bluuebunny/crossref_metadata_2025 huggingface dataset:
The safety of the combination therapy of recombinant factor VIIa and plasma-derived factor VIIa and factor X for refractory hemorrhage in acquired hemophilia A
Authors: Okayama Yusuke , Bingo Masato , Sakatoku Kazuki , Okamura Hiroshi , Nanno Satoru , Nishimoto Mitsutaka , Nakashima Yasuhiro , Koh Hideo , Hino Masayuki , Nakamae Hirohisa
Published: August 2023

Acquired hemophilia A (AHA) is a rare, life-threatening hemorrhagic disease caused by autoantibodies against factor VIII (FVIII), and bypassing agents (BPA) are used to control bleeding. However, some cases need a change of BPA or BPAs given sequentially or in combination for refractory bleeding. A 71-year-old man was admitted with subcutaneous hemorrhage. Laboratory investigations showed prolongation of activated partial thromboplastin time (APTT) and low-coagulation FVIII activity and FVIII inhibitor; we, therefore, diagnosed AHA. He was treated with recombinant factor VIIa (rFVIIa) BPA and prednisolone. However, his symptoms did not improve sufficiently, thus we switched BPA to activated prothrombin complex concentrate. Unfortunately, this was not effective and he suffered hemorrhagic shock. Therefore, we selected rFVIIa, with plasma-derived FVIIa and factor X (pd-FVIIa/FX) as combination therapy, and hemostasis was achieved without thrombosis. This case suggests that the combination of rFVIIa and pd-FVIIa/FX short-term can be well tolerated for refractory hemorrhage in AHA.
A study of fibrinolytic system components in donor groups depending on various titers of circulating anti-SARS-CoV-2 IgG in the bloodstream
Authors: Rachkovska Antonina , Krenytska Daryna , Karbovskyy Vitalii , Raksha Nataliia , Halenova Tetiana , Vovk Tetiana , Savchuk Olexii , Ostapchenko Liudmyla
Published: August 2023

The fibrinolytic system plays an important role in controlling blood coagulation at each stage, from thrombin generation to fibrin clot cleavage. Currently, long-term multiorgan dysfunction post-coronavirus disease 2019 (COVID-19) may include coagulation disorders. Little information is available about the potential causes of post-COVID-19 coagulopathy, but one of them may be subpopulation IgG produced by the immune system against SARS-CoV-2. This article describes the changes in the main parameters of the fibrinolytic system in donors with various titers of anti-SARS-CoV-2 IgG, which is part of a complex study of the hemostasis system in these donor groups. We determined the most significant parameters of the fibrinolytic system, such as potential activity and amount of plasminogen and tissue plasminogen activator (tPA), amount of plasminogen activator inhibitor-1 (PAI-1), inhibitory potentials of α-2-antiplasmin, α-1-antitrypsin, α-2-macroglobulin in the blood plasma of donor groups. The obtained results represent the maximum and minimum values of measurement parameters among donor groups with titers of anti-SARS-CoV-2 IgG at least 10 ± 3 Index (S/C), and their statistical differences from the reference point [donor group with titer of anti-SARS-CoV-2 IgG 0 Index (S/C)]. We established the changes in fibrinolytic parameters depending on the titers of anti-SARS-CoV-2 IgG. One conclusion can be drawn from this: anti-SARS-CoV-2 IgG population may influence coagulation in the post-COVID-19 period. Further research in-vitro and in-vivo experimental models using selected and purified IgG may confirm our previous findings.
Longitudinal surveillance of three biomarkers to predict recurrence of hepatocellular carcinoma after radical resection
Authors: Tong Jing-shu , Lu Cai-de , Lu Chang-jiang , Zheng Siming , Mao Shu-qi
Published: August 2023

Background

Radical resection is a curative treatment for patients with hepatocellular carcinoma (HCC), but the incidence of recurrence remains high. We aimed to explore the performance of predicting HCC recurrence by longitudinal surveillance of the protein induced by vitamin K absence (PIVKA-II), alpha- fetoprotein (AFP), and lectin-reactive AFP (AFP-L3) during postoperative follow-up.

