bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic and pharmacodynamic properties of polymyxin B in Escherichia coli and Klebsiella pneumoniae murine infection models
Authors: van der Meijden Aart , Aranzana-Climent Vincent , van der Spek Heleen , de Winter Brenda C M , Couet William , Meletiadis Joseph , Muller Anouk E , van den Berg Sanne
Published: January 2023

Background

Although polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index.

Methods

We determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains.

Results

The pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose–effect model for the fCmax/MIC index of E. coli fitted best, but was only modestly higher than the R2 of %fT>MIC and fAUC/MIC (R2 0.91–0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R2 of %fT>MIC and fCmax/MIC (R2 0.85–0.91). Static targets of polymyxin B fAUC/MIC were 27.5–102.6 (median 63.5) and 5.9–60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L.

Conclusions

This study confirms that fAUC/MIC can describe the exposure–response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy.
Deep-learning-based fault detection and recipe optimization for a plastic injection molding process under the class-imbalance problem
Authors: Ko Jin Uk , Lee Jinwook , Kim Taehun , Kim Yong Chae , Youn Byeng D
Published: January 2023

This paper proposes a supervised learning with a class-balancing loss function (SL-CBL) approach for fault detection and feature-similarity-based recipe optimization (FSRO) for a plastic injection molding process. SL-CBL is a novel method that can accurately classify an input sample as a normal or fault condition, even when the training data are severely class-imbalanced. The proposed class-balancing loss function consists of the weighted focal loss and the loss of the F1 score; together, these are used to correctly classify even a small number of faulty samples. SL-CBL is investigated with four classifiers of different structures; the classifiers consist of several fully connected and batch normalization layers. FSRO is an optimization scheme that finds the optimal recipe whose feature is similar to the features of normal samples. The optimal solution is obtained by minimizing the Euclidean distance to the centroid of the normal features. In this research, the proposed SL-CBL and FSRO methods are validated by applying them to an industrial plastic injection molding dataset. The validation results show that the proposed SL-CBL approach achieves the highest F1 score with the lowest misclassification rate, as compared to the alternative methods. When visualizing the feature space, the optimal recipe found by the FSRO scheme was found to be close to the centroid of the normal features, even if the initial recipe is classified as a fault. Furthermore, each variable of the optimized recipe lies within the confidence interval of 3${\rm{\sigma }}$ for the normal condition. This indicates that the optimal recipe is statistically similar to the normal samples.
Biology and Management of Lesser Mealworm Alphitobius diaperinus (Coleoptera: Tenebrionidae) in Broiler Houses
Authors: Sammarco Ben C , Hinkle Nancy C , Crossley Michael S
Published: January 2023

Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae), the lesser mealworm, is a ubiquitous generalist  pest of poultry broiler and layer facilities, originating in southern Africa and now found worldwide. They spend their full life cycle within the litter and manure of poultry, causing structural damage to poultry houses, injuring birds, and acting as a reservoir for several avian pathogens, notably Salmonella spp. and Escherichia coli. Management commonly consists of spraying walls and floors of poultry houses with organophosphates, pyrethroids, neonicotinoids, or spinosyns between flocks, and periodic removal and replacement of litter. Populations have been observed to become resistant to specific insecticides after ca. 10 yr of consistent use and exhibit cross resistance to insecticides of the same mode of action. Alternative cultural and biological control methods have been identified but are not currently implemented. More research is needed regarding the economic impact of A. diaperinus, the mechanisms of its insecticide resistance, and patterns and mechanisms of colonization for effective integrated pest management programs to be devised and implemented.
An integrated abundance model for estimating county-level prevalence of opioid misuse in Ohio
Authors: Hepler Staci A , Kline David M , Bonny Andrea , McKnight Erin , Waller Lance A
Published: January 2023

Opioid misuse is a national epidemic and a significant drug-related threat to the United States. While the scale of the problem is undeniable, estimates of the local prevalence of opioid misuse are lacking, despite their importance to policy-making and resource allocation. This is due, in part, to the challenge of directly measuring opioid misuse at a local level. In this paper, we develop a Bayesian hierarchical spatio-temporal abundance model that integrates indirect county-level data on opioid-related outcomes with state-level survey estimates on prevalence of opioid misuse to estimate the latent county-level prevalence and counts of people who misuse opioids. A simulation study shows that our integrated model accurately recovers the latent counts and prevalence. We apply our model to county-level surveillance data on opioid overdose deaths and treatment admissions from the state of Ohio. Our proposed framework can be applied to other applications of small area estimation for hard to reach populations, which is a common occurrence with many health conditions such as those related to illicit behaviours.
How many nerve fibers innervate the human glans clitoris: a histomorphometric evaluation of the dorsal nerve of the clitoris
Authors: Uloko Maria , Isabey Erika P , Peters Blair R
Published: January 2023

Introduction

It is frequently quoted in mainstream media that the clitoris has “8000 nerve endings.” However, no study has yet quantified the number of nerve fibers (axons) innervating the human clitoris. The dorsal nerves of the clitoris (DNCs) are the primary source of sensation and somatic clitoral innervation. Therefore, reporting the number of axons in the DNCs is an important step in our understanding of clitoral innervation and sexual response with implications for many fields of medical practice. The purpose of this study is to quantify the mean number of axons in the human DNCs and to report the approximate mean number of nerve fibers that innervate the human glans clitoris.

