bluuebunny/crossref_metadata_2025 huggingface dataset:
#71 Post-Exposure Prophylaxis for Varicella-Zoster Virus Exposure in High-Risk Children
Authors: Shteynberg Emily
Published: June 2022

Background

Despite universal childhood vaccination, Varicella-Zoster virus (VZV) remains a cause of severe infection following varicella exposure for immunocompromised children and high-risk infants. Post-exposure prophylaxis (PEP) is recommended to minimize this risk; however, providers may not consistently administer Varicella-specific immune globulin (VariZIG) as recommended in guidelines or may choose alternative regimens. The purpose of this study was to determine patterns of PEP for Varicella-Zoster Virus (VZV) at children’s hospitals.

Method

Using the Pediatric Health Information Systems database, clinical encounters with the ICD-9/10 codes for VZV exposure from 2009-2019 were reviewed. Only the first VZV exposure encounter for a given patient in the study period was included. Patients receiving prophylaxis or intravenous immunoglobulin (IVIG) within 30 days of the index encounter were also excluded. Presence of chronic illness or conditions at risk of progression to severe varicella disease was identified by reviewing ICD-9/10 codes for encounters in the prior 12 months. Choice and timing of PEP regimen exposure were identified, classified into the following categories: VZIG, intravenous immunoglobulin (IVIG), acyclovir, or combination prophylaxis. Clinical encounters for subsequent varicella disease within 30 days of exposure were recorded.

Results

There were 1770 children with first clinical encounters for VZV during the study period of which, 66 were excluded due to recent prior receipt of anti-viral therapy or IVIG. Of these 1704 children, 509 (29.9%) were prescribed PEP after VZV exposure, while 65 (3.8%) ultimately developed VZV disease. Of patients who received PEP, acyclovir was most frequently prescribed (n=195, 38.3%), divided between administration between1-4 days (n=132), 5-10 days (n=19), and both time periods (n=44), post-exposure. The proportion who received the other regimens was VariZIG (n=146, 28.7%), IVIG (n=115, 22.6%), and combination therapy (n=53, 10.4%). From 2009-2019, the proportion of children receiving acyclovir declined from 56% to 36%, VariZIG increased from 10 to 15%, IVIG decreased from 32 to 7%, while a similar percentage (8-9%) received a combination of Acyclovir and IG. The proportion of patients who subsequently had clinical encounters for varicella disease was highest for Acyclovir (30/195, 15.4%) followed by VariZIG (5/146, 3.4%), combination therapy (2/53, 3.8%), and IVIG alone (0/115). (p<0.0001). Of the 65 patients that developed VZV disease, 24/65 (36.9%) had at least one high-risk condition.

Conclusion

Varicella PEP in high-risk children was highly varied among children’s hospitals and often diverged from guideline recommendations. Use of acyclovir was associated with a higher rate of breakthrough infection. More consistent use of guideline-recommended agents like VariZIG may lead to less varicella disease and complications in high-risk children.
#77 Prevalence of Staphylococcus aureus bacteremia at Saint Damien Hospital, Nos Petits Frères et Sœurs January (HSD/NPFS) 2020-June 2021, Haiti
Authors: St Vil Ymeline Pateau
Published: June 2022

Background

Staphylococcus Aureus (SA) is one of the main agents implicated in healthcare-associated infections (HAI) [1]. These infections are associated with significant morbidity and mortality, particularly methicillin-resistant staphylococcal (MRSA) infections, and their costs are also a concern. Bacteremia is regularly monitored at Saint Damien Hospital (HSD), for the year 2020 an increase in Staphylococcus aureus (SA) bacteremia was observed in certain units of the hospital. In this context, all SA infections were reviewed during eighteen months to determine the prevalence of methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) staphylococcus aureus infections, their origins: in healthcare-associated infections (HAI), community-acquired infections (CI) and the distribution of MRSA per unit

Method

A Descriptive retrospective study was carried out at Saint Damien Hospital from January 2020 to June 2021. It includes all hospitalized children under fourteen years old (14) who had a positive blood culture for SA per site, only the 1st blood culture was taken into account. According to NHSN/CDC, are defined as infections associated with healthcare-associated infections occurring at ≥ 72 hours of hospitalization (HAI) and as community-acquired infectious infections occurring at = < 48 hours of hospitalization.. Data were collected from microbiology laboratory registers and patient records

Results

From January 2020 to June 2021, two thousand two hundred thirty five 2235 blood cultures were performed. The positivity rate was 21.43% (n=479/2235) distributed in different units. 16.49% SA strains were isolated (n=79/479), including fifty (50) strains of MRSA (63.29%) and twenty nine (29) strains of MSSA (36.70%) (n=29/79).From the strains of MRSA, 54% (n=27/50) were HAI and 46% community infections (CI) (n=23/50). The Origin of the infections (HAI/CI) was not significantly associated with MRSA and MSSA strains (p=0.6235), MRSA mainly came from emergency 48% (n=24/50) followed by neonatology 20% (n=10/50), intensive care 10% (5/50) and oncology at 10% (5/50). (n=19/79), the mortality rate attributable to MRSA and MSSA was 28% (n=14/50) and 17.24% (n=5/29), respectively. 46% of MRSA were resistant to more than 3 families of antibiotics (n = 23/50). SA strains were resistant to gentamycin at 30.37% (n=24/79) to 54.34% to sulfametoxazole (n=43/79) and 18.98% and to vancomycin (n=15/79

