years of age who achieved the targeted initial plasma trough concentrations was 7.3 mg/kg/day (IQR 6.8–11.0) for the DRT formulation and 9.8 mg/kg/day (IQR 7.4–11.7) for the IV formulation. The median daily dose among patients ≥ 13 years of age who achieved the targeted initial plasma trough concentrations was 4.9 mg/kg/day (IQR 4.1–6.5) for the DRT formulation and 5.6 mg/kg/day (IQR 3.9–5.8) for the IV formulation. Concomitant use of H2-receptor blockers (H2RA) and/or proton pump inhibitors (PPI) medications were not associated with failure to achieve target trough levels (P = 0.96). Thirty-six patients (67%) developed transaminitis, mostly grade 1.

Conclusions

Our results show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. It appears that neither a PPI nor an H2RA has an effect on the plasma exposure of the DRT.
#62: Safety of Live Attenuated Vaccines Administered after Pediatric Liver Transplantation
Authors: Tao-Kidoguchi Chiaki , Funaki Takanori , Shoji Kensuke , Akinari Fukuda , Seisuke Sakamoto , Mureo Kasahara , Miyairi Isao
Published: March 2021

Background

Live attenuated vaccines (LAVs) are currently contraindicated in immunocompromised patients such as solid-organ transplant (SOT) recipients. The guideline published by the Infectious Disease Society of America also cautions that LAVs after SOT are contraindicated. However, several articles have demonstrated that these patients may receive LAVs safely by adhering to a protocol consisting of an evaluation of many immunological parameters. The aim of this study was to evaluate the safety of LAVs, including measles, mumps, rubella, and varicella to liver transplant (LT) recipients under our clinically based immunization protocol for LT recipients.

Methods

We conducted a retrospective cohort study on the safety of live attenuated vaccines (LAVs) for measles, rubella, varicella, and mumps to LT recipients at the National Center for Child Health and Development from July 2010 to July 2019. Patients who underwent LT at age under 20 years, who visited our outpatient clinic for vaccination were included. Our institutional protocol for vaccination is shown in Table. Patients’ demographics, underlying diseases, administered vaccines, number and date of vaccination, and adverse events were extracted from their medical records. Adverse events occurring within 4 weeks after vaccination were collected and classified into 4 stages based on severity.

Results

During the study period, there were 1,904 outpatient clinic visits by 361 patients. Of these, multiple vaccines (median: 2, range: 1–7) including inactivated vaccines and LAVs were simultaneously administered during the 1,213 visits (64%). LAVs were administered to 422 times (209 patients) who met the criteria and included 225 doses of measles and rubella combination vaccine, 224 doses of varicella vaccine, and 215 doses of mumps vaccine. Underlying diseases included cholestatic liver disease (n = 125), followed by metabolic disease (n = 33), acute liver failure (n = 19). Eleven mild adverse events (2.6%) possibly associated with LAVs were reported, but there were no serious adverse events, including vaccine-strain infection, hospitalization, and death.

Conclusion

LAVs administration for LT recipients were safe without any serious adverse events under our relatively simplistic institutional protocol. However, further research is needed to closely monitor the efficacy and safety of LAVs to LT recipients.
#78: Use of Isavuconazonium for Treatment Of Invasive Fungal Infection in Immunocompromised Pediatric Patients
Authors: Mohandas Sindhu , Mongkolrattanothai Kanokporn , Stach Leslie , Orbach Regina , Neely Michael
Published: March 2021

Background

Isavuconazole (ISZ), dosed as the pre-drug isavuconazonium (ISM), is active against a wide variety of clinically important fungal pathogens. ISM is approved for the treatment of invasive aspergillosis and mucormycosis in adults ≥18 years of age. We present our experience with ISM to treat proven or probable fungal infection in immunocompromised pediatric patients.

Methods

Retrospective review of patients who received ISM at our institution between April 2016 and April 2019, we abstracted demographic information, primary diagnosis, indication for ISM therapy, ISZ serum concentrations if available, and outcomes.