Methods

DNC samples were obtained from 7 transmasculine patients undergoing gender-affirming phalloplasty surgery. At the time of nerve coaptation, a small excess of the DNC (5 mm) was collected for analysis at the proximal level of the clitoral body, just distal of the emergence of the DNCs from underneath the pubic symphysis. Samples were placed into 3% glutaraldehyde fixative, postfixed in 1% osmium tetroxide, and serially dehydrated in ethanol and toluene. Samples were then embedded in araldite, sectioned on an ultramicrotome into 1-μm cross sections, and counterstained with 1% toluidine blue. Histomorphometric evaluation was performed at 1000x magnification with a Leitz Laborlux S microscope and image analysis software (Clemex Vision Professional) to obtain an axon counts. Descriptive statistics were performed to yield a mean and standard deviation of the number of axons in the DNCs. Assuming anatomic symmetry between bilateral DNCs, mean total number of somatic nerve fibers innervating the human glans clitoris was obtained by doubling the mean count of the DNCs.

Results

Seven sample DNCs were collected. Of those, 5 were analyzed as 2 did not have sufficient nerve tissue present. The mean number of nerve fibers in the human DNCs was 5140 (SD = 218.4). The mean number of myelinated nerve fibers innervating the human clitoris was 10,281 (SD = 436.8).

Conclusion

This study is the first to report the number of axons in the human DNC, at a mean 5140. Given the bilateral nature of clitoral innervation and symmetry of anatomic structures, the approximate mean number of myelinated axons that innervate the human glans clitoris is 10,280. When the uncaptured unmyelinated fibers and contributions from the cavernosal innervation are accounted for, it is clear that far Moree than 8000 axons innervate the human clitoris.
Nearest-neighbor parameters for the prediction of RNA duplex stability in diverse in vitro and cellular-like crowding conditions
Authors: Ghosh Saptarshi , Takahashi Shuntaro , Banerjee Dipanwita , Ohyama Tatsuya , Endoh Tamaki , Tateishi-Karimata Hisae , Sugimoto Naoki
Published: January 2023

RNA performs various spatiotemporal functions in living cells. As the solution environments significantly affect the stability of RNA duplexes, a stability prediction of the RNA duplexes in diverse crowded conditions is required to understand and modulate gene expression in heterogeneously crowded intracellular conditions. Herein, we determined the nearest-neighbor (NN) parameters for RNA duplex formation when subjected to crowding conditions with an ionic concentration relevant to that found in cells. Determination of the individual contributions of excluded volume effect and water activity to each of the NN parameters in crowded environments enabled prediction of the thermodynamic parameters and their melting temperatures for plenty of tested RNA duplex formation in vitro and in cell with significant accuracy. The parameters reported herein will help predicting RNA duplex stability in different crowded environments, which will lead to an improved understanding of the stability-function relationship for RNAs in various cellular organelles with different molecular environments.
SPRTN-dependent DPC degradation precedes repair of damaged DNA: a proof of concept revealed by the STAR assay
Authors: Glumac Mateo , Polović Mirjana , Batel Anja , Gelemanović Andrea , Maček Boris , Velić Ana , Marinović-Terzić Ivana
Published: January 2023

DNA-protein crosslinks (DPCs), formed by the covalent conjugation of proteins to DNA, are toxic lesions that interfere with DNA metabolic processing and transcription. The development of an accurate biochemical assay for DPC isolation is a priority for the mechanistic understanding of their repair. Here, we propose the STAR assay for the direct quantification of DPCs, sensitive to physiologically relevant treatment conditions. Implementing the STAR assay revealed the formation of small cross-linked peptides on DNA, created by the proteolytic degradation of DPCs by SPRTN. The initial proteolytic degradation of DPCs is required for the downstream activation of DNA repair, which is mediated through the phosphorylation of H2Ax. This leads to the accumulation of DNA repair factors on chromatin and the subsequent complete removal of the cross-linked peptides. These results confirmed that the repair of DPCs is a two-step process, starting with proteolytic resection by SPRTN, followed by the repair of the underlying damage to the DNA.
An intellectual disability-related MED23 mutation dysregulates gene expression by altering chromatin conformation and enhancer activities
Authors: Yang Yenan , Li Chonghui , Chen Ziyin , Zhang Yiyang , Tian Qing , Sun Meiling , Zhang Shuai , Yu Miao , Wang Gang
Published: January 2023