Methods

Patients who underwent radical resection for HCC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and December 2020 were included. All enrolled patients regularly monitor PIVKA-II, AFP, AFP-L3 every 3 months during postoperative follow-up. The surveillance performance of PIVKA-II, AFP, AFP-L3 during follow-up for the prediction of HCC recurrence was compared in patients. The generalized estimation equation (GEE) was used to analyze the trends of the tumor biomarkers and interactions with time. Area under the receiver operator characteristic (AUROC) curves, the optimal cut-off value, the sensitivity and specificity were calculated to evaluate the performance of the three biomarkers. The recurrence-free survival (RFS) and overall survival (OS) of patients with any of the elevated biomarkers was analyzed by Kaplan–Meier curves and the log-rank test. Multivariate logistic regression models were used to analyze potential risk factors for recurrence.

Results

The GEE analysis indicated that PIVKA-II, AFP, AFP-L3 in the recurrence patients were higher than the no recurrence patients during follow-up, PIVKA-II and AFP showed increasing trends from 6 months before recurrence. In predicting recurrence, the AUROCs for PIVKA-II, AFP, AFP-L3 and their combination were 0.885, 0.754, 0.781 and 0.885 respectively, the optimal cut-off value for PIVKA-II, AFP, AFP-L3 was 29.5 mAU/ml, 10.7 ng/L, 1.5% respectively. The sensitivity in predicting recurrence for PIVKA-II, AFP, AFP-L3 and combination were 75.0, 54.7, 57.8 and 79.7% respectively. The RFS and the OS of patients with any of the biomarkers elevated during the follow-up was significantly shorter than that without elevated biomarkers (P < 0.001). Multivariate analysis showed that any of the biomarkers elevated was the independent risk factor of recurrence.

Conclusion

Longitudinal surveillance of PIVKA-II, AFP and AFP-L3 can effectively predict recurrence of HCC after operation.
Risk and incidence of colorectal stricture progressing to colorectal neoplasia in patients with inflammatory bowel disease: a systematic review and meta-analysis
Authors: Zhan Yanrong , Cheng Xianwen , Mei Pingping , Wu Jiyun , Ou Yan , Cui Yaping
Published: August 2023

This study aims to assess the risk of colorectal stricture progressing to colorectal neoplasia (CRN) in patients with inflammatory bowel disease (IBD). The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the date of databases’ creation to 5 November 2022. The Newcastle-Ottawa Scale was used to evaluate the quality of the included literature. Meta-analysis was conducted using the Stata 15 software and R 4.04 software. Two case-control studies and 12 cohort studies were eventually included. Colorectal stricture in patients with IBD increased the risk of progressing to CRN [odds ratio (OR): 1.52, 95% confidence interval (CI): 1.02–2.29, P = 0.042], but was irrelevant to the risk of progressing to ACRN (OR: 3.56, 95% CI 0.56–22.70, P = 0.180). The risk of CRN were further distinguished in patients with ulcerative colitis (UC) and Crohn’s disease (CD) Our findings showed that colorectal stricture may increase the risk of progressing to CRN in patients with UC (OR = 3.53, 95%CI 1.62–7.68, P = 0.001), but was irrelevant to the risk of progressing to CRN in patients with CD (OR = 1.09, 95% CI 0.54–2.21, P = 0.811). In conclusion, colorectal stricture in patients with IBD can be used as a risk factor for predicting CRN but cannot be used as a risk factor for predicting ACRN. Stricture is a risk factor for CRN in patients with UC but not in patients with CD. More prospective, multi-center studies with large samples are expected to confirm our findings.
Is histological healing more clinically valuable than endoscopic healing in Crohn’s disease?
Authors: Zhang Ting , Zhang Qi-De , Jin Tian , Li Wen-Jie , Wang Han-Ying , Lu Xiao-Yun , Li Xiu-Qing , Liu Shi-Jia , Yang Bo-Lin
Published: August 2023

Objectives

Small bowel (SB) endoscopic healing has not been well explored in patients with Crohn’s disease (CD). This study aimed to assess the clinical utility of SB endoscopic mucosal and histological healing in patients with CD.

Methods

In total, 99 patients with CD in clinical–serological remission were retrospectively followed after they underwent colonoscopy and double-balloon enteroscopy. Time until clinical relapse (CD activity index of >150 with an increase of >70 points) and serological relapse (abnormal elevation of C-reactive protein levels) constituted the primary endpoints.