Results

Of 14 patients who received ISM, 11 were ≤18 years of age (range 6–18 years). Underlying conditions included leukemia (n = 7), lymphoma (n = 1), post BMT (n = 1), diabetes (n = 1), and cardiac transplant (n = 1). Nine (82%) had proven invasive fungal infection (IFI) with aspergillosis (n = 2), zygomycosis (n = 3), mixed aspergillosis and zygomycosis (n = 2), mixed Rhizopus and Scedosporium (n = 1), and pathology only (n = 1) and 2 had probable IFI. Five of these 11 patients received combination ISM and liposomal amphotericin initially and the other 6 received liposomal amphotericin with or without other azoles prior to changing to ISM monotherapy. This was followed by monotherapy with ISM in 10 patients after a mean of 26 days (range 6–63) and continued dual therapy in the one. ISM dosing was 10 mg/kg q8h on days 1 and 2, followed by q24 thereafter, up to a maximum of 372 mg/dose. There were 19 measured ISZ serum concentrations obtained from 8 patients after >1 week of verified inpatient dosing, ranging from 1.0 to 7.5 mg/L, above the MIC in all cases when known. Three (27%) patients died of underlying non-mycological causes, 1 (9%) died of progressive scedosporiosis, and 7 (64%) improved. ISM was well tolerated with no dose-limiting, drug-related toxicities noted.

Conclusions

ISM is a well-tolerated therapeutic option in pediatric patients at risk for or with invasive mycosis. Only 1 of our 11 patients died from progressive fungal disease.
#77: Impact of Targeted Tacrolimus Levels on BK Polyomavirus DNAemia Among Pediatric Kidney Transplant Recipients
Authors: Yildirim I , Liverman R , Serluco S , George R , Garro R , Winterberg P
Published: March 2021

Background

Uncontrolled BK Polyomavirus (BK) DNAemia in kidney transplant recipients is a significant cause of allograft dysfunction that can lead to BK Polyomavirus-associated nephropathy with permanent damage and graft loss. BK virus DNAemia can occur early (within the first year) or late (after the first year) following a kidney transplant in children. Prospective monitoring for BK viremia with pre-emptive lowering of immunosuppression has been suggested as an effective approach to prevent BK nephropathy. We evaluated the impact of changes in targeted tacrolimus levels on the incidence of BK DNAemia early post-transplant.

Methods

In response to a cluster of early-onset BK virus DNAemia cases in the first quarter of 2015, we pursued a quality improvement study to determine whether changes to tacrolimus trough targets for the first 100 days post-transplant would reduce the incidence and severity of BK DNAemia. Targeted tacrolimus levels were decreased by approximately 25% (see Table) and patients receiving transplant from March 20, 2015, and December 31, 2018, were prospectively monitored. The incidence rates of BK DNAemia detected on monthly surveillance testing in the first-year post-transplant were compared for patients transplanted between January 1, 2013, and March 14, 2015 (pre-intervention) and March 15, 2015, to December 31, 2018 (post-intervention).

Results

Of 148 children who received kidney transplants during the study period, 52 (35%) were transplanted in the pre-intervention era and 96(65%) were transplanted during the post-intervention era. The median age at transplant was 13.9 years [interquartile range (IQR) 8.0–16.7 years]. Age at transplant, gender (overall 55% male), and race (overall 54% White, 35% Black) was not significantly different between the cohorts. The risk of early-onset BK DNAemia within the first 100 days post-transplant was 19 per 100 patients in the pre-intervention cohort and 13 per 100 patients in the post-intervention cohort, corresponding to a 35% reduction after lowering targeted tacrolimus levels. The median time to first detected BK DNAemia increased from 77 days (IQR 45–90 days) in pre-intervention to 104 days (IQR 47–174 days) in the post-intervention cohort.

Conclusions

BK DNAemia heralds a serious complication of kidney transplantation and may represent over immunosuppression and increased risk for other infectious complications. We were able to reduce the rate of early-onset BK DNAemia by reducing tacrolimus target levels in the first 12 weeks post-transplant. Preventing early uncontrolled viremia may decrease the need for immunosuppression reduction which increases the risk for rejection.
#24: Death is Antibiotic-Microbiota Dependent in a Humanized Mouse Model of Late-Onset Neonatal Sepsis
Authors: Schwartz D , D’Souza A , Crofts T , Ning J , Shalon N , Robinson J , Henderson J , Warner B , Tarr P , Dantas G
Published: March 2021

Background

Premature infants receive antibiotics frequently for culture-negative sepsis, which diminishes gut microbial diversity and increases susceptibility to infections by antibiotic-resistant pathogens. Neonates with decreased gut microbiota diversity, termed dysbiotic, have dysregulated immune systems marked by increased concentrations of circulating activated T cells and decreased concentrations of circulating neutrophils and dendritic cells. We hypothesize that antibiotics (1) enrich for pathobionts within the gut, (2) promote a systemic, proinflammatory host response, and (3) cause death in an antibiotic specific manner in a gnotobiotic model of preterm gut microbiota development.