Conclusion

The frequency of SA infections, specifically MRSA, is of great concern. Its existence in the community and its multiresistance, in particular to vancomycin, is an alert making this bacteremia a priority at Saint Damien Hospital, the standard precautions measures, the proper use of antibiotics by clinicians and epidemiological surveillance local would be needed to help control its spread.
#26 Prognostic Value of High Sensitivity C-Reactive Protein in Neonatal Early Onset Sepsis
Authors: Allen Garrett
Published: June 2022

Background

Inflammatory markers have been used to evaluate sepsis development in early-onset sepsis (EOS)in newborns. In some infants, antibiotics are started prophylactically for suspected sepsis for 48 hours pending the results of blood cultures, the clinical course, and the results of serial C-reactive protein (CRP) levels. When collected serially at birth, at 12 hours, and at 24 hours of life, CRP levels persistently lower than 1mg/dL have been associated with >90% negative predictive value (NPV) for the development of infection. Our practice has recently transitioned to using High sensitivity CRP (hs-CRP) which offers much lower detection limits. We thus hypothesized that in term infants, a single early hs-CRP level at a lower cutoff than 1 mg/dL would be highly predictive of normal clinical outcome defined as negative blood culture, clinically well-appearing infant, and 3 negative serial hs-CRPs.

Method

Retrospective chart review of infants born at ≥ 37 weeks gestational age (GA), started on antibiotics, and had serial hs-CRPs collected. The 12-hr hsCRP time point was chosen to evaluate the hypothesis. Infants were divided based on a cutoff level of 0.3 mg/dL.

Results

Forty infants were identified: mean birth weight of 3.19 (±0.47) kg and GA of 38 (± 1) weeks. 23 infants had a 12-hour HsCRP ≤0.30 mg/dL. They all had a negative blood culture, remained clinically well appearing, and all their serial hs-CRPs at ≤ 1 mg/dL. 22/23 infants received ≤48 hours antibiotics. One infant had antibiotics extended to 4 days due to hyperglycemia. 17 infants had their 12-hour hs-CRP >0.30 mg/dL. All had a negative blood culture and 6 infants received > 48 hours of antibiotics. Eleven infants had their third hs-CRP> 1mg/dl, figure. Using only a single HsCRP with a cutoff level ≤0.30 mg/dL led to a 96% NPV that infants would need antibiotics >48 hours. Sensitivity, specificity, and the positive predictive values were 86%, 67%, and 3% respectively.

Conclusion

Conclusion: At single HsCRP ≤0.30 mg/dl at 12 hours of life was associated with 96% NPV for infants being on antibiotics ≥ 48 hours. If confirmed in larger studies, these findings may help decrease the length of antibiotic therapy in well appearing term infants with suspected infection to 12 hours. Future directions would evaluate the NPV of HsCRP <0.3 mg/dL for holding off on starting antibiotics for cases with low index of suspected sepsis.
#28 Examining Adherence to World Health Organization (WHO) Latent Tuberculosis Pediatric Infection Guidelines Among 30 High Tuberculosis Burden Countries
Authors: Islam Sumaiya , Kiriella Dona , Oridota Olutobi , Dixit Avika
Published: June 2022

Background

Approximately 1.2 million children are estimated to be infected with tuberculosis (TB) worldwide. The World Health Organization (WHO) routinely updates guidelines for the treatment to lateen tuberculosis infection (LTBI) in children with the last update provided in 2020. The objective of our study was to assess the impact of these updates on national LTBI guidelines devised by 30 high burden countries.

Method

We collected National LTBI guidelines from health ministries of high burden countries. Eleven countries had guidelines that were in English and published in the last 6 years out of the 30 high burden countries. The guidelines from the respective countries were compared for concordance with the most recent WHO guidelines on LTBI management in the pediatric population.

Results

We identified four subsections of the WHO guidelines: at-risk groups for LTBI testing, algorithms to rule out active TB disease, testing for LTBI, and TB preventive treatment options. Guidelines from Nigeria and Pakistan had the highest concordance in identifying at-risk groups for LTBI at 83.3% each, whereas Namibia had the lowest concordance for this subcategory at 16.67% . Nigeria had 100% concordance in defining an algorithm to rule out active TB disease. Pakistan and Uganda had 80% concordance for algorithms to rule out disease. Philippines, Nigeria and Pakistan had 100% concordance with testing for LTBI, with Ethiopia, Kenya and Myanmar having the lowest concordance with 0%. Namibia and Myanmar had the highest concordance in regards to TB preventive treatment options, with 64% and 50% concordance respectively; all other included guidelines had low concordance for TB preventive treatment options.