Results

Of the 99 patients, 75 (74.7%) exhibited colonoscopic healing and 43 (43.4%) exhibited SB endoscopic healing. Clinical relapse, serological relapse, hospitalization, and surgery occurred in 8 (18.6%), 11 (25.6%), 11 (25.6%), and 2 (4.6%) patients, respectively. Of the 43 patients who exhibited SB endoscopic healing, 21 (48.8%) achieved histological healing. Clinical relapse, serological relapse, hospitalization, and surgery occurred in 4 (19.0%), 7 (33.3%), 7 (33.3%), and 1 (4.8%) patient, respectively. There was no statistically significant difference in the number of patients who relapsed, were hospitalized, or underwent surgery between those who exhibited histological healing and those who did not.

Conclusion

A substantial number of patients who were in clinical–serological remission did not undergo SB endoscopic healing, and the lesions increased their risk of clinical relapse. Thus, endoscopic healing may be of greater clinical value than histological healing when evaluating the remission of patients with CD.
Real-time assessment of H. pylori during the endoscopic assessment of individuals with gastric intestinal metaplasia: a possible way to reduce the burden of care
Authors: Esposito Gianluca , Libânio Diogo , Ligato Irene , Ramos Silva Diana , Dilaghi Emanuele , Ortigão Raquel , Carabotti Marilia , Chaves Jéssica , Annibale Bruno , Dinis-Ribeiro Mário
Published: August 2023

Objectives

The management of individuals with gastric intestinal metaplasia (GIM) includes biopsies for its staging and to diagnose Helicobacter pylori (Hp). Advanced-stage GIM can be estimated by endoscopy through EGGIM, and a new device permits the real-time assessment of ammonia for the identification of Hp infection. The aim of this study was to assess the simultaneous use of EGGIM and real-time assessment of ammonia to avoid biopsies and reduce the burden of care in clinical practice.

Methods

A multicentre study involving 101 consecutively enrolled patients [52% male; 65(18–85) years]. During endoscopy, gastric juice was aspirated and analysed; EGGIM was determined in real-time. Targeted biopsies were performed and histopathological assessment was used as gold standard.

Results

Advanced-stage GIM were detected in 14.9% of patients and Hp infection in 18.8%. EGGIM showed for advanced-stage GIM a sensitivity, specificity and NPV of 86.7%, 84.9% and 97.3%, whilst real-time assessment of ammonia, 83.3%, 78.2% and 95.4%, respectively. Gastric juice was insufficient in 5 (5.0%). Overall, 64 (67%) patients were correctly diagnosed by EGGIM and real-time assessment of ammonia. If the 47 (49%) patients negative to both assessments would have avoided biopsies, only 4 (4.2%) would have been missed: two with advanced-stage GIM and two with Hp infection.

Conclusion

The combination of endoscopic assessment and real-time analysis of Hp allows the exclusion of advanced-stage GIM or Hp infection without the need of biopsies in a significant proportion of individuals. This may allow in specific situations to abstain from biopsies reducing the burden of care.
Cultivation-based characterization of biliary microbiota in bile samples collected during routine endoscopic retrograde cholangiography: 10 years of experience at a tertiary center
Authors: Forster Kilian , Klein Friederike , Simon Nicolas , Chhatwal Patrick , Ziesing Stefan , Heidrich Benjamin , Solbach Philipp
Published: August 2023

Introduction

Bile has long been considered sterile. Recent studies show that bacteria can frequently be detected in bile and certain bacterial species are associated with bile duct-associated liver disease.

Objectives

To detect bacterial species and antibiotic resistance in bile in bile duct-associated liver disease.

Methodology

To evaluate microbiological findings of bile samples obtained during ERCP at a tertiary center from 2009 to 2019.