Methods

We colonized germ-free (GF) dams and sires with stools from preterm infants. Mouse pups acquire this neonatal microbiota, and at 10 days of life (DOL), we treat them with clinically relevant doses of antibiotics subcutaneously for 3 days. We use metagenomic shotgun sequencing of individual pup fecal samples longitudinally to ascertain phylogenetic composition, and use flow cytometry and multiplex cytokine arrays to determine the local and peripheral immune response.

Results

Using two representative microbiota from human neonates (hereafter referred to as microbiota A or B), we show that 94% of pups given microbiota A survive vs. 64% given microbiota B after meropenem/probenecid treatment (Figure 1; P < 0.05; n = 18–28 mice in > independent experiments). 40% of pups given microbiota A treated with ampicillin/gentamicin/probenecid survived (Figure 1; P < 0.01 relative to meropenem/probenecid or probenecid). Klebsiella species dominated the gut microbiota of microbiota A-humanized pups who succumbed and were found in the lung, liver, and spleen of one animal at necropsy. Enterococci dominated the gut microbiota of microbiota B-humanized pups who died during treatment. Pups colonized with microbiota B had increased peripheral CD4+ T cells at sacrifice after treatment compared with microbiota A-humanized pups (61% vs. 44% of circulating T cells, P < 0.0005).

Conclusions

Our model of preterm microbiota development and perturbation by antibiotics demonstrates potential bacterial translocation, proinflammatory immune response, and death dependent on the microbiota–antibiotic combination. Our transgenerational humanized-microbiota mouse model can be utilized to determine antibiotic by microbiota perturbation and examine risks of late-onset sepsis from antimicrobials.
#64: An odyssey Beyond the Capsule: Genetic Determinants of Pediatric Invasive Streptococcus pneumoniae Empyema
Authors: Pershing Nicole L , Kapusta Aurélie , Nielsen Shannon , Crandall Hillary , Korgenski E Kent , Byington Carrie L , Ampofo Krow , Blaschke Anne J
Published: March 2021

Background

Streptococcus pneumoniae is among the most common causes of invasive bacterial infections in children, including pneumonia, bacteremia, and meningitis. Over 90 different serotypes (ST) of pneumococcus exist, with enrichment of some ST within specific invasive phenotypes. Other than capsular genes, molecular determinants of particular invasive phenotypes remain largely unknown. Although vaccination targeting especially invasive ST capsular antigens has successfully decreased the incidence of invasive pneumococcal disease (IPD), new ST have emerged, suggesting methods to target other aspects of pneumococcal invasiveness are needed.

Methods

Pneumococcal isolates from IPD were collected from children presenting to Primary Children’s Hospital from 1996–2018. All viable isolates underwent next-generation sequencing (Illumina), quality control filtering for contamination and low coverage, de novo genome assembly with SPADES, and annotation with PROKKA. Clinical phenotypes were manually validated with physician chart review. Isolates were serotyped via Quelling and in silico using SeroBA. ROARY was used for pan-genome assembly, and SCOARY for microbial genome-wide association studies. RAxML was used for phylogenetic analysis.

Results

A total of 354 viable pneumococcal isolates were available for genomic analysis including a spectrum of invasive phenotypes: pneumonia (n = 138, of which 54 were complicated by empyema), CNS infection (n = 50), SSTI/bone infections (n = 42), and isolated bacteremia (n = 68). Thirteen samples were censored for poor coverage or genetic contamination. Invasive isolates spanned 37 capsular ST. The pneumococcal pan-genome comprised 6462 genes, of which only 23% were shared by at least 99% of samples. Phylogenetic relatedness resulted in clustering of some ST (e.g., ST1, ST3), whereas others (eg ST19A) were more broadly distributed. Empyema and meningitis phenotypes were distributed across the phylogenetic tree, but enriched in distinct clusters that crossed ST clusters. Genes involved in empyemagenic pneumococcal capsule production, and those implicated in sensing of preferred sugars or non-preferred sugar metabolism were statistically correlated with the empyema phenotype.

