bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited Commentary: The Role of Tuberculosis Screening Among Migrants to Low-Incidence Settings in (Not) Achieving Elimination
Authors: Campbell Jonathon R , Schwartzman Kevin
Published: June 2021

The cost-effectiveness of migrant tuberculosis prevention programs is highly relevant to many countries with low tuberculosis incidence as they attempt to eliminate the disease. Dale et al. (Am J Epidemiol. 2022;191(2):255–270) evaluated strategies for tuberculosis infection screening and treatment among new migrants to Australia. Screening for infection before migration, and then administering preventive treatment after arrival, was more cost-effective than performing both screening and treatment after arrival. From the Australian health payer perspective, the improved cost-effectiveness of premigration screening partly reflected the shift of screening costs to migrants, which may raise ethical concerns. Key sensitivity analyses highlighted the influence of health disutility associated with tuberculosis preventive treatment, and of posttreatment sequelae of tuberculosis disease. Both considerations warrant greater attention in future research. For all strategies, the impact on tuberculosis incidence among migrants was modest (<15%), suggesting enhanced migrant screening will not achieve tuberculosis elimination in low-incidence settings. This emphasizes the need to increase investment and effort in global tuberculosis prevention and care, which will ultimately reduce the prevalence of tuberculosis infection and therefore the risk of tuberculosis disease among migrants. Such efforts will benefit high and low tuberculosis incidence countries alike, and advance all countries further toward tuberculosis elimination.
PolarProtPred: predicting apical and basolateral localization of transmembrane proteins using putative short linear motifs and deep learning
Authors: Dobson Laszlo , Zeke András , Tusnády Gábor E
Published: June 2021

Motivation

Cell polarity refers to the asymmetric organization of cellular components in various cells. Epithelial cells are the best-known examples of polarized cells, featuring apical and basolateral membrane domains. Mounting evidence suggests that short linear motifs play a major role in protein trafficking to these domains, although the exact rules governing them are still elusive.

Results

In this study we prepared neural networks that capture recurrent patterns to classify transmembrane proteins localizing into apical and basolateral membranes. Asymmetric expression of drug transporters results in vectorial drug transport, governing the pharmacokinetics of numerous substances, yet the data on how proteins are sorted in epithelial cells is very scattered. The provided method may offer help to experimentalists to identify or better characterize molecular networks regulating the distribution of transporters or surface receptors (including viral entry receptors like that of COVID-19).

Availability and implementation

The prediction server PolarProtPred is available at http://polarprotpred.ttk.hu.

Supplementary information

Supplementary data are available at Bioinformatics online.
MMpred: a distance-assisted multimodal conformation sampling for de novo protein structure prediction
Authors: Zhao Kai-Long , Liu Jun , Zhou Xiao-Gen , Su Jian-Zhong , Zhang Yang , Zhang Gui-Jun
Published: June 2021

Motivation

The mathematically optimal solution in computational protein folding simulations does not always correspond to the native structure, due to the imperfection of the energy force fields. There is therefore a need to search for more diverse suboptimal solutions in order to identify the states close to the native. We propose a novel multimodal optimization protocol to improve the conformation sampling efficiency and modeling accuracy of de novo protein structure folding simulations.

Results

A distance-assisted multimodal optimization sampling algorithm, MMpred, is proposed for de novo protein structure prediction. The protocol consists of three stages: The first is a modal exploration stage, in which a structural similarity evaluation model DMscore is designed to control the diversity of conformations, generating a population of diverse structures in different low-energy basins. The second is a modal maintaining stage, where an adaptive clustering algorithm MNDcluster is proposed to divide the populations and merge the modal by adjusting the annealing temperature to locate the promising basins. In the last stage of modal exploitation, a greedy search strategy is used to accelerate the convergence of the modal. Distance constraint information is used to construct the conformation scoring model to guide sampling. MMpred is tested on a large set of 320 non-redundant proteins, where MMpred obtains models with TM-score≥0.5 on 291 cases, which is 28% higher than that of Rosetta guided with the same set of distance constraints. In addition, on 320 benchmark proteins, the enhanced version of MMpred (E-MMpred) has 167 targets better than trRosetta when the best of five models are evaluated. The average TM-score of the best model of E-MMpred is 0.732, which is comparable to trRosetta (0.730).

Availability and implementation

The source code and executable are freely available at https://github.com/iobio-zjut/MMpred.

Supplementary information

Supplementary data are available at Bioinformatics online.
Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway
Authors: Zhang Yalun , Zhang Yi , Aman Yahyah , Ng Cheung Toa , Chau Wing-Hin , Zhang Zhigang , Yue Ming , Bohm Christopher , Jia Yizhen , Li Siwen , Yuan Qiuju , Griffin Jennifer , Chiu Kin , Wong Dana S M , Wang Binbin , Jin Dongyan , Rogaeva Ekaterina , Fraser Paul E , Fang Evandro F , St George-Hyslop Peter , Song You-Qiang
Published: June 2021

The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
Action Observation Responses Are Influenced by Movement Kinematics and Target Identity
Authors: Savaki Helen E , Kavroulakis Eleftherios , Papadaki Efrosini , Maris Thomas G , Simos Panagiotis G
Published: June 2021