Transcriptional Mediator controls diverse gene programs for various developmental and pathological processes. The human Mediator MED23/R617Q mutation was reported in a familial intellectual disability (ID) disorder, although the underlying mechanisms remain poorly understood. Constructed by gene editing, the Med23/R617Q knock-in mutant mice exhibited embryonic lethality due to the largely reduced Med23/R617Q protein level, but the R617Q mutation in HEK293T cells didn’t change its expression and incorporation into Mediator Complex. RNA-seq revealed that MED23/R617Q mutation disturbed gene expression, related to neural development, learning and memory. Specifically, R617Q mutation reduced the MED23-dependent activities of ELK1 and E1A, but in contrast, upregulated the MAPK/ELK1-driven early immediate genes (IEGs) JUN and FOS. ChIP-seq and Hi-C revealed that the MED23 R617Q mutation reprogramed a subset of enhancers and local chromatin interactions, which correlated well with the corresponding gene expression. Importantly, the enhancers and chromatin interactions surrounding IEGs were unchanged by the R617Q mutation, but DACH1, an upstream repressor of IEGs, showed reduced enhancer-promoter interactions and decreased expression in mutant cells, thus relieving its inhibition to the intellectual-related IEGs. Overall, unraveling the MED23-DACH1-IEG axis provides a mechanistic explanation for the effects of the MED23/R617Q mutation on gene dysregulation and inherited ID.
Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing
Authors: He Liu , Lever Rebecca , Cubbon Andrew , Tehseen Muhammad , Jenkins Tabitha , Nottingham Alice O , Horton Anya , Betts Hannah , Fisher Martin , Hamdan Samir M , Soultanas Panos , Bolt Edward L
Published: January 2023

DNA strand breaks are repaired by DNA synthesis from an exposed DNA end paired with a homologous DNA template. DNA polymerase delta (Pol δ) catalyses DNA synthesis in multiple eukaryotic DNA break repair pathways but triggers genome instability unless its activity is restrained. We show that human HelQ halts DNA synthesis by isolated Pol δ and Pol δ-PCNA-RPA holoenzyme. Using novel HelQ mutant proteins we identify that inhibition of Pol δ is independent of DNA binding, and maps to a 70 amino acid intrinsically disordered region of HelQ. Pol δ and its POLD3 subunit robustly stimulated DNA single-strand annealing by HelQ, and POLD3 and HelQ interact physically via the intrinsically disordered HelQ region. This data, and inability of HelQ to inhibit DNA synthesis by the POLD1 catalytic subunit of Pol δ, reveal a mechanism for limiting DNA synthesis and promoting DNA strand annealing during human DNA break repair, which centres on POLD3.
Application of microfluidic chip electrophoresis for high-throughput nucleic acid fluorescence fragment analysis assays
Authors: Sun Yali , Lu Zhi-xiang , Miller Michael , Perroud Thomas , Tong Yanhong
Published: January 2023

Nucleic acid fragment analysis via separation and detection are routine operations in molecular biology. However, analysis of small single-stranded nucleic acid fragments (<100nt) is challenging and mainly limited to labor-intensive polyacrylamide gel electrophoresis or high-cost capillary electrophoresis methods. Here we report an alternative method, a microfluidic chip electrophoresis system that provides a size resolution of 5nt and a detection time of one minute per sample of fluorescence-labeled DNA/RNA fragments. The feasibility of this system was evaluated by quantifying CRISPR-Cas9 cleavage efficiency and the detection resolution was evaluated by analyzing ssDNA/RNA adenylation and phosphorylation. We employed this system to study the RNA capping efficiency and double-stranded DNA unwinding efficiency in isothermal amplification as two examples for assay design and evaluation. The microfluidic chip electrophoresis system provides a rapid, sensitive, and high-throughput fluorescence fragment analysis (FFA), and can be applied for enzyme characterization, reaction optimization, and product quality control in various molecular biology processes.
The Scottish COVID Cancer Immunity Prevalence Study: A Longitudinal Study of SARS-CoV-2 Immune Response in Patients Receiving Anti–Cancer Treatment
Authors: Purshouse Karin , Thomson John P , Vallet Mahéva , Alexander Lorna , Bonisteel Isaac , Brennan Maree , Cameron David A , Figueroa Jonine D , Furrie Elizabeth , Haig Pamela , Heck Mattea , McCaughan Hugh , Mitchell Paul , McVicars Heather , Primrose Lorraine , Silva Ines , Templeton Kate , Wilson Natalie , Hall Peter S
Published: January 2023

Background

Cancer and anti-cancer treatment (ACT) may be risk factors for severe SARS-CoV-2 infection and limited vaccine efficacy. Long–term longitudinal studies are needed to evaluate these risks. The Scottish COVID cancer immunity prevalence (SCCAMP) study characterizes the incidence and outcomes of SARS-CoV-2 infection and vaccination in patients with solid tumors undergoing ACT. This preliminary analysis includes 766 patients recruited since May 2020.

Methods

Patients with solid-organ cancers attending secondary care for active ACT consented to the collection of routine electronic health record data and serial blood samples over 12 months. Blood samples were tested for total SARS-CoV-2 antibody.

Results

A total of 766 participants were recruited between May 28, 2020 and October 31, 2021. Most received cytotoxic chemotherapy (79%). Among the participants, 48 (6.3%) were tested positive for SARS-CoV-2 by PCR. Infection rates were unaffected by ACT, largely aligning with the local population. Mortality proportion was not higher with a recent positive SARS-CoV-2 PCR (10.4% vs 10.6%). Multivariate analysis revealed lower infection rates in vaccinated patients regardless of chemotherapy (HR 0.307 [95% CI, 0.144-0.6548]) or immunotherapy (HR 0.314 [95% CI, 0.041-2.367]) treatment. A total of 96.3% of patients successfully raised SARS-CoV-2 antibodies after >2 vaccines. This was independent of the treatment type.