Conclusion

There is marked genetic diversity among invasive pneumococcal isolates, potentially contributing to the variability of disease phenotypes observed. Clustering of invasive phenotypes across ST suggests a genetic signature for invasive phenotypes other than capsule genes alone, further supported by enrichment of specific genes associated with alternative sugar metabolism in empyema isolates. Critical determinants of invasive phenotypes will inform future efforts at disease prevention and treatment.
#91: Human Antibodies Neutralize Enterovirus D68 and Protect Against Infection and Paralytic Disease
Authors: Vogt Matthew R , Kose Nurgun , Williamson Lauren E , Bochkov Yury A , Gern James E , Crowe James E
Published: March 2021

Background

Enterovirus D68 (EV-D68) causes worldwide outbreaks of human respiratory illness with spatiotemporally related outbreaks of acute flaccid myelitis (AFM). The major circulating clade of EV-D68 has changed since the largest ever recorded outbreak, which occurred in the United States in 2014. Numerous seroepidemiology studies show that essentially all adult humans have EV-D68-neutralizing antibodies in their serum, even in serum collected prior to large outbreaks. But some studies show a lack of neutralizing antibodies in pediatric populations. We sought to isolate human monoclonal antibodies (mAbs) from B cells in peripheral blood mononuclear cells (PBMCs) of immune subjects, induced by natural infection, to further understand human humoral immunity to EV-D68.

Methods

We obtained PBMCs from donors with known infection during 2014. We used EV-D68 virus isolates from this outbreak as antigen in an indirect ELISA to screen immortalized PBMCs for antigen-specificity, then fused B cells with myeloma cells to create hybridomas.

Results

We isolated >60 naturally occurring anti-EV-D68 human mAbs. These mAbs exhibit diverse binding affinities when compared across clades of recent EV-D68 isolates. Many mAbs neutralize EV-D68 quite potently in vitro, with [ng/mL] half-maximal effective concentrations. Some mAbs like EV68-228 neutralize diverse clades, whereas others are highly clade-specific. Binding of antibodies to at least three, but likely more, major antigenic sites on the virus leads to neutralization. When given as either prophylaxis before or treatment after EV-D68 inoculation, mAb EV68-228 protects mice from both respiratory and neurologic disease, whereas equivalent doses of polyclonal human immunoglobulin protect only partially.

Conclusions

We observed a qualitative difference among antibodies isolated from patients who had a history of natural infection. These differences could contribute to certain individuals being susceptible to respiratory disease and AFM. These studies of humoral immunity are especially important for a disease with nearly universal apparent seroprotection, in which the virus somehow persistently causes outbreaks across the world. Furthermore, no licensed vaccines or treatments exist for EV-D68. These mAbs have therapeutic benefit in vivo and show promise for the prevention and/or treatment of EV-D68-related diseases in humans. We are pursuing the use of mAb EV68-228 in humans with partners in industry and government agencies.
#80: Developing and Implementing an Infectious Diseases Training Seminar for Global Healthcare Providers for Children with Cancer
Authors: Caniza M , Homsi M , Rodriguez-Galindo C
Published: March 2021

Background

Well-trained and dedicated personnel for infection care and prevention is essential for optimal care in pediatric oncology centers. Feedback from global collaborators consistently identifies education and training as a priority. We collaboratively designed and implemented a blended methodology training course focused on four essential themes: infectious complications in pediatric cancer; quality in infection care; quality in infection prevention; and, sustainability, research, and dissemination.

Methods

Using our team’s subject matter expertise and experience developing training materials, we designed the training seminar comprising two components: (1) an 8-week distance-learning segment delivered online through our free, education website (www.Cure4Kids.org) which focuses on building foundational knowledge in the identified essential themes of infection diseases; and, (2) a 2-week residential training seminar delivered face-to-face at St. Jude Children’s Hospital, which consolidates training through interactive lectures, workshops, clinical and research area tours, and research project presentations.