Conclusion

Our study examined general concordance of national LTBI guidelines with the WHO guidelines and in the domains of identification, testing, algorithms, treatment, and prevention. Most guidelines among the high burden countries had high concordance in identifying at-risk groups for LTBI testing and algorithms to rule out active TB disease. Further research is needed to assess factors that lead to discordance between national and WHO guidelines.
#68 Prevalence of Staphylococcus aureus bacteremia at Saint Damien Hospital, Nos Petits Frères et Sœurs January 2020-June 2021, Haiti
Authors: St Vil Ymeline Pateau
Published: June 2022

Background

Nosocomial bacteremia is a healthcare-associated infection. It presents significant morbidity and mortality. Its prevention is based on the control of the risk factors, collection, and analysis of data to set up actions and measures aimed at educating staff, patients, and families to mitigate complications. Bacteremia is regularly monitored at Saint Damien Hospital (HSD);an increase in Staphylococcus aureus (SA) bacteremia was observed in January 2020. All SA infections were reviewed at St Damien during eighteen months to determine the prevalence of Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA) and the distribution by unit. Also, the frequency of nosocomial and community SA was determined. Nosocomial infections and those associated with SA remain a public health concern because of the antimicrobial resistance, the death rate, and the associated cost.

Method

A descriptive retrospective study was carried out over a period from January 2020 to June 2021 for all patients hospitalized in pediatrics who underwent a blood culture and whose results reported SA. Data were collected from microbiology laboratory registers and patient records.

Results

From January 2020 to June 2021, two thousand two hundred thirty-five (n = 2235) blood cultures were performed for a total of four thousand two hundred eighty-seven (n=4287) admissions. From these blood cultures performed, 11% of microorganisms (n=479) were isolated, of which 18.37% are SA (n=88). From these SA 68% were resistant to methicillin/MRSA (n=60), 32% sensitive to methicillin/MSSA (n=28).51% (n= 45) were associated with nosocomial infections (NI), 49% (n= 43) related to community infections. From the MRSA strains, 57% (n=34) are of nosocomial (NI) and 43% (n=26) are of community infection. These strains mainly came from emergency services 40% (n=24) followed by neonatology 22% (13) and intensive care 17% (10 ). The mortality rate for MRSA and MSSA were 32% (n=19) and 18% (n=5), respectively. 40% of MRSA isolates were multi-drug resistant (n=24). The resistance rate was 76% for penicillin (n=67) 65% for oxacillin (n=57) 35% for cefoxitin (n=31).

Conclusion

The frequency of isolation of Staphylococcus Aureus (SA) as well as the prevalence of SA and MRSA infections, was relatively high during this period. Its existence in a community setting and multidrug resistance to antibiotics is an alert making this bacteremia a public health priority to be monitored and brought under control.
Anomalous phenomena in cyclopropenylidene (c-C3H2) with accurate collisional rate coefficients
Authors: Sharma Mohit K , Chandra Suresh
Published: June 2022

Collisional rate coefficients are important parameters, but their calculation is a tedious task. Accurate collisional rate coefficients for collisional transitions between pure rotational levels of cyclopropenylidene (c-C3H2), colliding with He atom, are now available. Strong anomalous absorption line 220–211 at 21.587 GHz of cyclopropenylidene is found ubiquitous in interstellar medium. It is therefore worth to analyse the line spectrum of c-C3H2 using accurate collisional rate coefficients. After performing the Sobolev analysis of c-C3H2, we have found four anomalous absorption lines namely 22,0–21,1, 44,0–43,1, 33,0–32,1, and 43,2–50,5. We have also found two weak MASER lines, 40,4–33,1 and 51,4–44,1, which may make the detection of c-C3H2 in a cosmic object more convenient. Even for low kinetic temperature and low column density of cyclopropenylidene, the detection of 22,0–21,1 transition is possible, and it may be the reason for its detection in a large number of cosmic objects. The stability of results is tested.
A panchromatic view of star cluster formation in a simulated dwarf galaxy starburst
Authors: Lahén Natalia , Naab Thorsten , Kauffmann Guinevere
Published: June 2022

We present a photometric analysis of star and star cluster (SC) formation in a high-resolution simulation of a dwarf galaxy starburst that allows the formation of individual stars to be followed. Previous work demonstrated that the properties of the SCs formed in the simulation are in good agreement with observations. In this paper, we create mock spectral energy distributions and broad-band photometric images using the radiative transfer code skirt 9. We test several observational star formation rate (SFR) tracers and find that 24 $\mu$m, total infrared and Hα trace the underlying SFR during the (post)starburst phase, while UV tracers yield a more accurate picture of star formation during quiescent phases prior to and after the merger. We then place the simulated galaxy at distances of 10 and 50 Mpc and use aperture photometry at Hubble Space Telescope resolution to analyse the simulated SC population. During the starburst phase, a hierarchically forming set of SCs leads inaccurate source separation because of crowding. This results in estimated SC mass function slopes that are up to ∼0.3 shallower than the true slope of ∼−1.9 to −2 found for the bound clusters identified from the particle data in the simulation. The masses of the largest clusters are overestimated by a factor of up to 2.9 due to unresolved clusters within the apertures. The aperture-based analysis also produces a relation between cluster formation efficiency and SFR surface density that is slightly flatter than that recovered from bound clusters. The differences are strongest in quiescent SF environments.
Hot-mode accretion and the physics of thin-disc galaxy formation
Authors: Hafen Zachary , Stern Jonathan , Bullock James , Gurvich Alexander B , Yu Sijie , Faucher-Giguère Claude-André , Fielding Drummond B , Anglés-Alcázar Daniel , Quataert Eliot , Wetzel Andrew , Starkenburg Tjitske , Boylan-Kolchin Michael , Moreno Jorge , Feldmann Robert , El-Badry Kareem , Chan T K , Trapp Cameron , Kereš Dušan , Hopkins Philip F
Published: June 2022