In order to inform the debate whether cortical areas related to action observation provide a pragmatic or a semantic representation of goal-directed actions, we performed 2 functional magnetic resonance imaging (fMRI) experiments in humans. The first experiment, involving observation of aimless arm movements, resulted in activation of most of the components known to support action execution and action observation. Given the absence of a target/goal in this experiment and the activation of parieto-premotor cortical areas, which were associated in the past with direction, amplitude, and velocity of movement of biological effectors, our findings suggest that during action observation we could be monitoring movement kinematics. With the second, double dissociation fMRI experiment, we revealed the components of the observation-related cortical network affected by 1) actions that have the same target/goal but different reaching and grasping kinematics and 2) actions that have very similar kinematics but different targets/goals. We found that certain areas related to action observation, including the mirror neuron ones, are informed about movement kinematics and/or target identity, hence providing a pragmatic rather than a semantic representation of goal-directed actions. Overall, our findings support a process-driven simulation-like mechanism of action understanding, in agreement with the theory of motor cognition, and question motor theories of action concept processing.
Differential Effects of the Inactivation of Anterior and Posterior Orbitofrontal Cortex on Affective Responses to Proximal and Distal Threat, and Reward Anticipation in the Common Marmoset
Authors: Stawicka Zuzanna M , Massoudi Roohollah , Oikonomidis Lydia , McIver Lauren , Mulvihill Kevin , Quah Shaun K L , Cockcroft Gemma J , Clarke Hannah F , Horst Nicole K , Wood Christian M , Roberts Angela C
Published: June 2021

Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in affective disorders that manifest anxiety-related symptoms. However, research into the functions of primate OFC has predominantly focused on reward-oriented rather than threat-oriented responses. To redress this imbalance, the present study performed a comprehensive analysis of the independent role of 2 distinct subregions of the central OFC (anterior area 11; aOFC and posterior area 13; pOFC) in the processing of distal and proximal threat. Temporary inactivation of both aOFC and pOFC heightened responses to distal threat in the form of an unknown human, but not to proximal threat assessed in a discriminative Pavlovian conditioning task. Inactivation of the aOFC, however, did unexpectedly blunt conditioned threat responses, although the effect was not valence-specific, as conditioned appetitive responses were similarly blunted and appeared restricted to a discriminative version of the task (when both CS− and CS+ are present within a session). Inactivation of the pOFC did not affect conditioned responses to either proximal threat or reward and basal cardiovascular activity was unaffected by manipulations of activity in either subregion. The results highlight the contribution of aOFC and pOFC to regulation of responses to more distal uncertain but not proximal, certain threat and reveal their opposing contribution to that of the immediately adjacent medial OFC, area 14.
Rpsa Signaling Regulates Cortical Neuronal Morphogenesis via Its Ligand, PEDF, and Plasma Membrane Interaction Partner, Itga6
Authors: Blazejewski Sara M , Bennison Sarah A , Ha Ngoc T , Liu Xiaonan , Smith Trevor H , Dougherty Kimberly J , Toyo-Oka Kazuhito
Published: June 2021

Neuromorphological defects underlie neurodevelopmental disorders and functional defects. We identified a function for Rpsa in regulating neuromorphogenesis using in utero electroporation to knockdown Rpsa, resulting in apical dendrite misorientation, fewer/shorter extensions, and decreased spine density with altered spine morphology in upper neuronal layers and decreased arborization in upper/lower cortical layers. Rpsa knockdown disrupts multiple aspects of cortical development, including radial glial cell fiber morphology and neuronal layering. We investigated Rpsa’s ligand, PEDF, and interacting partner on the plasma membrane, Itga6. Rpsa, PEDF, and Itga6 knockdown cause similar phenotypes, with Rpsa and Itga6 overexpression rescuing morphological defects in PEDF-deficient neurons in vivo. Additionally, Itga6 overexpression increases and stabilizes Rpsa expression on the plasma membrane. GCaMP6s was used to functionally analyze Rpsa knockdown via ex vivo calcium imaging. Rpsa-deficient neurons showed less fluctuation in fluorescence intensity, suggesting defective subthreshold calcium signaling. The Serpinf1 gene coding for PEDF is localized at chromosome 17p13.3, which is deleted in patients with the neurodevelopmental disorder Miller–Dieker syndrome. Our study identifies a role for Rpsa in early cortical development and for PEDF-Rpsa-Itga6 signaling in neuromorphogenesis, thus implicating these molecules in the etiology of neurodevelopmental disorders like Miller–Dieker syndrome and identifying them as potential therapeutics.
Predictors of Cell-Associated Human Immunodeficiency Virus (HIV)-1 DNA Over 1 Year in Very Early Treated Infants
Authors: Kuhn Louise , Paximadis Maria , Da Costa Dias Bianca , Shen Yanhan , Mncube Sizanani , Strehlau Renate , Shiau Stephanie , Patel Faeezah , Burke Megan , Technau Karl-Günter , Sherman Gayle , Loubser Shayne , Abrams Elaine J , Tiemessen Caroline T
Published: June 2021

Background

Younger age of antiretroviral therapy (ART) initiation is associated with smaller viral reservoirs in perinatally acquired HIV-1 infection, but there is wide variability among early-treated infants. Predictors of this variability are not fully described.