Results

The initial launch in 2017 trained 22 healthcare providers from 17 healthcare institutions in 10 countries. Knowledge gain from pretest to posttest for each module was significant (P < 0.001). Satisfaction with course delivery was high; most participants (93–100%) found each module’s content relevant to their daily practice. For residential training, participants rated each day as either good (median: 10%; range: 5–25%) or outstanding (median: 90%; range: 75–95%). Individual research projects developed by course participants focused on bloodstream infections, febrile neutropenia, multi-drug-resistant organisms, fungal infections, hand hygiene, antibiotic prophylaxis, and infection prevention. After the course conclusion, nearly half (n = 9) implemented their project idea in their clinical practice or prepared it for submission as academic merit or to a scientific conference. Now in its fourth year, the course has also incorporated training in leadership and quality. As of December 2019, this Infectious Diseases Training Seminar has trained 145 participants from 102 institutions in 48 countries. Graduates of the course formed two professional networks, one in Latin America and another in the Asia Pacific region. Members of the network participate in local capacity building, research, quality improvement, and education in infection care and prevention.

Conclusions

The course has and continues to meet the verbalized need for education and training opportunities in infection care and prevention for the pediatric cancer patient population. Our experience models how targeted training efforts can strengthen the quality of the healthcare workforce for improving outcomes in pediatric cancer care globally.
#71: Single-cell RNA Sequencing Analysis of Zika Virus Infection in Human Stem Cell-Derived Neuroprogenitor Cells and Cerebral Organoids
Authors: Ocwieja K E , Hughes T K , Antonucci J M , Richards A L , Stanton A C , Shalek A , Jaenisch R , Gehrke L
Published: March 2021

Background

The molecular mechanisms underpinning the neurologic and congenital pathologies caused by Zika virus (ZIKV) infection remain poorly understood. It is also unclear why congenital ZIKV disease was not observed prior to the recent epidemics in French Polynesia and the Americas, despite evidence that the Zika virus has actively circulated in parts of Africa and Asia since 1947 and 1966, respectively.

Methods

Due to advances in stem cell-based technologies, we can now model ZIKV infections of the central nervous system in human stem cell-derived neuroprogenitor cells and cerebral organoids, which recapitulate complex three-dimensional neural architecture. We apply Seq-Well—a simple, portable platform for massively parallel single-cell RNA sequencing—to characterize these neural models infected with ZIKV. We detect and quantify host mRNA transcripts and viral RNA with single-cell resolution, thereby defining transcriptional features of both uninfected and infected cells.

Results

In neuroprogenitor cells, single-cell sequencing reveals that while uninfected bystander cells strongly upregulate interferon pathway genes, these are largely suppressed in cells infected with ZIKV within the same culture dish. In our organoid model, single-cell sequencing allows us to identify multiple cellular populations, including neuroprogenitor cells, intermediate progenitor cells, and terminally differentiated neurons. In this model of the developing brain, we identify preferred tropisms of ZIKV infection. Our data additionally reveal differences in cell-type frequencies and gene expression within organoids infected by historic and contemporary ZIKV strains from a variety of geographic locations.

Conclusions

These findings may help explain phenotypic differences attributed to the viruses, including variable propensities to cause microcephaly. Overall, our work provides insight into normal and diseased human brain development and suggests that both virus replication and host response mechanisms underlie the neuropathology of ZIKV infection.
#72: Implementing an Algorithm-based Approach for Treatment of Fever and Neutropenia in Pediatric Oncology Patients in Tegucigalpa, Honduras
Authors: Ordóñez Sara , Luque Marco , Zacasa Pamela , Fu Ligia , Peña Armando , Caniza Miguela , Mukkada Sheena
Published: March 2021

Background

Fever and neutropenia (FN) is a frequent complication in pediatric oncology patients, especially in high-risk patients. In our institution, 43% of acute lymphoblastic leukemia (ALL) patients in induction have at least one hospitalization for FN. A lack of institutional guidelines has led to misuse of antibiotics, prolonged antibiotic wait time and hospitalizations, and unnecessary venipunctures, among others. Implementing an algorithm has provided us with a baseline of previous FN management, and has led to an improvement in management as a whole and to critical areas such as lowering antibiotic wait time in these patients.