Results

There were 1885 bile samples from 992 patients examined by cultural microbiological analysis. Germs were detected in 91% of the samples. Most bile samples (n) were obtained from patients who had undergone liver transplantation (LTX; n = 556), followed by patients with primary sclerosing cholangitis (PSC; n = 287). Enterococci were detected in 67% of samples, followed by E. coli (32.2%) and Klebsiella (28.2%). Of 1151 enterococci detected, 13.1% were vancomycin (VRE)s and of 216 staphylococci detected, 10% were ORSA. The proportion of VRE increased with the number of tests performed during ERCPs (P < 0.01; chi-square) and increased 2.5-fold over 10 years, whereas the detection of ORSA remained stable. Patients with cholecystolithiasis were significantly more likely to have evidence of VRE in bile compared to LTX and PSC patients (P = 0.02, P < 0.01; chi-square). The most abundant bacterial genera showed highly statistically significant differences in their levels of liver enzymes and c-reactive protein (P < 0.001).

Conclusion

Knowledge of the bacterial composition of bile in various bile duct-associated liver diseases may allow more targeted antibiotic use in the future.
Acute paraquat poisoning complicated by acute kidney injury and lung fibrosis: a case report from Nepal
Authors: Yadav Rupesh K. , Gurung Shekhar , Karki Saurab , Lama Susan , Tamang Shrejung , Poudel Manish
Published: August 2023

Introduction and importance:

While incidents are rare elsewhere, paraquat herbicide poisoning is a serious medical issue in some parts of Asia. It can cause the failure of various organs, including the heart, kidneys, liver, adrenal glands, central nervous system, muscles, and spleen. Due to its inherent toxicity and lack of available therapies, paraquat has a very high case fatality rate.

Case presentation:

The authors discuss a case of a 15-year-old female with an alleged history of paraquat ingestion who presented with complaints of vomiting, abdominal pain, and loose stools. Initially, she had gastrointestinal symptoms, but she developed renal failure and respiratory symptoms and died of multiple organ failure.

Clinical discussion:

Acute gastrointestinal tract necrosis and multiorgan failure are the initial effects of paraquat intake, and among those who survive the immediate post-ingestion interval, the lung is the target organ for poisoning. Ingestion of large amounts of liquid concentrates results in fulminant organ failure: pulmonary edema, cardiac, renal, and hepatic failure, and convulsions. The course of treatment can range from supportive care alone to various integration of immune modulation, antioxidant therapy, hemoperfusion, and hemodialysis.

Conclusion:

Patients presenting to the emergency department with an alleged history of ingestion of paraquat poisoning should be admitted even if they have mild symptoms initially. There is no specific antidote available. Early renal failure, along with progressive pulmonary fibrosis, can lead to death.
Exploring the transformative role of 3D printing in advancing medical education in Africa: a review
Authors: Olatunji Gbolahan , Osaghae Osadebamwen W. , Aderinto Nicholas
Published: August 2023

With the increasing demand for quality healthcare and the scarcity of resources, medical education in Africa faces numerous challenges. Traditional teaching methods often need help to adequately prepare medical students for the complex and diverse healthcare scenarios they will encounter in practice. 3D printing technology holds significant promise in addressing these challenges by providing innovative solutions for medical education. This review examines the various applications of 3D printing in medical education, focusing on its potential to enhance anatomy education, surgical training and medical device development. It explores how 3D printing can offer realistic and customisable anatomical models, enabling students to understand human anatomy better and improve their surgical skills through realistic simulations. Furthermore, this paper discusses the potential of 3D printing in developing low-cost medical devices, prosthetics and surgical instruments, which can significantly benefit resource-limited settings in Africa. It explores the concept of distributed manufacturing, where 3D printing can decentralise the production of essential medical equipment, reducing reliance on external suppliers and improving access to healthcare. The review also highlights the challenges and limitations associated with implementing 3D printing in medical education in Africa, such as limited infrastructure, high costs and the need for specialised training. However, it presents successful initiatives and collaborations that have overcome these obstacles, demonstrating the feasibility and potential impact of integrating 3D printing into medical education in Africa.
Standardizing Care of the Late Preterm Infant
Authors: Smith Pamela C. , Yonkaitis Catherine F. , Reigart Melissa M.
Published: August 2023

Background:

Late preterm infants are infants born between 34 and 36 6/7 weeks gestation. Compared to term infants, late preterm infants are at increased risk for breastfeeding difficulties, hypoglycemia, hyperbilirubinemia, and hypothermia due to their relative physiologic and metabolic immaturity.

Problem:

Medical record reviews performed at a level III maternal and newborn hospital in central Illinois revealed only 64% of late preterm infants admitted to the newborn nursery received care per the unit late preterm infant policy. The aim of this quality improvement project was to increase nurse adherence to the policy to 80%.