We use FIRE simulations to study disc formation in z ∼ 0, Milky Way-mass galaxies, and conclude that a key ingredient for the formation of thin stellar discs is the ability for accreting gas to develop an aligned angular momentum distribution via internal cancellation prior to joining the galaxy. Among galaxies with a high fraction ($\gt 70{{\ \rm per\ cent}}$) of their young stars in a thin disc (h/R ∼ 0.1), we find that: (i) hot, virial-temperature gas dominates the inflowing gas mass on halo scales (≳20 kpc), with radiative losses offset by compression heating; (ii) this hot accretion proceeds until angular momentum support slows inward motion, at which point the gas cools to $\lesssim 10^4\, {\rm K}$; (iii) prior to cooling, the accreting gas develops an angular momentum distribution that is aligned with the galaxy disc, and while cooling transitions from a quasi-spherical spatial configuration to a more-flattened, disc-like configuration. We show that the existence of this ‘rotating cooling flow’ accretion mode is strongly correlated with the fraction of stars forming in a thin disc, using a sample of 17 z ∼ 0 galaxies spanning a halo mass range of 1010.5 M⊙ ≲ Mh ≲ 1012 M⊙ and stellar mass range of 108 M⊙ ≲ M⋆ ≲ 1011 M⊙. Notably, galaxies with a thick disc or irregular morphology do not undergo significant angular momentum alignment of gas prior to accretion and show no correspondence between halo gas cooling and flattening. Our results suggest that rotating cooling flows (or, more generally, rotating subsonic flows) that become coherent and angular momentum-supported prior to accretion on to the galaxy are likely a necessary condition for the formation of thin, star-forming disc galaxies in a ΛCDM universe.
Tree House Explorer: A Novel Genome Browser for Phylogenomics
Authors: Harris Andrew J , Foley Nicole M , Williams Tiffani L , Murphy William J
Published: June 2022

Tree House Explorer (THEx) is a genome browser that integrates phylogenomic data and genomic annotations into a single interactive platform for combined analysis. THEx allows users to visualize genome-wide variation in evolutionary histories and genetic divergence on a chromosome-by-chromosome basis, with continuous sliding window comparisons to gene annotations, recombination rates, and other user-specified, highly customizable feature annotations. THEx provides a new platform for interactive phylogenomic data visualization to analyze and interpret the diverse evolutionary histories woven throughout genomes. Hosted on Conda, THEx integrates seamlessly into new or pre-existing workflows.
A Dual Barcoding Approach to Bacterial Strain Nomenclature: Genomic Taxonomy ofKlebsiella pneumoniaeStrains
Authors: Hennart Melanie , Guglielmini Julien , Bridel Sébastien , Maiden Martin C J , Jolley Keith A. , Criscuolo Alexis , Brisse Sylvain
Published: June 2022

Sublineages (SLs) within microbial species can differ widely in their ecology and pathogenicity, and their precise definition is important in basic research and for industrial or public health applications. Widely accepted strategies to define SLs are currently missing, which confuses communication in population biology and epidemiological surveillance. Here, we propose a broadly applicable genomic classification and nomenclature approach for bacterial strains, using the prominent public health threat Klebsiella pneumoniae as a model. Based on a 629-gene core genome multilocus sequence typing (cgMLST) scheme, we devised a dual barcoding system that combines multilevel single linkage (MLSL) clustering and life identification numbers (LINs). Phylogenetic and clustering analyses of >7,000 genome sequences captured population structure discontinuities, which were used to guide the definition of 10 infraspecific genetic dissimilarity thresholds. The widely used 7-gene multilocus sequence typing (MLST) nomenclature was mapped onto MLSL SLs (threshold: 190 allelic mismatches) and clonal group (threshold: 43) identifiers for backwards nomenclature compatibility. The taxonomy is publicly accessible through a community-curated platform (https://bigsdb.pasteur.fr/klebsiella), which also enables external users’ genomic sequences identification. The proposed strain taxonomy combines two phylogenetically informative barcode systems that provide full stability (LIN codes) and nomenclatural continuity with previous nomenclature (MLSL). This species-specific dual barcoding strategy for the genomic taxonomy of microbial strains is broadly applicable and should contribute to unify global and cross-sector collaborative knowledge on the emergence and microevolution of bacterial pathogens.
Contemplation
Authors: Hare John E
Published: June 2022

The topic of the present article is a conceptualization of the notion of contemplation and will develop its reflection around three principal questions: (1) What is the role of desire in contemplation? (2) Is it we who contemplate, or the god who contemplates in us? (3) What is the relation between contemplation and the rest of human life?
Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer
Authors: Akıncılar Semih Can , Chua Joelle Yi Heng , Ng Qin Feng , Chan Claire Hian Tzer , Eslami-S Zahra , Chen Kaijing , Low Joo-Leng , Arumugam Surendar , Aswad Luay , Chua Clarinda , Tan Iain Beehuat , DasGupta Ramanuj , Fullwood Melissa Jane , Tergaonkar Vinay
Published: June 2022

Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. Elevated β-catenin and JunD level in CRC facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression. Pharmacological screens uncovered salinomycin, which inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter. Our results showed for the first time how known CRC alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.
Experimental paradigms revisited: oxidative stress-induced tRNA fragmentation does not correlate with stress granule formation but is associated with delayed cell death
Authors: Sanadgol Nasim , König Lisa , Drino Aleksej , Jovic Michaela , Schaefer Matthias R
Published: June 2022

tRNA fragmentation is an evolutionarily conserved molecular phenomenon. tRNA-derived small RNAs (tsRNAs) have been associated with many cellular processes, including improved survival during stress conditions. Here, we have revisited accepted experimental paradigms for modeling oxidative stress resulting in tRNA fragmentation. Various cell culture models were exposed to oxidative stressors followed by determining cell viability, the production of specific tsRNAs and stress granule formation. These experiments revealed that exposure to stress parameters commonly used to induce tRNA fragmentation negatively affected cell viability after stress removal. Quantification of specific tsRNA species in cells responding to experimental stress and in cells that were transfected with synthetic tsRNAs indicated that neither physiological nor non-physiological copy numbers of tsRNAs induced the formation of stress granules. Furthermore, the increased presence of tsRNA species in culture medium collected from stressed cells indicated that cells suffering from experimental stress exposure gave rise to stable extracellular tsRNAs. These findings suggest a need to modify current experimental stress paradigms in order to allow separating the function of tRNA fragmentation during the acute stress response from tRNA fragmentation as a consequence of ongoing cell death, which will have major implications for the current perception of the biological function of stress-induced tsRNAs.
RBFOX2-regulated TEAD1 alternative splicing plays a pivotal role in Hippo-YAP signaling
Authors: Choi Sunkyung , Lee Hyo Seong , Cho Namjoon , Kim Inyoung , Cheon Seongmin , Park Chungoo , Kim Eun-Mi , Kim Wantae , Kim Kee K
Published: June 2022

Alternative pre-mRNA splicing is key to proteome diversity; however, the biological roles of alternative splicing (AS) in signaling pathways remain elusive. Here, we focus on TEA domain transcription factor 1 (TEAD1), a YAP binding factor in the Hippo signaling pathway. Public database analyses showed that expression of YAP-TEAD target genes negatively correlated with the expression of a TEAD1 isoform lacking exon 6 (TEAD1ΔE6) but did not correlate with overall TEAD1 expression. We confirmed that the transcriptional activity and oncogenic properties of the full-length TEAD1 isoform were greater than those of TEAD1ΔE6, with the difference in transcription related to YAP interaction. Furthermore, we showed that RNA-binding Fox-1 homolog 2 (RBFOX2) promoted the inclusion of TEAD1 exon 6 via binding to the conserved GCAUG element in the downstream intron. These results suggest a regulatory mechanism of RBFOX2-mediated TEAD1 AS and provide insight into AS-specific modulation of signaling pathways.
Salivary potassium measured by genetically encoded potassium ion indicators as a surrogate for plasma potassium levels in hemodialysis patients—a proof-of-concept study
Authors: Deak Andras T , Belić Katarina , Meissl Anna-Maria , Artinger Katharina , Eller Kathrin , Rechberger Bernd , Niedrist Tobias , Graier Wolfgang F , Malli Roland , Bischof Helmut , Burgstaller Sandra , Blass Sandra , Avian Alexander , Rosenkranz Alexander R , Kirsch Alexander H
Published: June 2022

Background

Hyperkalemia is a common complication in cardiorenal patients treated with agents interfering with renal potassium (K+) excretion. It frequently leads to discontinuation of potentially life-saving medication, which has increased the importance of K+ monitoring. Non-invasive means to detect hyperkalemia are currently unavailable, but would be of potential use for therapy guidance. The aim of the present study was to assess the analytical performance of genetically encoded potassium-ion indicators (GEPIIs) in measuring salivary [K+] ([K+]Saliva) and to determine whether changes of [K+]Saliva depict those of [K+]Plasma.

Methods

We conducted this proof-of-concept study: saliva samples from 20 healthy volunteers as well as plasma and saliva from 29 patients on hemodialysis (HD) before and after three consecutive HD treatments were collected. We compared [K+]Saliva as assessed by the gold standard ion-selective electrode (ISE) with GEPII measurements.

Results

The Bland–Altmann analysis showed a strong agreement (bias 0.71; 95% limits of agreement from –2.79 to 4.40) between GEPII and ISE. Before treatment, patients on HD showed significantly higher [K+]Saliva compared with healthy controls [median 37.7 (30.85; 48.46) vs 23.8 (21.63; 25.23) mmol/L; P < .05]. [K+]Plasma in HD patients decreased significantly after dialysis. This was paralleled by a significant decrease in [K+]Saliva, and both parameters increased until the subsequent HD session. Despite similar kinetics, we found weak or no correlation between [K+]Plasma and [K+]Saliva.