Methods

Throughout 2017 we created and revised an algorithm for the management of FN based on current international FN guidelines and, tailored to our specific setting and needs. Orientation began 2 months prior to implementation, with intense training of residents, attendings, and nursing staff one month prior, and for the first 2 months of implementation. Active surveillance of adherence and outcomes, plus periodic retraining has been done throughout implementation. Adherence measurements include antibiotic wait time, use of antibiotics according to risk stratification, number of algorithm deviations, and collection of blood cultures.

Results

Seventy-four patients met inclusion criteria from May 2018 to April 2019. Results were compared between early implementation, (first 3 months: group 1), to the remaining 9 months of the first year (group 2). Time to initial evaluation decreased by 75%, from 76.8 minutes in group 1 to 20.6 minutes in group 2 (P < 0.05). Antibiotic wait time decreased by 54.9%, from 5.18 hours to 2.3 hours (P = 0.0074). Time to blood culture was reduced by 65.3%, from 248 minutes to 85 minutes (P = 0.0040). Incorrect use of antibiotics according to risk stratification decreased by 59.2%, from 42% in group 1 to 17% in group 2 (P = 0.10). Total number of deviations decreased from 1.39 per patient to 1.17 per patient (P = 0.22; Table 1).

Conclusions

Through initial and periodical training and active surveillance, key targets for adherence showed significant improvement throughout the first year of implementation. Maintaining communication with providers through monthly reports of audits, discussions of cases, and retraining improved awareness and willingness to adhere to protocol. Implementation has been particularly useful to residents and attendings outside of the Oncology Ward, where 49% of FN patients in our hospital are treated. It has provided standardized management, improved detection of cases, and reduced delays in care.
#20: Bloodstream Infections in Pediatric Hematology/Oncology Patients: 3 Years’ Experience of a Specialty Pediatrics Hospital in Tuxtla Gutierrez Chiapas. Mexico
Authors: Nava Ruiz E A , Feliciano M , López Argüello C , Caniza M
Published: March 2021

Background

Bloodstream infections are the major cause of morbidity, increased cost, prolonged hospitalization, and mortality in pediatric patients. During treatment, cancer patients require a central vascular access; however, central venous catheters are an important source of bloodstream infections. Rigorous infection control measures and continuous surveillance are required to curb the frequency of these infections.

Objective

We aimed to identify the causative microorganisms in patients with central line–associated bloodstream infection (CLABSI) in hematology-oncology pediatric patients.

Material and Methods

All pediatric hematology-oncology patients with CLABSI of Specialty Pediatrics Hospital between January 2016 and September 2019 were reviewed. We defined CLABSI according to the Centers of Disease Control and Prevention definition. Demographic data and microbiologic isolation were analyzed.

Results

Seventy-five cases of CLABSI in 432 patients (mean age 9.5 years) were reported. The incidence of CLABSI was 0.9/1000 catheter-days (80,232 total catheter-days). Patients with acute lymphoblastic leukemia had the highest infection density 2.5 /1000 patients-day. Coagulase-negative staphylococci was isolated in 38.5% (30/75) of significant blood culture (CoNS 38.5%); P. aeruginosa in 18.6% (14/75); K. pneumoniae in 10.6% (3/75); E. coli in 6.6% (5/75); and Candida tropicalis in 5.3%(4/75) of cases. Enterobacteriaceae were broad-spectrum betalactamase producers; P. aeruginosa was susceptible to antibiotics betalactamics with antipseudomonal action and Candida spp. was susceptible to azoles. We did not use lock antibiotic therapy and all the catheters were removed once CLABSI was diagnosed. Empiric antibiotic treatment in CLABSI in Specialty Pediatrics Hospital based on these findings includes ceftazidime plus vancomycin.

Conclusions

CoNS and P. aeruginosa are the predominant pathogens in CLABSI among pediatric hematology-oncology patient. Antibiotic susceptibility profile has no change during the period of time analyzed, so empiric therapy remains appropriate.
#83: Leukocytes and C-Reactive Protein Levels in Children with Influenza-positive and Influenza-negative Viral Pneumonia in a Third-level Pediatric Center in Mexico City from 2011 to 2016
Authors: Cristerna Tarrasa G H , González Saldaña N , Hernández Porras M , Fortes Gutiérrez S
Published: March 2021

Background

Influenza has been a major source of morbidity and mortality worldwide. Children are one of the most susceptible groups for severe influenza. Clinical differentiation between viral and bacterial pneumonia is difficult to assess in children, so the aid of the complete blood count (CBC) and C-reactive protein (CRP) are used to differentiate between them. However, differential diagnosis between influenza-positive and -negative viral pneumonia is difficult. CRP levels have been found to be higher in H1N1 influenza adult patients. However, there are no studies regarding CBC, and CRP levels in pediatric patients with influenza-positive and -negative pneumonia.