Methods:

Between May 2022 and September 2022, several interventions were implemented for maternal–child nurses and support clinicians: an education offering, creation of a late preterm infant-specific breastfeeding log, and electronic medical record updates. Post-intervention medical record reviews measured policy adherence through documentation of feeding sessions, hypoglycemia, hypothermia, and hyperbilirubinemia. Descriptive statistics were performed to determine improvement.

Results:

Nurse adherence to the late preterm infant policy increased to 90% over the period of the project.

Clinical Implications:

Late preterm infant care protocols should be in place in all newborn nurseries. Late preterm infant policy adherence can be supported through electronic medical record prompts, use of a late preterm infant-specific breastfeeding log, and continuing education.
Bartonella raoultii sp. nov., isolated from infected rodents (Mastomys erythroleucus) in Senegal
Authors: Hammoud Alissa , Medkour Hacène , Zgheib Rita , Louni Meriem , Diatta Georges , Bassene Hubert , Sambou Masse , Gaye Mapenda , Haddad Gabriel , Fenollar Florence , Sokhna Cheikh , Mediannikov Oleg
Published: August 2023

Bartonella

species are involved in various human diseases, causing a range of clinical manifestations; animals are considered as the main reservoirs, transmitting diverse species of

Bartonella

through direct contact and haematophagous insects. Here, we characterize a new species,

Bartonella raoultii

sp. nov., within the genus

Bartonella

, using a taxonogenomic polyphasic approach. Strain 094T (= CSUR B1097T=DSM 28004T), isolated from the blood of an infected rodent (Mastomys erythroleucus) in Senegal, is an aerobic and rod-shaped bacterium. The annotated non-contiguous genome sequence is 1 952322 bp long and contains 37.2 mol% G+C content, 1686 protein-coding genes and 50 RNA genes, including seven rRNA genes.
Natrinema salsiterrestre sp. nov., an extremely halophilic archaeon isolated from a hypersaline soil
Authors: Straková Dáša , Sánchez-Porro Cristina , de la Haba Rafael R. , Ventosa Antonio
Published: August 2023

An extremely halophilic archaeal strain, designated S1CR25-10T, was isolated from hypersaline soil sampled in the Odiel Saltmarshes Natural Area in Southwestern Spain (Huelva) and subjected to a polyphasic taxonomic characterization. The cells were Gram-stain-negative, motile and their colonies were pink-pigmented. It was a strictly aerobic haloarchaeon that could grow at 25–55 °C (optimum, 37 °C), at pH 6.0–9.0 (optimum, pH 7.0–8.0) and in the presence of 12–30 % (w/v) total salts (optimum, 20–25 %, w/v). The phylogenetic analysis based on the comparison of the 16S rRNA gene sequences revealed that strain S1CR25-10T belongs to the genus

Natrinema

, with 98.9 % similarity to

Natrinema salinisoli

SLN56T. In addition, the values of orthologous average nucleotide identity, digital DNA–DNA hybridization and average amino acid identity were below the threshold limits accepted for prokaryotic species delineation, with

N. salinisoli

SLN56T showing the highest relatedness values (92.6 % and 48.4 %, respectively). The major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and a glycolipid chromatographically identical to sulfated diglycosyl diether. The DNA G+C content of the isolate was 63.8 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic characterization and the whole genome results, strain S1CR25-10T represents a new species within the genus

Natrinema

, for which the name Natrinema salsiterrestre sp. nov., with type strain S1CR25-10T (=CECT 30623T=CCM 9251T), is proposed.
Analysis of 3,760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes
Authors: Cao Xueqi , Huber Sandra , Ahari Ata Jadid , Traube Franziska R. , Seifert Marc , Oakes Christopher C. , Secheyko Polina , Vilov Sergey , Scheller Ines , Wagner Nils , Yépez Vicente A. , Blombery Piers , Haferlach Torsten , Heinig Matthias , Wachutka Leonhard , Hutter Stephan , Gagneur Julien
Published: August 2023

Background

Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging.

Methods

To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3,760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes.

Results

We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptorLRP1Btranscript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggestsLRP1Bas a novel marker for a HCL-V subclass and a yet unreported functional role ofLRP1Bwithin these rare entities.