Methods

Sixty-three neonates diagnosed with HIV-1 <48 hours after birth in Johannesburg, South Africa, were started on ART as soon as possible. Fifty-nine (94%) infants received nevirapine prophylaxis from birth until ART start. Viably preserved peripheral blood mononuclear cells (PBMCs) collected at regular intervals to 48 weeks, and from mothers at enrollment, were tested using integrase-targeted, semi-nested, real-time quantitative hydrolysis probe (TaqMan) PCR assays to quantify total HIV-1 subtype C viral DNA (vDNA). Predictors were investigated using generalized estimating equation regression.

Results

Thirty-one (49.2%) infants initiated ART <48 hours, 24 (38.1%) <14 days, and 8 (12.7%) >14 days of birth. Three-quarters were infected despite maternal antenatal ART (however, only 9.5% of women had undetectable viral load closest to delivery) and 86% were breastfed. Higher infant CD4+ T-cell percentage and viral load <100 000 copies/mL pre-ART were associated with lower vDNA in the first 48 weeks after ART start. No antenatal maternal ART and breastfeeding were also associated with lower vDNA. Older age at ART initiation had a discernible negative impact when initiated >14 days.

Conclusions

Among very early treated infants, higher CD4+ T-cell percentage and viral load <100 000 copies/mL pre-ART, infection occurring in the absence of maternal antenatal ART, and breastfeeding were associated with lower levels of HIV-1 DNA in the first 48 weeks of treatment.

Clinical Trials Registration. clinicaltrials.gov (NCT02431975).
How to modulate the formation of negative volatile sulfur compounds during wine fermentation?
Authors: Jimenez-Lorenzo Rafael , Bloem Audrey , Farines Vincent , Sablayrolles Jean-Marie , Camarasa Carole
Published: June 2021

Beyond the production of positive aromas during alcoholic fermentation, Saccharomyces cerevisiae metabolism also results in the formation of volatile compounds detrimental to wine quality, including a wide range of volatile sulfur compounds (VSCs). The formation of these VSCs during wine fermentation is strongly variable and depends on biological and environmental factors. First, the comparison of the VSCs profile of 22 S. cerevisiae strains provided a comprehensive overview of the intra-species diversity in VSCs production: according to their genetic background, strains synthetized from 1 to 6 different sulfur molecules, in a 1- to 30-fold concentration range. The impact of fermentation parameters on VSCs production was then investigated. We identified yeast assimilable nitrogen, cysteine, methionine and pantothenic acid contents – but not SO2 content – as the main factors modulating VSCs production. In particular, ethylthioacetate and all the VSCs deriving from methionine catabolism displayed a maximal production at yeast assimilable nitrogen concentrations around 250 mg/L; pantothenic acid had a positive impact on compounds deriving from methionine catabolism through the Ehrlich pathway but a negative one on the production of thioesters. Overall, these results highlight those factors to be taken into account to modulate the formation of negative VSCs and limit their content in wines.
Evolution of recombination landscapes in diverging populations of bread wheat
Authors: Danguy des Déserts Alice , Bouchet Sophie , Sourdille Pierre , Servin Bertrand
Published: June 2021

Reciprocal exchanges of DNA (crossovers) that occur during meiosis are mandatory to ensure the production of fertile gametes in sexually reproducing species. They also contribute to shuffle parental alleles into new combinations thereby fuelling genetic variation and evolution. However, due to biological constraints, the recombination landscape is highly heterogeneous along the genome which limits the range of allelic combinations and the adaptability of populations. An approach to better understand the constraints on the recombination process is to study how it evolved in the past. In this work we tackled this question by constructing recombination profiles in four diverging bread wheat (Triticum aestivum L.) populations established from 371 landraces genotyped at 200,062 SNPs. We used linkage disequilibrium (LD) patterns to estimate in each population the past distribution of recombination along the genome and characterize its fine-scale heterogeneity. At the megabase scale, recombination rates derived from LD patterns were consistent with family-based estimates obtained from a population of 406 recombinant inbred lines. Among the four populations, recombination landscapes were positively correlated between each other and shared a statistically significant proportion of highly recombinant intervals. However, this comparison also highlighted that the similarity in recombination landscapes between populations was significantly decreasing with their genetic differentiation in most regions of the genome. This observation was found to be robust to SNPs ascertainment and demography and suggests a relatively rapid evolution of factors determining the fine-scale localization of recombination in bread wheat.
Do not put eggs in one basket: related variety and export resilience in the post-crisis era
Authors: He Canfei , Chen Tao , Zhu Shengjun
Published: June 2021

Region’s capability to retain economic growth and resist external shocks is important, particularly in the increasingly globalized economy with a plethora of political and economic uncertainties. This paper uses Chinese custom data to investigate the ways in which regional export resilience has been affected by related variety in the post-crisis era. The hypothesis is that regions with a large number of related industries are more vulnerable to external shocks due to the risk-spreading effect, where the negative effects of external shocks on certain industries may be easily transferred to other related industries. Empirical results support our hypothesis that cities with many related industries are often less economically resilient to external shocks and tend to face greater economic decline in the post-crisis era. We also find that industries with high levels of related variety are also vulnerable to external demand shocks.
An evaluation of prophylactic and therapeutic antibiotic prescribing in Lebanese dental practice
Authors: Chehabeddine Nadine , Lahoud Nathalie , Noujeim Ziad E F , Zeidan Rouba K , El Toum Sami , Maison Patrick , Saleh Nadine
Published: June 2021

Objectives

To evaluate antibiotic prescribing patterns and correlates among Lebanese dentists.