Conclusion

GEPIIs have shown an excellent performance in determining [K+]Saliva. [K+]Plasma and [K+]Saliva exhibited similar kinetics. To determine whether saliva could be a suitable sample type to monitor [K+]Plasma, further testing in future studies are required.
OFFICE BLOOD PRESSURE MEASUREMENT: MEAN OF TWO OR OF THREE VALUES?
Authors: Paini Anna , Aggiusti Carlo , Bertacchini Fabio , Capellini Sara , Arnoldi Chiara , Cannata Marco , Caletti Stefano , Gatta Roberto , Stassaldi Deborah , Muiesan Maria Lorenza , Salvetti Massimo
Published: June 2022

Objective:

ESC/ESH 2018 hypertension guidelines recommend the calculation of the average of the last 2 blood pressure(BP) measurements(out of 3).This recommendation does not strictly correspond to previous recommendations of the ESC/ESH guidelines and to those of other international Societies.Furthermore, in several clinical trials mean BP values were calculated in different ways, more frequently by using the mean of three values(out of 3 measurements),or the mean of the last two (out of 2 or out of 3).

Aim of the study was to evaluate the effect of different methods for the calculation of the mean BP values on observed BP values and their relationship with hypertension mediated organ damage.

Design and method:

In 206 patients BP was measured by a physician with an automated validated oscillometric device(3 measurements at 1 min intervals after 5 minutes of rest).Mean values were computed by using a)the first two measurements (SAP1/2 and DAP1/2)or b)the last two(SAP2/3 and DAP2/3)or c)three measurements (SAP1/2/3 and DAP1/2/3).All patients also underwent an echocardiogram.

Results:

Mean age was 58 ± 15 years,57%F,BMI 27 ± 5,85% were hypertensives(78%treated).BP values were as follows:SAP1/2:135.5 ± 17.4; SAP1/2/3:134.0 ± 17.1;SAP2/3:132.4 ± 16.9 mmHg(ANOVA p < 0.01 for all comparisons);DAP1/2:77.4 ± 11.0;DAP1/2/3:77.0 ± 11.0;DAP2/3:76.7 ± 11.3(ANOVA p < 0.01 only for DAP1/2 vs DAP2/3).Left ventricular mass index(LVMI/h2.7) was correlated with all three means of SAP:(SAP1/2: r = 0.164, p < 0.05;SAP1/2/3:r = 0.168;SAP2/3:r = 0.185).Despite a trend for a better correlation between LVMI/h2.7 and SAP2/3,no difference between the correlation coefficients was observed at the Steiger’s Zeta test.Also the correlations between mean BP values and left atrial volume were similar (SAP1/2: r = 0.174;SAP1/2/3:r = 0.169;SAP2/3:r = 0.170,p < 0.05).

Conclusions:

BP values are lower when the mean of the last two values out of three is calculated as recommended by the 2018 ESC/ESH guidelines. Despite this, no difference in the correlations of mean BP values with cardiac organ damage were observed.
Trends in Primary Gallbladder Cancer Incidence and Incidence-based Mortality in the United States, 1973 to 2015
Authors: Low Soon Khai , Giannis Dimitrios , Thuong Nguyen D. , Nam Nguyen Hai , Alshareef Abdulmueti , Koulas Ioannis , Geropoulos Georgios , Moris Dimitrios , Molmenti Ernesto P. , Huy Nguyen Tien
Published: June 2022

Objectives:

Primary gallbladder cancer (GBC) is the most common biliary tract cancer with poor survival despite aggressive treatment. This study aimed to investigate the trends of GBC incidence and incidence-based mortality (IBM) over the last 4 decades.

Materials and Methods:

GBC cases diagnosed between 1973 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Incidence rates, IBM rates, and annual percent changes (APCs) were calculated and stratified according to population and tumor characteristics.

Results:

The cohort consisted of 10,792 predominantly white (81%) and female (71%) GBC patients. The overall GBC incidence decreased by 1.65% (95% confidence interval [CI]: 1.45% to 1.84%) per year since 1973, but has plateaued since 2002. IBM decreased by 1.69% (95% CI: 1.22% to 2.16%) per year from 1980 to 2015; the rate of decrease in IBM rates was lower during 1997 to 2015 (APC: −1.19%, 95% CI: −1.68% to −0.71%) compared with 1980 to 1997 (APC: −3.13%, 95% CI: −3.68% to −2.58%).

Conclusions:

The incidence and IBM rates of GBC have been decreasing over the last 40 years, but the decrease plateaued over the last 2 decades. The effects of treatment modalities, including laparoscopic cholecystectomy, adjuvant chemotherapy, and radiation on the incidence and IBM of GBC need to be further investigated.
Periocular Pigmented Basal Cell Carcinomas: Clinicopathologic Features and Mutational Profile
Authors: Hassanin Fadi , Al Hussain Hailah , Maktabi Azza , Adly Nouran , Alsuabeyl Mohammad , Abedalthagafi Malak , Edward Deepak P. , Strianese Diego
Published: June 2022

Purpose:

Pigmented basal cell carcinomas (PBCC) is an uncommon variant of basal cell carcinoma of the periocular region with limited information in the literature. We highlight the clinicopathological profile and somatic mutations in periocular PBCC.

Methods:

The clinicopathological features and somatic mutations in patients with periocular PBCC were examined and compared with periocular non-PBCC reported in the literature. Next-generation sequencing panel analysis for the excised tumors identified somatic mutations.