Conclusion

This is the largest on-going longitudinal real-world dataset of patients undergoing ACT during the early stages of the COVID-19 pandemic. This preliminary analysis demonstrates that patients with solid tumors undergoing ACT have high protection from SARS-CoV-2 infection following COVID-19 vaccination. The SCCAMP study will evaluate long–term COVID-19 antibody trends, focusing on specific ACTs and patient subgroups.
Neuroimaging the effects of smartphone (over-)use on brain function and structure—a review on the current state of MRI-based findings and a roadmap for future research
Authors: Montag Christian , Becker Benjamin
Published: January 2023

The smartphone represents a transformative device that dramatically changed our daily lives, including how we communicate, work, entertain ourselves, and navigate through unknown territory. Given its ubiquitous availability and impact on nearly every aspect of our lives, debates on the potential impact of smartphone (over-)use on the brain and whether smartphone use can be “addictive” have increased over the last years. Several studies have used magnetic resonance imaging to characterize associations between individual differences in excessive smartphone use and variations in brain structure or function. Therefore, it is an opportune time to summarize and critically reflect on the available studies. Following this overview, we present a roadmap for future research to improve our understanding of how excessive smartphone use can affect the brain, mental health, and cognitive and affective functions.
Stalled Racial Progress and Japanese Trade in the 1970s and 1980s
Authors: Batistich Mary Kate , Bond Timothy N
Published: January 2023

We assess the impact of a rapid rise in Japanese import competition on the growth in racial earnings and employment gaps during the 1970s and 80s. Using commuting zone level variation in exposure, we find Japanese competition led to a decrease in manufacturing employment and labour force participation for blacks. This was driven by a shift in demand for skill in manufacturing. The difference in effects between the 10th percentile most and least exposed commuting zone was equivalent to 36–46% of the relative rise in black non-labour force participation, and 78–96% of the relative decline in black median male earnings.
The Triad of Childhood-Onset Schizophrenia, Autism Spectrum Disorder, and Catatonia: A Case Report
Authors: Leslie Alison C , O’Sullivan Michael
Published: January 2023

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia with an estimated prevalence of 1/10,000. Schizophrenia and Autism spectrum disorder (ASD) have shared phenotypic features and shared genetic etiology. There is growing research surrounding the co-occurrence of psychomotor syndromes like catatonia with neurodevelopmental disorders like ASD or psychiatric disorders like schizophrenia. In 2013, Shorter and Wachtel described a phenomenon of the ‘Iron Triangle’ where COS, ASD, and catatonia often co-occur. The Iron Triangle theory is based on observation of historical case literature, which showed that all three diagnoses in the Iron Triangle were routinely assigned to children and adolescents. The pattern of this “Iron Triangle” suggests there may be a single underlying pathology resulting in a unique mixed form of catatonia, autism, and psychosis. We describe the case of a boy with sequential development of COS, ASD, and catatonia who also has syndromic facial and musculoskeletal features. This case highlights overlapping diagnostic features of these three disorders and can help us better understand how “hidden” features of catatonia may occur in patients with COS or ASD but go unrecognized, because they are grouped as features under autism/schizophrenia rather than a distinct diagnosis of catatonia. Further study is warranted to elucidate if this phenotypic pattern constitutes a new single diagnosis that is not well understood, an endophenotype of schizophrenia, or if this is the result of phenomenological overlap between catatonia, ASD, and COS.
Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior inDrosophila melanogaster
Authors: Olivares Gonzalo H , Núñez-Villegas Franco , Candia Noemi , Oróstica Karen , González-Ramírez M Constanza , Vega-Macaya Franco , Zúñiga Nolberto , Molina Cristian , Oliva Carlos , Mackay Trudy F C , Verdugo Ricardo A , Olguín Patricio
Published: January 2023

The mechanisms by which the genotype interacts with nutrition during development to contribute to the variation of complex behaviors and brain morphology of adults are not well understood. Here we use the Drosophila Genetic Reference Panel to identify genes and pathways underlying these interactions in sleep behavior and mushroom body morphology. We show that early-life nutritional restriction effects on sleep behavior and brain morphology depends on the genotype. We mapped genes associated with sleep sensitivity to early-life nutrition, which were enriched for protein-protein interactions responsible for translation, endocytosis regulation, ubiquitination, lipid metabolism, and neural development. By manipulating the expression of candidate genes in the mushroom bodies (MBs) and all neurons, we confirm that genes regulating neural development, translation and insulin signaling contribute to the variable response of sleep and brain morphology to early-life nutrition. We show that the interaction between differential expression of candidate genes with nutritional restriction in early life resides in the MBs or other neurons and that these effects are sex-specific. Natural variations in genes that control the systemic response to nutrition and brain development and function interact with early-life nutrition in different types of neurons to contribute to the variation of brain morphology and adult sleep behavior.
Unrelated Donor Cord Blood Transplantation in Children: Lessons Learned Over 3 Decades
Authors: Kurtzberg Joanne , Troy Jesse D , Page Kristin M , El Ayoubi Hanadi Rafii , Volt Fernanda , Maria Scigliuolo Graziana , Cappelli Barbara , Rocha Vanderson , Ruggeri Annalisa , Gluckman Eliane
Published: January 2023

Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al. reported the first successful matched sibling cord blood transplant (CBT) in a child with Fanconi Anemia. In 1991, Rubinstein et al. established an unrelated donor CB bank, and in 1993, the first unrelated CBT used a unit from this bank. Since that time, >40 000 CBTs have been performed worldwide. Early outcomes of CBT were mixed and demonstrated the importance of cell dose from the CB donor. We hypothesized that improvements in CB banking and transplantation favorably impacted outcomes of CBT today and performed a retrospective study combining data from Eurocord and Duke University in 4834 children transplanted with a single unrelated CB unit (CBU) from 1993 to 2019. Changes in standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic graft-versus-host disease [GvHD], treatment related mortality [TRM], and relapse) over 3 time periods (1: <2005; 2: 2005 to <2010; and 3: >2010 to 2019) were studied. Increased cell dose and degree of HLA matching were observed over time. OS, times to engraftment, and DFS improved over time. The incidence of TRM and GvHD decreased while the incidence of relapse remained unchanged. Relative contributions of cell dose and HLA matching to transplant outcomes were also assessed and showed that HLA matching was more important than cell dose in this pediatric cohort.
Phylogenetic origin of Helicobacter pylori pathogenicity island and risk of stomach cancer and high-grade premalignant gastric lesions
Authors: Canzian Federico , Rizzato Cosmeri , Stein Angelika , Flores-Luna Lourdes , Camorlinga-Ponce Margarita , Mendez-Tenorio Alfonso , Chen Wei , Kasamatsu Elena , Mercedes Bravo Maria , Torres Javier , Muñoz Nubia , Kato Ikuko
Published: January 2023

Infection by Helicobacter pylori (Hp) has been causally linked to risk of gastric cancer (GC). The coevolution of Hp and humans shaped the risk of GC as our species left Africa and migrated to the other continents. Latin America (LatAm) is a high GC incidence region where Hp evolved uniquely in the 500 years since European colonization. Differential virulence of the Hp cagA-pathogenicity island (cagPAI) by ancestral origin has been reported. We hypothesized that Hp phylogenetic origin might play a role in determining GC risk in LatAm. We used genotypes of 50 Hp genetic variants mapping to the Hp cagPAI, studied in 1220 subjects from Venezuela, Colombia, Mexico and Paraguay, who were infected with cagA-positive Hp, including 150 GC, 177 high-grade premalignant lesions (HGPMLs) and 893 low-grade premalignant lesions. We estimated the phylogenetic origin of Hp cagPAI in all study subjects by use of the STRUCTURE software and principal component analysis (PCA) and tested whether the estimated African ancestry percentage was associated with the risk of GC or HGPML. African ancestral component estimates by STRUCTURE and PCA were highly correlated. STRUCTURE-based African origin estimate was not significantly associated with the risk of HGPML, but it was inversely associated with GC risk: the OR associated with the continuous values of African component was 0.09 (95% CI, 0.01–0.85; P = 0.035). Similar trends were observed for GC with PCA-based estimates, but the association was not statistically significant. These results suggest that Hp ancestral origin may play a role in gastric carcinogenesis.
Molecular profiling of primary uveal melanoma: results of a Polish cohort
Authors: Kowalik Artur , Karpinski Pawel , Markiewicz Anna , Orlowska-Heitzman Jolanta , Romanowska-Dixon Bozena , Donizy Piotr , Hoang Mai P.
Published: January 2023

There is no published data regarding the molecular alterations of Polish patients with primary uveal melanoma. We performed whole exome sequencing of 20 primary uveal melanomas (UMs), 10 metastasizing and 10 non-metastasizing cases to identify significant molecular alterations. We detected mutations and copy number variants in the BAP1 gene in 50% (10 cases) of the cases. GNA11 mutations were detected in 50% (10 cases) including nine p.Q209L and one p.R183C. GNAQ mutations gene were detected in 40% (8 cases) and all were p.Q209P. SF3B1, EIF1AX, PLCB4, and PALB2 mutations were detected in one case each. Genetic aberrations of FBXW7 were detected in 55% of cases, with copy number loss of 10 and missense mutation in one. Gain or loss of copy number was observed in 60%, 60%, and 10% of cases in MYC, MLH1, and CDKN2A genes, respectively. BAP1 and GNAQ tumor suppressor genes are more often mutated in UM with metastasis, while GNA11 mutations are more frequently detected in non-metastasizing tumors. MYC copy gain was present twice as frequently (80% versus 40%) in cases with versus those without metastases. BAP1 mutation correlated with worse overall survival; while GNA11 mutation and CDKN2A loss correlated with better and worse progression-free survival, respectively. We have confirmed BAP1 prognostic potential and documented frequent MYC amplification in metastasizing cases. Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.
Effectiveness of Remdesivir Treatment Protocols Among Patients Hospitalized with COVID-19: A Target Trial Emulation
Authors: Breskin Alexander , Wiener Catherine , Adimora Adaora A. , Brown Robert S. , Landis Charles , Reddy K. Rajender , Verna Elizabeth C. , Crawford Julie M. , Mospan Andrea , Fried Michael W. , Brookhart M. Alan
Published: January 2023

Background:

Remdesivir is recommended for certain hospitalized patients with COVID-19. However, these recommendations are based on evidence from small randomized trials, early observational studies, or expert opinion. Further investigation is needed to better inform treatment guidelines with regard to the effectiveness of remdesivir among these patients.