Methods

A descriptive observational study was conducted, from the first of April to the end of May 2017. Dentists who specialized in oral dental surgery or general dental practitioners were eligible to participate in this study. All patients who sought consultation with the selected dentists over a 1 month period were included.

Key findings

A total of 2323 oral and dental procedures were performed by 60 dentists; 553 antibiotic prescriptions were prescribed, representing 23.8% (52.35% for prophylactic purposes and 47.65% for curative purposes). Prophylactic indications were mainly for implant surgery (36.3%) with only 1% appropriate. Curative use was mainly for periodontal abscesses/abscesses (indeterminate) (22.8%), followed by pulpal diseases and periradicular complications (20.5%); it was appropriate in only 1.7 and 1.9% of cases respectively. Amoxicillin–clavulanic acid was the antibiotic that was mostly prescribed for both curative and prophylactic uses (57.6 and 55.9%, respectively), followed by amoxicillin for prophylactic purposes and a combination of spiramycin plus metronidazole for curative purposes. Adherence to guidelines was low for both curative and prophylactic purposes (17.4 and 21.8%, respectively), but was better in patients who were younger [adjusted odds ratio

(aOR) = 0.96], male (aOR = 0.40), or had cardiac disease with moderate or high infective endocarditis risk (aOR = 21.72), and when prescribed by oral surgeons (aOR = 0.15).

Conclusions

This study showed evidence of the overuse of antibiotics among Lebanese dentists. It can serve as a basis for future studies to optimize antibiotic use among dentists in Lebanon.
Dietary supplementation of aSaccharomyces cerevisiaefermentation product attenuates exercise-induced stress markers in young horses
Authors: Valigura Hannah C , Leatherwood Jessica L , Martinez Rafael E , Norton Sharon A , White-Springer Sarah H
Published: June 2021

Mitigation of exercise-induced stress is of key interest in determining ways to optimize performance horse health. To test the hypothesis that dietary supplementation of a Saccharomyces cerevisiae fermentation product would decrease markers of exercise-induced stress and inflammation in young horses, Quarter Horse yearlings (mean ± SD; 9 ± 1 mo) were randomly assigned to receive either no supplementation (CON; n = 8) or 21 g/d S. cerevisiae fermentation product (10.5 g/feeding twice daily; SCFP; n = 10) top-dressed on a basal diet of custom-formulated grain as well as ad libitum Coastal bermudagrass hay. After 8 wk of dietary treatments, horses underwent a 2-h submaximal exercise test (SET) on a free-stall mechanical exerciser. Serum was collected before dietary treatment supplementation (week 0), at week 8 pre-SET, and 0, 1, and 6 h post-SET and analyzed for concentrations of cortisol and serum amyloid A (SAA) by commercial enzyme-linked immunosorbent assay (ELISA) and for cytokine concentrations by commercial bead-based ELISA. Data were analyzed using linear models with repeated measures in SAS v9.4. From week 0 to 8 (pre-SET), serum cortisol decreased (P = 0.01) and SAA did not change, but neither were affected by diet. Serum concentrations of all cytokines decreased from week 0 to 8 (P ≤ 0.008), but granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and interleukin-8 (IL-8) decreased to a greater extent in CON than in SCFP horses (P ≤0.003). In response to the week 8 SET, serum cortisol increased in all horses (P < 0.0001) but returned to pre-SET levels by 1 h post-SET in horses receiving SCFP. At 6 h post-SET, cortisol concentrations in CON horses returned to pre-SET concentrations, whereas cortisol declined further in SCFP horses to below pre-SET levels (P = 0.0002) and lower than CON (P = 0.003) at that time point. SAA increased at 6 h post-SET in CON (P < 0.0001) but was unchanged through 6 h in SCFP horses. All cytokines except G-CSF increased in response to the SET (P < 0.0001) but showed differing response patterns. Concentrations of IL-1β, IL-6, and tumor necrosis factor-alpha were lesser (P ≤ 0.05), and concentrations of G-CSF and IL-18 tended to be lesser (P ≤ 0.09) in SCFP compared with CON horses throughout recovery from the SET. In summary, 8 wk of dietary supplementation with 21 g/d of SCFP may mitigate cellular stress following a single, prolonged submaximal exercise bout in young horses.
Ectopic BH3-only protein Bim acts as a cochaperone to positively regulate Hsp70 in yeast
Authors: Pan Hao , Song Ting , Wang Ziqian , Guo Yafei , Zhang Hong , Ji Tong , Cao Keke , Zhang Zhichao
Published: June 2021