Methods

From 2011 to 2016, we found children less than 18 years old with viral pneumonia who had positive viral RT–PCR test for adenovirus, bocavirus, influenza, parainfluenza, metapneumovirus, rhinovirus, coronavirus or respiratory syncytial virus (RSV). Means for white blood cells (WBC), neutrophils, lymphocytes and CRP were calculated. Comparisons between influenza and other respiratory viral pneumonia WBC and CRP means were made. Student’s t-test was used for statistical analysis.

Results

We analyzed 183 patients with positive viral pneumonia cases; of which, 37 (20.2%) had two viruses detected. Mean age was 1 year old and 56.5% were male. Viral detections were rhinovirus 75 (40.9%), RSV 45 (24.5%), influenza 31 (16.9%), metapneumovirus 30 (16.3%), bocavirus 20 (10.9%), parainfluenza 14 (7.6%), coronavirus 3 (1.6%) and adenovirus 2 (1.1%). Mean influenza WBC were 10,900 ± 2040/μL, neutrophils were 6998 ± 1510/μL, lymphocytes 2882 ± 826/μL and CRP 5.41 ± 1.9 mg/dL. Mean influenza negative, viral-positive pneumonia were WBC 12227 ± 868/μL, neutrophils 6787 ± 696/μL, lymphocytes 4469 ± 426/μL, CRP 2.81 ± 0.56 mg/dL. Lower lymphocyte counts (P = 0.002) and higher CRP levels (P = 0.019) were found in patients with influenza comparing them with pneumonia caused by other viruses.

Conclusions

In our study, children with positive influenza pneumonia showed lower levels of lymphocytes and higher levels of CRP compared with negative influenza. Lower lymphocyte counts and high CRP levels have been found in influenza-positive patients mainly in adult studies. In children with suspected influenza pneumonia, lower lymphocyte counts and higher CRP levels can aid clinical diagnosis before molecular confirmation in influenza pneumonia.
The Anxious Elementary School Child
Authors: Kearney Christopher A.
Published: March 2021

This chapter provides an overview of anxious elementary schoolchildren who have difficulty attending school due to substantial distress while there. The chapter focuses on understanding the feeling, thinking, and doing parts of distress; easing physical feelings of distress through better breathing and relaxation; dealing with the thinking part of distress or when a child says he does not want to go to school; and managing the doing part of distress by gradually reintroducing a child to school and increasing his time in the classroom. The chapter is designed to educate parents about these parts of distress and presents strategies for addressing each one. These strategies include breathing retraining and muscle relaxation training and gradual exposure to the school setting. The chapter also covers special topics and circumstances that are common to this type of situation.
The Anxious Middle/High School Adolescent
Authors: Kearney Christopher A.
Published: March 2021

This chapter provides an overview of anxious middle/high school adolescents who have difficulty attending school due to substantial anxiety in social and performance situations. The chapter focuses on understanding the feeling, thinking, and doing parts of distress, easing physical feelings of distress through better breathing and relaxation, dealing with the thinking part of distress, and managing the doing part of distress by gradually reintroducing a child to school and increasing his time in the classroom. The chapter is designed to educate parents about these parts of distress and presents strategies for addressing each one. These strategies emphasize cognitive strategies to replace distressing thoughts with more realistic thoughts. The chapter also covers special topics and circumstances that are common to this type of situation.
The Impacts of Unrecognized Language and Cultural Barriers During an Educational and Training Activity
Authors: Owens Michael D , Nzumba Franck A
Published: March 2021

Language and cultural barriers are associated with poor health outcomes. Communication is arguably the most important variable associated with a successful educational and training Global Health Engagement (GHE) and often unrecognized even when attempts are made to address this barrier. Madagascar’s GHE activity improved after the addition of local Malagasy translation to fully translated official French instruction.
Extreme emission-line galaxies in SDSS – I. Empirical and model-based calibrations of chemical abundances
Authors: Pérez-Montero E , Amorín R , Sánchez Almeida J , Vílchez J M , García-Benito R , Kehrig C
Published: March 2021