Results:

In a total of 31 patients, PBCC was common in females (54%; p = 0.03); as a unilateral lower eyelid (n = 22; 71%), solitary mass (n = 30; 98%). Pathologic subtypes were variable. Most were nodular or mixed variants (n = 23; 74%). During the follow up (2.5–4.5 years), 1 patient (3.5%) had a recurrence. The clinical and pathologic features of PBCC were similar to those reported in nonperiocular locations. Somatic mutations detected in 25/31 tumors. Variants in 50/161 genes in the panel were noted. PTCH1 (14/31), TERT (12/31), and SMO (7/31) variants were common. Fifteen patients had novel drivers, including POLE, FANCD2, and CREBBP. SMO mutations were significantly more common in females (7/7), lower eyelid (5/7), and TERT mutations were more common in nodular subtype (10/12).

Conclusions:

In this large cohort of a relatively uncommon variant of BCC, the clinicopathological features and tumor behavior of PBCC was similar to periocular non-PBCC. The somatic mutation spectrum of PBCC resembles that reported in nonperiocular cutaneous BCC with novel drivers identified. We identified several potential actionable mutations that could be targeted with molecular therapy.
Wells Syndrome Presenting as Atypical Periorbital Cellulitis
Authors: Vongsachang Hursuong , Bleicher Isaac D. , Reshef Edith R. , Stagner Anna M. , Wolkow Natalie
Published: June 2022

A 62-year-old man presented with diffuse, painless, left-sided preseptal edema, erythema, and woody induration extending to the left temple. The induration generated an orbital compartment syndrome with markedly elevated intraocular pressure necessitating lateral canthotomy and cantholysis. Although atypical for an infectious etiology, empiric broad-spectrum intravenous antibiotics were initiated with no improvement. A tissue biopsy demonstrated extensive perivascular and interstitial eosinophils with focal flame figures, and the patient was diagnosed with a severe hypersensitivity reaction or eosinophilic cellulitis (Wells syndrome). The disease process remitted rapidly upon initiation of oral prednisone. Wells syndrome is a rare inflammatory eosinophilic dermatosis, most often presenting in the limbs and trunk, with few reports of facial and periorbital involvement. This case highlights the importance of considering Wells syndrome in the differential diagnosis of atypical periorbital cellulitis that is nonresponsive to antibiotics and reviews the clinicopathologic nature of this disease.
Ophthalmic Presentation and Outcome for Sinonasal Mucoceles
Authors: Malik Mohsan , Vahdani Kaveh , Rose Geoffrey E.
Published: June 2022

Purpose:

The purpose of this study was to evaluate ophthalmic features and outcomes for patients who present with sinonasal mucoceles expanding into the orbit.

Patients and Methods:

Retrospective chart review for patients seen in a specialist orbital clinic over 25 years, with a review of demographics, clinical characteristics, imaging features, and outcomes after treatment.

Results:

Sixty patients (38 males; 63%) presented at a mean age of 51 years (range 3–89). Symptom duration was extremely variable (1 week–15 years) with a mean of 14 months and median of 4 months—the commonest being periorbital swelling (33/62 orbits) or ache (20 orbits), proptosis (30 orbits), and diplopia (19/50 patients without visual impairment; 38%). Of mucoceles affecting orbital function, 60/62 (97%) were of frontal and/or ethmoid sinus origin, and probable predispositions included past trauma (12/62 orbits) or prior ipsilateral sinus surgery (14 orbits). Forty-two of the 59 (71%) patients who underwent sinus surgery had complete resolution of symptoms within 6 months. Of 10 orbits presenting with moderate to severe visual loss (Snellen 20/60 or worse), the acuity improved in 7/10 (70%) of these after sinus surgery. Although 12/62 (19%) of eyes presented with epiphora, this persisted after sinus surgery in 9 orbits, and areas of occult malignant change were found in 3/9 (33%).

Conclusion:

Sinus mucoceles expanding into the orbit can cause significant globe displacement, dysmotility, or visual impairment. Symptoms usually resolve within several months after functional sinus surgery, but where symptoms persist (particularly periorbital swelling or epiphora) this might indicate underlying secondary causes, such as occult malignancy.
Meta-analysis and Systematic Review of Bronchoscopic Lung Volume Reduction Through Endobronchial Valves in Severe Emphysema
Authors: Patel Maulin , Chowdhury Junad , Zhao Huaqing , Lu Xiaoning , Roth Stephanie , Giovacchini Coral X. , Wahidi Momen M. , Criner Gerard
Published: June 2022

Background:

Pharmacologic therapeutics for advanced emphysema have limited benefit. Bronchoscopic lung volume reduction with endobronchial valves (EBVs) have reported improvements in lung function, breathlessness, and quality of life through randomized clinical trials, with less morbidity as comparted to Surgical Lung volume Reduction. We here present a Meta-analysis and systematic review of bronchoscopic lung volume reduction in advanced chronic obstructive lung disease patients

Methods:

PubMed (NLM), Embase (Elsevier), and Web of Science (Clarivate Analytics) search was conducted using a combination of keywords and subject headings. The search was confined to the last 15 years and was completed on October 23, 2020. Only placebo-controlled randomized control trials of emphysema patients with EBV were included. Quality assessment was done by 2 independent reviewers.