The chaperone heat shock protein 70 (Hsp70) is conserved from bacteria to humans and is crucial for avoiding protein misfolding under stress. Bim functions, mainly as one of the B-cell lymphoma 2 (Bcl-2) family proapoptotic members, were identified to be a cochaperone of Hsp70. Herein, we reported that ectopic Bim could constitute the interactions with intrinsic Hsp70 and translate its positive cochaperone activity in vitro to the yeast growth promotion and help Hsp70 to fold its client Ras-like protein. With the help of a specific Hsp70/Bim disruptor, we illustrated that Hsp70/Bim dimers rescue yeast from heat shock. In an organism lacks apoptotic Bcl-2 factors, the proapoptotic Bim in mammalian cells exhibits prosurvival functions.
The Impact of Roads on the Redistribution of Plants and Associated Arthropods in a Hyper-Arid Ecosystem
Authors: Cohen Shahar , Groner Elli , Peeters Aviva , Segoli Michal
Published: June 2021

The construction of vehicular roads likely affects the distribution of natural resources. Although the effects of roads on different ecosystem aspects have been extensively studied, studies in arid and, particularly, in hyper-arid ecosystems are scarce. In drylands, where water is the main limiting factor, the effect of roads on the redistribution of water may have strong subsequent effects on the ecosystem, especially when roads cross natural water flow paths. To fill this knowledge gap, we studied the effects of a road that runs across a slope on the distribution of plants and animals in a hyper-arid environment. Changes in shrub cover, below and above the road, were quantified by remote sensing and image classification, while plant-associated arthropods were vacuum-sampled from shrub canopies and from open (inter-shrub) areas. We found that the spatial distribution of shrubs, a vital resource facilitating many other organisms, was affected by the road, with an increase in the shrub cover immediately above the road and a decrease below it. Arthropod abundance generally followed shrub cover, but the exact pattern depended on the specific group sampled. While some arthropod groups (e.g., aphids, parasitic wasps and barklice) thrived under the disturbed conditions above the road, other arthropod groups (e.g., mites and true bugs) were less abundant in the disturbed patches. Our results highlight the strong effects of human-made structures on the distribution of flora and fauna in arid ecosystems.
#2: Use of Plasma Metagenomic Next Generation Sequencing for Pathogen Identification in Pediatric Endocarditis
Authors: To Rachel K , Ramchandar Nanda , Gupta Aamisha , Pong Alice , Cannavino Christopher , Foley Jennifer , Farnaes Lauge , Coufal Nicole G
Published: June 2021

Background

Pediatric infective endocarditis (IE) incurs significant morbidity and most commonly occurs among children with underlying heart disease. Identification of causative pathogens on blood culture allows for more targeted antibiotic therapy, optimizing patient outcomes. However, standard diagnostic testing has limited sensitivity. As a result, there is an opportunity to explore alternative methods to identify pathogens in IE using cell-free plasma next generation sequencing (mNGS). mNGS utilizes a high-throughput approach that is culture-independent and non-invasive to detect microbial DNA. We describe a single center retrospective case series of children with IE in whom plasma mNGS was sent as part of the diagnostic evaluation.

Methods

In this case series, we evaluated the impact of mNGS on the clinical management of IE by conducting a retrospective chart review of children hospitalized with IE from January 1, 2017 to January 17, 2020. Inclusion criteria included subjects 0–21 years of age who had a diagnosis of IE based on admission diagnosis and problem list. Demographics, echocardiography and diagnostics were obtained by chart review.

Results

We identified 14 children who were diagnosed with IE, 10 of whom had mNGS sent for diagnostic testing. mNGS detected an organism in 8 of 10 (80%) children as compared to standard of care blood cultures and 16S PCR which identified an organism in only 5 of 10 (30%). Out of 8 subjects with organisms identified by mNGS, clinical management was impacted in 4 of 8 subjects and 3 subjects were only diagnosed through mNGS.

Conclusion

Although blood and tissue cultures are the historical gold standard for organism identification in IE, new diagnostic modalities such as mNGS may be more sensitive. This could lead to more targeted and possibly more effective therapeutic regimens in cases when empiric antibiotic therapy may hinder pathogen identification. In at least one instance, a change in antibiotic choice to penicillin to target Corynebacterium diphtheriae resulted in a clinical cure that may not have otherwise been achieved. As a result of mNGS, three other subjects also had changes in management that resulted in narrowing of antibiotic choice or adjustments to the antibiotic regimen. Our observations suggest that mNGS is more sensitive than standard blood cultures and that the clinical utility of mNGS may be beneficial to the management of infective endocarditis in children.
#3: Gram-Negative Antibacterial Resistance Prevalence at a Tertiary Care Hospital in Central America
Authors: Dantuluri Keerti , Forrester Jeanne , Benincasa Lisette Castro , Posadas Sofia , Quiñónez Fabiola , Karunanandaa Aravinth , Morris Lee
Published: June 2021

Background

Latin America has some of the highest rates of multi-drug resistant gram-negative bacteria worldwide. However, local surveillance registries to compare rates of resistance among countries are lacking, particularly in Central America. Awareness of local resistance patterns in this region is critical to improve antibiotic use and patient outcomes. We sought to measure the prevalence of resistant gram-negative bacilli (GNB) at a tertiary hospital in Guatemala.