Methods:

We emulated a randomized target trial using chargemaster data from 333 US hospitals from 1 May 2020 to 31 December 2021. We compared three treatment protocols: remdesivir within 2 days of hospital admission, no remdesivir within the first 2 days of admission, and no remdesivir ever. We used baseline comorbidities recorded from encounters up to 12 months before admission and identified the use of in-hospital medications, procedures, and oxygen supplementation from charges. We estimated the cumulative incidence of mortality or mechanical ventilation/extracorporeal membrane oxygenation with an inverse probability of censoring weighted estimator. We conducted analyses in the total population as well as in subgroups stratified by level of oxygen supplementation.

Results:

A total of 274,319 adult patients met the eligibility criteria for the study. Thirty-day in-hospital mortality risk differences for patients adhering to the early remdesivir protocol were −3.1% (95% confidence interval = −3.5%, −2.7%) compared to no early remdesivir and −3.7% (95% confidence interval −4.2%, −3.2%) compared to never remdesivir, with the strongest effect in patients needing high-flow oxygen. For mechanical ventilation/extracorporeal membrane oxygenation, risk differences were minimal.

Conclusions:

We estimate that, among hospitalized patients with COVID-19, remdesivir treatment within 2 days of admission reduced 30-day in-hospital mortality, particularly for patients receiving supplemental oxygen on the day of admission.
A Summary of Chinese Guidelines on Diagnosis and Management of Hyperglycemia in Pregnancy (2022)
Authors:   Maternal-Fetal Medicine Committee, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association; Chinese Society of Perinatal Medicine, Chinese Medical Association; Professional Committee of Gestational Diabetes Mellitus, Chinese Maternal and Child Health Association, Wang Chen , Juan Juan , Yang Huixia
Published: January 2023

Hyperglycemia is one of the most common complications women encounter during pregnancy, and is associated with a higher incidence of short- and long-term health risks for both the mother and offspring. In 2022, the Maternal-Fetal Medicine Committee of the Chinese Society of Obstetrics and Gynecology, Chinese Medicine Association, worked with the Chinese Society of Perinatal Medicine and the Professional Committee of Gestational Diabetes Mellitus of the Chinese Maternal and Child Health Association to update the Guidelines for the diagnosis and management of hyperglycemia in pregnancy in China. The aim was to further standardize the management of hyperglycemia in pregnancy from the aspects of screening, diagnosis, monitoring, treatment, and prevention of gestational diabetes mellitus, and consequently to further improve the health of mother and child.
Expert consensus on the clinical application of Xuanfei Baidu granule
Authors: Liu Qingquan , Zhang Hongchun , Wang Chengxiang , Miao Qing , Yang Fengwen , Huang Yuhong , Zheng Wenke ,   on behalf of the XFBD expert consensus working group
Published: January 2023

Xuanfei Baidu granule is an effective prescription for COVID-19, which is modified from classical famous prescriptions. In order to further standardize clinician’s rational use of Xuanfei Baidu granule, enhance clinical efficacy, improve rational medication level, and let it play a more significant role, the frontline clinical experts are invited for discussion on the major functions, usage, adverse reactions, and considerations of Xuanfei Baidu granule to form the consensus. The consensus is that: Xuanfei Baidu granule has the efficacy of promoting the lung and resolving dampness, clearing heat and removing pathogeneses, purging the lung and depoisoning; it can be used for the treatment of patients with mild, moderate, and heavy COVID-19 and other common upper respiratory tract infectious diseases such as influenza; acute tracheitis and bronchitis and community-acquired lower respiratory tract infectious diseases all belong to damp-toxin constraint in the lungs, Xuanfei Baidu granule can relieve cough, expectoration, and other symptoms caused by an acute exacerbation of the chronic obstructive pulmonary disease, with definite clinical efficacy and good safety. According to the principles of evidence-based medicine, this expert consensus will be updated regularly.
Awareness, Prevalence, and Knowledge of Dry Eye Among Internet Professionals: A Cross-sectional Study in China
Authors: Fan Zixin , Du Yueshanyi , Tang Caiyun , Tian Ruyin , Lu Xiaofeng , Zheng Lei , Zhang Shaochong , Zhang Guoming
Published: January 2023

Objectives:

To investigate awareness, prevalence, and knowledge of dry eye among Internet professionals in China.