Results:

Nine studies were included for the meta-analysis with a total number of 1383 patients of whom 888 received EBV and 495 standard of care (SOC) medications. Our Metanalysis show statistically significant improvement in forced expiratory volume in first second, percentage forced expiratory volume in first second, St. George’s respiratory questionnaire, and 6-minute walk distance in EBV group compared with SOC. Residual volume had statistically significant reduction after EBV placement compared with SOC. These differences continued to be present during short-term (<=6 mo) and long-term follow-up (>=6 mo). These improvements were even higher when the EBV patients’. Collateral ventilation was negative/fissure was intact (CV−/FI >90%). The rate of hemoptysis and pneumothorax was higher in the EBV group compared with SOC, however, did not lead to increased fatal outcomes.

Conclusion:

In conclusion, EBV has favorable effects on patients’ outcomes in patients who have heterogeneous emphysema particularly with no collateral ventilation.
Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death
Authors: Avelar Rita A. , Armstrong Amy J. , Carvette Gracie , Puleo Noah , Gupta Riya , Colina Jose , Joseph Peronne , Sobeck Alex , O’Connor Caitlin M. , Gandhi Agharnan , Dziubinski Michele L. , Ma Daniel Shanhuai , Waggoner Steven , Zanotti Kristine , Nagel Christa , Resnick Kimberly , Singh Sareena , Thomas Daffyd , Skala Stephanie , Zhang Junran , Narla Goutham , DiFeo Analisa
Published: June 2022

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, only ∼30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for transformation (B56α,B56γ and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and -deficient cells and in patient-derived xenograft models. Our studies identify PP2A as novel regulator of HR and introduces PP2A activators as a potential treatment for HGSC tumors. Our studies further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 has presented benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.
Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2
Authors: Planchais Cyril , Reyes-Ruiz Alejandra , Lacombe Robin , Zarantonello Alessandra , Lecerf Maxime , Revel Margot , Roumenina Lubka T. , Atanasov Boris P. , Mouquet Hugo , Dimitrov Jordan D.
Published: June 2022

SARS-CoV-2 infects cells by attachment to its receptor – the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS-CoV-2 variants of concern (VOC). Data on kinetics, activation- and equilibrium thermodynamics of binding of the receptor binding domain (RBD) from VOC with ACE2 as well as data from computational protein electrostatics revealed a profound remodeling of the physicochemical characteristics of the interaction during the evolution. Thus, as compared to RBDs from Wuhan strain and other VOC, Omicron RBD presented as a unique protein in terms of conformational dynamics and types of non-covalent forces driving the complex formation with ACE2. Viral evolution resulted in a restriction of the RBD structural dynamics, and a shift to a major role of polar forces for ACE2 binding. Further, we investigated how the reshaping of the physicochemical characteristics of interaction affect the binding specificity of S proteins. Data from various binding assays revealed that SARS-CoV-2 Wuhan and Omicron RBDs manifest capacity for promiscuous recognition of unrelated human proteins, but they harbor distinct reactivity patterns. These findings might contribute for mechanistic understanding of the viral tropism, and capacity to evade immune responses during evolution.
Unexpected death from hepatic abscess 16 months after toothbrush ingestion
Authors: Zhao Guoting , Zhao Shuquan , Wang Songjun , Liu Xia , Qi Qian , Li Yingmin , Zuo Min
Published: June 2022

The development of a hepatic abscess secondary to foreign body (FB) ingestion remains rare in forensic practice. Herein, we present a case of a prisoner who died in the hospital and a forensic autopsy was performed to confirm the cause of death. A 14.5‐cm‐long toothbrush handle was found in the duodenum and had penetrated the right lobe of the liver, consistent with the repeated abdominal pain in his clinical history. The clinical history and investigation confirmed that he had ingested the toothbrush handle 16 months prior. This case highlights a rare complication of intentional ingestion of foreign bodies, and pathologists should be aware of this rare entity which links hepatic abscess and FB ingestion.
Exsanguination from ruptured femoral artery pseudoaneurysm – A fatal complication of groin heroin injection
Authors: Leković Aleksa , Živković Vladimir , Nikolić Slobodan
Published: June 2022

Intravenous drug users (IDUs) eventually encounter a common problem– a need to turn to a new vessel to inject drugs. Whether it is because no other spot is available due to scarring or convenience, the groin is the preferred spot for some. Chronic puncture of femoral vessels can lead to a rare but significant complication– femoral artery pseudoaneurysm (FAP). Its fatal consequence– rupture and bleeding is well recognized, but the forensic literature on this subject is limited. We present eight cases of exsanguination due to the ruptured FAP in IDUs who share most or all the following characteristics: long‐term heroin use and/or pronounced drug use stigmata, chronic groin injection‐related lesions, absence of significant precipitating pseudoaneurysm trauma, and no or minimal concentrations of heroin metabolites in blood. The FAP presentation varied greatly, from palpable fist‐sized mass or slight elevation under the skin defect to infundibular arterio‐cutaneous fistula that ruptured through the skin induration. In some, surrounding skin or soft tissue showed signs of inflammation but without suppuration. The most prominent FAP characteristic was smooth‐surface cavitation on cross‐sections. We performed microscopic evaluation in two cases and verified disruption of the artery wall (i.e., pseudoaneurysm) with elements of acute and chronic inflammation and fibrosis; foci of fibrinoid necrosis were noticed on the arterial wall. All subjects were pale, with faint hypostasis and organ anemia, consistent with reported massive hemorrhage. Because such sudden, unwitnessed, and suspicious deaths may raise the question of injury infliction, proper autopsy evaluation is crucial, for which we propose guidelines.