Local star-forming galaxies show properties that are thought to differ from galaxies in the early Universe. Among them, the ionizing stellar populations and the gas geometry make the recipes designed to derive chemical abundances from nebular emission lines to differ from those calibrated in the Local Universe. A sample of 1969 extreme emission-line galaxies (EELGs) at a redshift 0 ≲ z ≲ 0.49, selected from the Sloan Digital Sky Survey (SDSS) to be local analogues of high-redshift galaxies, was used to analyse their most prominent emission lines and to derive total oxygen abundances and nitrogen-to-oxygen ratios following the direct method in the ranges 7.7 < 12 + log(O/H) < 8.6 and –1.8 < log(N/O) < –0.8. They allow us to obtain new empirically calibrated strong-line methods and to evaluate other recipes based on photoionization models that can be later used for a chemical analysis of actively star-forming galaxies in very early stages of galaxy evolution. Our new relations are in agreement with others found for smaller samples of objects at higher redshifts. When compared with other relations calibrated in the local Universe, they differ when the employed strong-line ratio depends on the hardness of the ionizing radiation, such as O32 or Ne3O2, but they do not when the main dependence is on the ionization parameter, such as S23. In the case of strong-line ratios depending on [N ii] lines, the derivation of O/H becomes very uncertain due to the very high N/O values derived in this sample, above all in the low-metallicity regime. Finally, we adapt the Bayesian-like code H ii-chi-mistry for the conditions found in this kind of galaxies and we prove that it can be used to derive within errors both O/H and N/O, in consistency with the direct method.
Characterizing the abundance, properties, and kinematics of the cool circumgalactic medium of galaxies in absorption with SDSS DR16
Authors: Anand Abhijeet , Nelson Dylan , Kauffmann Guinevere
Published: March 2021

In order to study the circumgalactic medium (CGM) of galaxies we develop an automated pipeline to estimate the optical continuum of quasars and detect intervening metal absorption line systems with a matched kernel convolution technique and adaptive S/N criteria. We process ∼ one million quasars in the latest Data Release 16 (DR16) of the Sloan Digital Sky Survey (SDSS) and compile a large sample of ∼ 160 000 Mg ii absorbers, together with ∼ 70 000 Fe ii systems, in the redshift range 0.35 < zabs < 2.3. Combining these with the SDSS DR16 spectroscopy of ∼1.1 million luminous red galaxies (LRGs) and ∼200 000 emission line galaxies (ELGs), we investigate the nature of cold gas absorption at 0.5 < z < 1. These large samples allow us to characterize the scale dependence of Mg ii with greater accuracy than in previous work. We find that there is a strong enhancement of Mg ii absorption within ∼50 kpc of ELGs, and the covering fraction within 0.5rvir of ELGs is 2–5 times higher than for LRGs. Beyond 50 kpc, there is a sharp decline in Mg ii for both kinds of galaxies, indicating a transition to the regime where the CGM is tightly linked with the dark matter halo. The Mg ii-covering fraction correlates strongly with stellar mass for LRGs, but weakly for ELGs, where covering fractions increase with star formation rate. Our analysis implies that cool circumgalactic gas has a different physical origin for star-forming versus quiescent galaxies.
The anisotropy of the power spectrum in periodic cosmological simulations
Authors: Rácz Gábor , Szapudi István , Csabai István , Dobos László
Published: March 2021

The classical gravitational force on a torus is anisotropic and always lower than Newton’s 1/r2 law. We demonstrate the effects of periodicity in dark matter only N-body simulations of spherical collapse and standard Lambda cold dark matter (ΛCDM) initial conditions. Periodic boundary conditions cause an overall negative and anisotropic bias in cosmological simulations of cosmic structure formation. The lower amplitude of power spectra of small periodic simulations is a consequence of the missing large-scale modes and the equally important smaller periodic forces. The effect is most significant when the largest mildly non-linear scales are comparable to the linear size of the simulation box, as often is the case for high-resolution hydrodynamical simulations. Spherical collapse morphs into a shape similar to an octahedron. The anisotropic growth distorts the large-scale ΛCDM dark matter structures. We introduce the direction-dependent power spectrum invariant under the octahedral group of the simulation volume and show that the results break spherical symmetry.