Methods:

A cross-sectional study was conducted among 1,265 randomly selected Internet professionals aged ≥18 years. A self-administered questionnaire was used to assess dry eye awareness, dry eye symptoms, and knowledge about dry eye risk factors. Data on demographics and complete medical history were also collected. The primary outcome was the rate of dry eye awareness determined by the answer to the question “Have you seen or heard anything about dry eye recently?”

Results:

Of the 1,265 included individuals aged 20 to 49 years, 519 (41.0%) were women. 54.4% (688 of 1,265) of participants had seen or heard something about dry eye recently and most had obtained information through Internet. 50.8% (643 of 1,265) of participants were identified as subjects with symptoms of dry eye. Dry eye awareness was greater in contact lens wearers (odds ratio [OR], 6.49; 95% confidence interval [CI], 3.70-11.38; P<0.001), those with a refractive surgical history (OR, 5.09; 95% CI, 2.34-11.08; P<0.001), relatives and/or friends of ophthalmologists (OR, 2.76; 95% CI, 1.39-5.49; P=0.004), those with symptoms of dry eye (OR, 1.87; 95% CI, 1.47-2.38; P<0.001) and female subjects (OR, 1.44; 95% CI, 1.13-1.86; P=0.004). Knowledge of nonmodifiable and modifiable risk factors for dry eye was poor in substantial numbers of the participants.

Conclusions:

The level of dry eye awareness and knowledge of its risk factors is suboptimal in Internet professionals, although the Internet professionals are at high risk of the disease.
Metabolic regulation of NK cell function: implications for immunotherapy
Authors: Sohn Hyogon , Cooper Megan A.
Published: January 2023

Natural killer (NK) cells are innate immune lymphocytes capable of rapidly responding to tumors and infection without prior sensitization. There is increasing interest and success in harnessing NK cell function for the treatment of disease, in particular cancers. NK cell activation is dependent on integration of signals through cytokine and germline-encoded activating and inhibitory receptors. The availability of metabolic fuels and pathways is required for NK effector functions including proliferation, killing, and production of interferon gamma (IFN-γ). An understanding of NK cell immunometabolism is thus essential for developing immunotherapy approaches that will allow for optimal effector functions in patients. Studies in mice and humans have demonstrated stimulation-dependent metabolic changes that are required for NK cell function. Here we review the most recent findings in NK cell immunometabolism relevant to disease models and translation to therapy of patients.
Nutrition and physical activity knowledge, attitudes, and practices of inpatient cirrhosis care providers
Authors: Hazra Deepan , Mohamed Mahmod , Hyde Ashley M. , Rempel Hannah , Oleschuk Alicia , Miller Angela , Raman Maitreyi , Taylor Lorian , Gramlich Leah , Watt Makayla , Tandon Puneeta
Published: January 2023

Background

Hospitalization is a high-risk period for cirrhosis-associated sarcopenia and frailty. This study aimed to measure the knowledge, attitudes, and practice patterns (KAP) of multidisciplinary cirrhosis providers about inhospital nutrition and physical activity care.

Methods

We conducted an online survey of cirrhosis care providers at a combination of 38 hospitals and healthcare centres in Alberta, Canada. Analysis included descriptive statistics and content analysis.

Results

Three hundred thirty-eight responses were analyzed. Across all providers, nutrition and physical activity knowledge and attitude (KA) scores were higher than practice (P) scores. Physicians had lower nutrition KA (P = 0.010) and nutrition P (P < 0.001) scores than nonphysicians. Previous cirrhosis-related nutrition or physical activity education was associated with higher nutrition KA (P < 0.001), nutrition P (P = 0.036), and physical activity P scores (P < 0.001). Over half of the participants reported not providing patients with educational resources for nutrition or physical activity and not carrying out nutrition screening. Participant suggestions to optimize care included enhancing patient and provider education, standardizing screening and intervention processes, increasing patient-centered support, and promoting collaboration within the healthcare team. Eighty percentage of participants were willing to provide patients with resources if these were readily available.

Conclusion

While provider knowledge and attitudes about the importance of nutrition and physical activity in hospitalized patients with cirrhosis are reasonable, there is considerable room to optimize the delivery of best practices in this patient population. Optimization will require readily available educational and personnel resources and interdisciplinary collaboration to promote system change.
Longitudinal analysis of transplant candidates with primary sclerosing cholangitis in an Asian liver transplant center
Authors: Yu Ping-Jui , Ho Cheng-Maw , Hsiao Chih-Yang , Wu Yao-Ming , Ho Ming-Chih , Lee Po-Huang , Hu Rey-Heng
Published: January 2023

Background

Primary sclerosing cholangitis (PSC) is a rare disease in Asia, and few studies have investigated the disease in this ethnicity, particularly in wait-listed patients for liver transplantation (LT). We aimed to investigate the prognostic factors and outcomes of wait-listed patients with PSC in an Asian transplant center.

Methods

Survival was retrospectively analyzed.