Methods

We retrospectively conducted a single-center study to measure the percentage of GNB that were non-susceptible to various antibiotics between April and October of 2017. All cultures (blood, urine, cerebrospinal fluid, and other body fluids) were collected as part of routine clinical care during the study period. Duplicate isolates, defined as multiple specimens with the same organism from the same patient, were excluded. Antibiotic susceptibility testing was performed by disk diffusion method. Bacterial isolates were categorized as susceptible, intermediate, or resistant based upon the Clinical Laboratory Standard Institute 27th edition per guidance from the National Laboratory of Guatemala.

Results

A total of 969 unique gram-negative isolates from 818 patients were included. Urine was the most common culture type. The most frequently isolated bacteria were Escherichia coli and Klebsiella species. The percentage of GNB which were non-susceptible to individual antibiotics are detailed in Table 1. Of the isolates tested, 12 – 66% of GNB were non-susceptible to cephalosporins, 7 – 31% were non-susceptible to carbapenems, and 14 – 44% were non-susceptible to fluroquinolones.

Conclusions

The prevalence of multi-drug resistant GNB is high in Escuintla, Guatemala. Continued surveillance is vital to guide judicious and appropriate empiric antibiotic use in the setting of rising rates of antibiotic resistance. Local and regional resistance rates are known to vary, underlying the importance of developing more regional and national antibiotic resistance surveillance networks within Guatemala and other countries in Central America where there is a paucity of data.
#30: Coronavirus Disease 2019 (COVID-19) Incidence in Pediatric Oncology Patient: Does Routine Screening Affect the Risk for the Transmission in the Hospital
Authors: Adrizain Riyadi , Sari Nurmelani
Published: June 2021

Background

Cancer patients are at higher risk of COVID-19 infection and more likely they have higher morbidity and mortality than the general population. On the other hand, the oncology patient sometimes can show asymptomatic COVID-19 disease with a risk of longer viral shedding and spreading the infection to others immunosuppressed individuals. Oncology patients also regularly travel between hospital and sometimes lodge in boarding house for routine chemotherapy. As we known, prevention strategy for COVID-19 among pediatric oncology patients can be implemented by minimizing these risks factors for transmission by identifying all patients infected with COVID-19. Here, we report our experience before and after implementing COVID-19 testing policy of patients with hematology and oncology diseases in our center.

Method

We collected data of pediatric oncology patients admitted to Hasan Sadikin General hospital between July 1st, 2020 to January 8th, 2021. The data consisted of the total number of patients and COVID-19 status by using SARS-CoV-2 Nucleic Acid Amplification Test (NAAT) performed in the patient during two periods. In the first period, we performed NAAT if the patient was suspected of COVID-19. In the second period, after the policy was changed, NAAT was performed routinely as screening for all oncologic patients admitted to the hospital.

Results

Between July 1st to December 2nd, 2020, the first period, there was 3 positive results from 36 suspected COVID-19 patients among 181 total pediatric oncology patients. In the second period, we found 8 positive results from 121 hospitalized patients, none of them had signs and symptoms of COVID-19; and 4 of them came from boarding house.

Conclusion

Routine screening for COVID-19 should be considered as a policy for hospitalization of a pediatric oncology patient because of the high risk that asymptomatic COVID-19 patients can transmit the infection to other patient and to health care workers in the hospital.
#42: COVID-19 in Pediatric Hemato-Oncology Patients from Three Hispaniola Hospitals
Authors: Santana Genara , Gil María Dolores , Morel Manauri H , Contreras Johanny , Rivera Karina , Castillo María , Gassant Pascale Yola , Fleury Marie Immacula , Happ Brooke , Vázquez Milka , Homsi Maysam R , Caniza Miguela A
Published: June 2021

Background

In late 2019, a novel coronavirus, SARS-CoV-2, was reported in China, which rapidly spread across the globe. The WHO declared a pandemic of coronavirus disease (COVID-19) in early 2020. In March, both the Dominican Republic and Haiti reported their first cases. The three pediatric oncology units (POUs) that make up the St. Jude Global Infectious Diseases Hispaniola Project began to see COVID-19 among patients in Santo Domingo in March and in both Santiago and Port-au-Prince in June. We report the experience of managing pediatric hemato-oncology patients with COVID-19 in these three POUs.

Methods

We added COVID-19 data to our ongoing healthcare-associated infection surveillance in the POUs of the Hispaniola Project. The population studied included all patients tested for SARS-CoV-2 by PCR and/or serological methods. Patient data was recorded on a basic line listing. Cases were categorized using a published clinical symptom severity scale and case definition criteria from the WHO and the US Centers for Disease Control and Prevention (CDC).

Results

In total, 31 pediatric oncology patients met either the WHO and/or CDC case definition for COVID-19. The average age was 8 years (range: 5 months to 15 years). Just over half (17, 55%) of cases were female. The most common oncology diagnosis was acute lymphoblastic leukemia in 17 of the cases, followed by acute myeloid leukemia (5) and solid tumor (4). Five (16%) cases were in the consolidation phase, 7 (23%) in induction, and 11 (35%) in maintenance. Using the symptom severity scale, 13 (32%) cases were asymptomatic; symptoms were considered mild in 14 (45%) cases, moderate in 3 (10%), severe in 0 (0%), and critical in 1 (3%). Three deaths were attributed to COVID-19. Eighteen cases met the WHO criteria, 13 (72%) of which were confirmed, 1 probable, and 4 suspected. Twenty-six cases met the CDC criteria, 13 (50%) of which were confirmed and 13 (50%) were suspected; there were 0 probable cases.

Conclusions

Our findings about COVID-19 in pediatric oncology patients are consistent with data reported globally that disease presentation is mostly asymptomatic or mild but with increased mortality. The high contagiousness and unpredictable clinical response of children with cancer call for rigorous measures to prevent infections in this population. In low resource settings, the scarcity of antiviral, immunologic, and supportive medications further underscores this need. Additionally, we observed differences in our data depending on which COVID-19 case criteria were used (WHO versus CDC); this highlights the importance of standardized definitions that can be used at all resource levels to promote reliable measurement of disease burden.
#46: Changes in the hospital admission profile in a Peruvian National Tertiary Children’s Hospital during the First Year of Covid-19 Pandemic
Authors: Baca Yeni , Muñante Cesar , Santillan Carlos
Published: June 2021

Background

During the first year of the current COVID-19 pandemic, health systems around the world have faced the challenge of maintaining health services for patients with non-communicable diseases, despite the logistical and personnel constraints. Despite SARS-CoV-2 infection is usually more benign in children, there is limited information about how this pandemic affected their healthcare at a population level.

Methods

We performed a cross sectional study at the Peruvian National Children′s Hospital San Borja, which is a 312-bed tertiary National referral health center, in Lima. We include all hospital admissions during 2020, with respect to the two previous years. We defined hospital admission as the permanence at the hospital for more than 24 hours irrespectively of patient′s initial destination (emergency observation unit, regular medical floor, or intensive care unit). We described demographic characteristics among hospitalized patients and compared them between 2018–19 and 2020 using standard descriptive tests. We use the International Classification of Diseases 10th (ICD-10) codes from the electronic patient registration system to ascertain three major non-communicable conditions: congenital cardiopathies, hematooncological disorders and burns non-communicable conditions. We set level for statistical significance at 0.05.

Results

There were 11635 patients admitted during 2018–19 period and 3480 patients admitted during 2020. The average daily hospital admission during 2018–19 was different compared to 2020 (15.9±6.1 vs. 9.6±6.0, p<0.001). There were also differences in the frequency of the gender (male 55.1% vs. 58.9%, p<0.001) and if the patient′s place of origin was outside Lima (49.0% vs. 41.1%, p<0.001). Among hospitalized patients, 3036 presented one of the three non-communicable conditions during the baseline period and 871 during 2020. There was a significant difference between the distribution of hospitalization among patients with one of the three non-communicable conditions (p<001), towards a decrease in hospitalizations due to congenital heart disease, and an increase in the hospitalizations due to burns.

Conclusion

During the first year of COVID-19 pandemic, there was a decrease in the number of hospitalizations of children with non-communicable conditions compared to the previous two years. It will be important to consider the implementation of public health policies aimed to increase accessibility to health care for children with non-communicable conditions during the coming months of the pandemic in Peru.
#56: A novel test for diagnosis and surveillance of Wuchereria bancrofti infection
Authors: Greene Sarah E , Curtis Kurt , Fischer Peter U , King Christopher L , Weil Gary J
Published: June 2021

Background

Elephantiasis or Lymphatic filariasis (LF) is a parasitic infection that causes significant morbidity and impacts hundreds of millions of people in 73 countries. Most LF is caused by the nematode Wuchereria bancrofti, but Brugia species cause LF in some areas of Southeast Asia. The global program to eliminate LF uses mass drug administration (MDA) of antifilarial drugs in endemic areas to kill the microfilaria (MF) stage of the parasite that is required for ongoing transmission by mosquitos. Better tools are needed for assessing the success of MDA, because of limitations of available diagnostic tests. MF testing is often not feasible, because it requires collection of blood at night in most endemic areas. Existing antibody and antigen tests remain positive long after effective treatment, and their results do not correlate well with current infectivity. The Brugia Rapid test detects antibodies to BmR1, a Brugia protein that is expressed by MF. These antibodies disappear 2–3 years after effective treatment, and that makes the Brugia Rapid test a useful marker for persistent infection in the few countries with brugian filariasis. We set out to develop a novel antibody test for W. bancrofti infection based on a BmR1 homologue in W. bancrofti.

Methods

We cloned, expressed and purified a Wuchereria bancrofti protein (provisional name WbN1) that is a homologue of the Brugia malayi protein BmR1. Sera from patients infected with Wuchereria bancrofti as well as sera from patients infected with other closely related filarial species were tested for IgG4 antibodies to WbN1 by indirect ELISA.