Results

Eighteen (10 male and 8 female) wait-listed patients with PSC, with a median age at diagnosis of 44.5 years, were included. Compared with men, women had significantly higher aspartate aminotransferase to platelet ratio index scores (3.28 vs. 1.13; P = 0.012) and bilirubin levels (7.68 vs. 4.03 mg/dl; P = 0.043) and more often presented with decompensating events, including ascites [5 (63%) vs. 1 (10%); P = 0.043] and splenomegaly [8 (100%) vs. 4 (40%); P = 0.013]. Compared with the non-LT group, the LT group exhibited a superior survival rate for women (P = 0.004) but not for men. In the univariable analysis, significant risk factors associated with overall survival included malignancies with a hazard ratio (95% confidence interval) of 5.53 (1.00–30.51) and esophageal varices (EV) [4.18 (1.05–16.61)], whereas female gender [25.00 (1.49–500.00)], LT [0.09 (0.01–0.80)] and EV [39.03 (2.92–521.96)] were indicated in the multivariable analysis.

Conclusions

For Asian wait-listed patients with PSC, EV and female gender were the risk factors related to overall survival, and LT was the protective factor. Our experiences suggested that LT brings more benefits in female patients. Strategies are needed to provide equivalent transplant benefits.
The Status of Adolescent Testing and Treatment in PEPFAR-Supported Programs, October 2017 to September 2020
Authors: Hrapcak Susan , Hast Marisa , Okegbe Tishina , Gross Jessica , Williams Jessica , Patel Monita , Wolf Hilary , Siberry George , Lee Lana , Wiersma Steven , Agaba Patricia , Carpenter Deborah , Rivadeneira Emilia ,   PEPFAR Adolescent Group
Published: January 2023

Background:

Adolescents have poorer outcomes across the HIV cascade compared with adults. We aimed to assess progress in HIV case finding, antiretroviral treatment (ART), viral load coverage (VLC), and viral load suppression (VLS) among adolescents enrolled in the US President's Emergency Plan for AIDS Relief (PEPFAR)–supported programs over a 3-year period that included the beginning of the COVID-19 pandemic.

Methods:

We analyzed PEPFAR program data in 28 countries/regions for adolescents aged 10–19 years between year 1 (October 2017to September 2018), year 2 (October 2018 to September 2019), and year 3 (October 2019 to September 2020). We calculated the number and percent change for HIV tests, HIV-positive tests, and total number on ART. Calculated indicators included positivity, percent of positives newly initiated on ART (ART linkage), VLC (percent of ART patients on ART for ≥6 months with a documented viral load result within the past 12 months), and VLS (percent of viral load tests with <1000 copies/mL).

Results:

Between years 1 and 3, the number of HIV tests conducted decreased by 44.2%, with a 29.1% decrease in the number of positive tests. Positivity increased from 1.3%–1.6%. The number of adolescents receiving ART increased by 10.4%. In addition, ART linkage increased (77.8%–86.7%) as did VLC (69.4%–79.4%) and VLS (72.8%–81.5%).

Conclusions:

Our findings demonstrate PEPFAR's success in increasing the adolescent treatment cohort. We identified ongoing gaps in adolescent case finding, linkage, VLC, and VLS that could be addressed with a strategic mix of testing strategies, optimal ART regimens, and adolescent-focused service delivery models.
How to differentiate skin rash in covid, mononucleosis, chickenpox, sixth disease and measles
Authors: Errichetti Enzo , Stinco Giuseppe
Published: January 2023

Purpose of review

Skin rashes seen during COVID-19 usually feature maculopapular or vesicular morphology, thus mimicking cutaneous eruptions occurring in other common infectious dermatoses, such as mononucleosis, chickenpox, sixth disease and measles, with possible diagnostic mistakes. In this review article, we sought to provide a practical overview about clinical appearance of skin rashes related to SARS-CoV-2 infection.

Recent findings

The study summarizes literature evidence on clinical patterns of COVID-19-associated maculopapular or vesicular rash, with a particular emphasis on the principal points of differentiation with possible mimickers.

Several differences do exist between rashes due to SARS-CoV-2 infection and other viral eruptions, mainly including lesions morphology, spreading pattern, symptoms and mucosal involvement. The increase of awareness of such features among clinicians may help promptly recognize COVID-19-related exanthemas in order to take proper action to manage the infection.
Kidney Bioengineering for Transplantation
Authors: Ibi Yutaro , Nishinakamura Ryuichi
Published: January 2023

The kidney is an important organ for maintenance of homeostasis in the human body. As renal failure progresses, renal replacement therapy becomes necessary. However, there is a chronic shortage of kidney donors, creating a major problem for transplantation. To solve this problem, many strategies for the generation of transplantable kidneys are under investigation. Since the first reports describing that nephron progenitors could be induced from human induced pluripotent stem cells, kidney organoids have been attracting attention as tools for studying human kidney development and diseases. Because the kidney is formed through the interactions of multiple renal progenitors, current studies are investigating ways to combine these progenitors derived from human induced pluripotent stem cells for the generation of transplantable kidney organoids. Other bioengineering strategies, such as decellularization and recellularization of scaffolds, 3-dimensional bioprinting, interspecies blastocyst complementation and progenitor replacement, and xenotransplantation, also have the potential to generate whole kidneys, although each of these strategies has its own challenges. Combinations of these approaches will lead to the generation of bioengineered kidneys that are transplantable into humans.