Results

The ELISA has a sensitivity of 90.7% for infection with W. bancrofti based on the 80 bancrofti patient samples tested thus far. Specificity was 91.5% with 59 sera samples from patients infected with Onchocerca volvulus or Loa loa, which are filarial parasites that are co-endemic with W. bancrofti in Africa. Specificity was 97.9% with North American control samples. ELISA with sera from a clinical trial in Sri Lanka demonstrated that antibodies to WbN1 decreased significantly faster after treatment than antibodies to the previously described filarial antigen Bm14. Similar declines in antibody to WbN1 occurred after patients in Papua New Guinea received a single dose of triple drug treatment for LF with Ivermectin Diethylcarbamazine and Albendazole, that is effective for clearing MF from the blood without clearing filarial antigenemia.

Conclusions

While additional studies are needed, this ELISA for IgG4 antibody to the recombinant protein WbN1 could be a promising new surveillance tool for assessing for ongoing transmission of LF following MDA.
How professional actions connect and protect
Authors: Faulconbridge James , Folke Henriksen Lasse , Seabrooke Leonard
Published: June 2021

Below we provide responses to the ongoing debate sparked by Mirko Noordegraaf’s intervention in suggesting that we are moving toward forms of ‘connective professionalism’. Critics in this debate have objected to Noordegraaf in a number of ways. Some object to a conflation of ideal types and empirical description. Others assert that Noordegraaf suggests a staged process of moving from protective to connective types of professionalism does not ring true; that we can finds forms of connection and protection in contemporary professionalism and in professional action. Our companions in this issue (Alvehus, Avnoon, and Oliver) suggest that greater connectiveness also permits new forms of protection as part of professionalism. Our short essays contribute to the Noordegraaf debate by focusing less on professionalism and more on how forms of professional action lead to mechanisms of connection and protection.
Narrow Therapeutic Index drugs: clinical pharmacology perspective
Authors: Habet Sam
Published: June 2021

Objectives

Historically, the identification of drugs with the Narrow Therapeutic Index (NTI) has been empirically based on the clinical practice. In general terms, NTI drugs can be defined based on the steepness of the dose–response relationship and the degree of overlap between the effective and the toxic concentrations.

Key findings

The current definition in the Code of Federal Regulations is based on animal data and as such lacks direct clinical relevance. By basing these criteria on those factors that affect the degree of separation of the concentrations that elicit the therapeutic and the adverse effects, it was attempted to avoid the vagaries inherent in preparing a list of individual drugs themselves.

The overall conclusions are: (1) The issue of NTI drugs is still highly controversial, (2) The lists of NTI drugs are arbitrary and (3) Variability may contribute to the safety and efficacy. The objectives are to (1) To facilitate consensus on the definition of a NTI, (2) To identify characteristics of NTI and (3) To develop criteria for identifying NTI. The FDA should consider not only the pharmacokinetics (PK) studies, but also comparative efficacy and safety studies, for the NTI drugs to further to try ‘convince or educate’ the prescribers.
The heat is on: how crop growth, development, and yield respond to high temperature
Authors: Zhu Tingting , Fonseca De Lima Cassio Flavio , De Smet Ive
Published: June 2021

Plants are exposed to a wide range of temperatures during their life cycle and need to continuously adapt. These adaptations need to deal with temperature changes on a daily and seasonal level and with temperatures affected by climate change. Increasing global temperatures negatively impact crop performance, and several physiological, biochemical, morphological, and developmental responses to increased temperature have been described that allow plants to mitigate this. In this review, we assess various growth-, development-, and yield-related responses of crops to extreme and moderately high temperature, focusing on knowledge gained from both monocot (e.g. wheat, barley, maize, and rice) and dicot crops (e.g. soybean and tomato) and incorporating information from model plants (e.g. Arabidopsis and Brachypodium). This revealed common and different responses between dicot and monocot crops, and defined different temperature thresholds depending on the species, growth stage, and organ.
Transcription factors DkBZR1/2 regulate cell wall degradation genes and ethylene biosynthesis genes during persimmon fruit ripening
Authors: He Yiheng , Liu Hui , Li Huan , Jin Mijing , Wang Xianglan , Yin Xueren , Zhu Qinggang , Rao Jingping
Published: June 2021

BRASSINAZOLE RESISTANT (BZR) transcription factors are critical components of the brassinosteroid signalling pathway, but their possible roles in fruit ripening have rarely been reported. In this study, four BZR sequences were isolated from persimmon fruit. Among the four BZR genes, DkBZR1/2 were expressed in persimmon fruit; DkBZR1 protein amount decreased and dephosphorylated DkBZR2 gradually accumulated during the storage period. DkBZR1/2 proteins were localized in both the nucleus and cytoplasm and accumulated in the nucleus after 24-epibrassinolide treatment. DkBZR1 suppressed the transcription of Diospyros kaki endo-1,4-betaglucanase 1 (DkEGase1) and 1-aminocyclopropane-1-carboxylate synthase 1 (DkACS1) by binding to the BR response element (BRRE) in their promoters, and DkBZR2 activated the transcription of pectate lyase 1 (DkPL1) and 1-aminocyclopropane-1-carboxylate oxidase 2 (DkACO2) by binding to the E-box motif in their promoters. Transient overexpression of DkBZR2 promoted the conversion of acid-soluble pectin to water-soluble pectin and increased ethylene production in persimmon fruit. Our findings indicate that DkBZR1 and DkBZR2 serve as repressors and activators of persimmon fruit ripening, respectively.