Conclusions

Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.
Migration and the Emergence of Chagas Disease Vectors in the Growing City of El Pedregal, Peru
Authors: Gonçalves Raquel , Hacker Kathryn P. , Condori Carlos , Xie Sherrie , Borrini-Mayori Katty , Riveros Lina Mollesaca , Apaza Roger Quispe , Arratea Manuel Ysidro , Nativio Gustavo , Castillo-Neyra Ricardo , Paz-Soldan Valerie A. , Levy Michael Z.
Published: August 2023

The city of El Pedregal grew out of a desert, following an agricultural irrigation project in Southern Peru. We conducted door-to-door entomological surveys to document the emergence of triatomines and bed bugs into this new urban environment. We inspected 5,191 households forTriatoma infestans(known locally as theChirimacha); 21 (0.41%) were infested. These were extremely spatially clustered (Ripley’s K p-value <0.001 at various spatial scales). Using remote sensing we compared the year of construction of infested to un-infested households and found that infested houses were older than controls (Wilcoxon rank-sum: W=33; p=0.02). We confirmed infestations through a subsequent bed bug specific inspection in 34 households. These households were more spatially disperse across El Pedregal. To gain a better understanding of the context surrounding triatomine infestations, we conducted in-depth interviews with residents to explore their migration histories and previous experiences withChirimachas. Main reasons for migration includes searching for work on land, opportunity to buying a house, and scape adverse climate effects. Permanent migration flow and poor housing conditions create suitable environment for emergence triatomine infestation. We discuss how changes in the landscape could potentially heighten vulnerability to vector-borne illnesses.

Author summary

Large-scale irrigation and changes in land-use have been linked with emergence of infectious disease worldwide. In El Pedregal, Southern Peru, the Majes-Siguas irrigation was designed to supply water to agribusiness companies installed in a desert area. This project has propelled a constant migration flow and the growth of this new city, promoting conditions to emergence ofTriatoma infestans, an insect vector of Chagas disease, as well as bed bugs. Triatomine infestation presented a clustered pattern, its dispersion limited by unoccupied houses. Triatomine infested houses tend to be older than other houses. Bed bug infestations were more spread out, and not related to construction age. Householders’ stories of migration shed light on some of the socioeconomic determinants that promote conditions for infestation. Amongst these, living in poor housing conditions, and the constant migration flow; driven by seeking opportunities to work, to buy a house, or to escape from adverse climate effects in other farming regions. Environmental and socioeconomic impacts of large-scale development disproportionately affect vulnerable populations. Design of surveillance systems that account for these contexts is urgently needed to support early detection and control of emergence of vector-borne diseases.
Sensitivity and consistency of long- and short-read metagenomics and epicPCR for the detection of antibiotic resistance genes and their bacterial hosts in wastewater
Authors: Lou Esther G. , Fu Yilei , Wang Qi , Treangen Todd J. , Stadler Lauren B.
Published: August 2023

Wastewater surveillance is a powerful tool to assess the risks associated with antibiotic resistance in communities. One challenge is selecting which analytical tool to deploy to measure risk indicators, such as antibiotic resistance genes (ARGs) and their respective bacterial hosts. Although metagenomics is frequently used for analyzing ARGs, few studies have compared the performance of long-read and short-read metagenomics in identifying which bacteria harbor ARGs in wastewater. Furthermore, for ARG host detection, untargeted metagenomics has not been compared to targeted methods such as epicPCR. Here, we 1) evaluated long-read and short-read metagenomics as well as epicPCR for detecting ARG hosts in wastewater, and 2) investigated the host range of ARGs across the WWTP to evaluate host proliferation. Results highlighted long-read revealed a wider range of ARG hosts compared to short-read metagenomics. Nonetheless, the ARG host range detected by long-read metagenomics only represented a subset of the hosts detected by epicPCR. The ARG-host linkages across the influent and effluent of the WWTP were characterized. Results showed the ARG-host phylum linkages were relatively consistent across the WWTP, whereas new ARG-host species linkages appeared in the WWTP effluent. The ARG-host linkages of several clinically relevant species found in the effluent were identified.
Association of Life’s Essential 8 with Cardiovascular Events and Mortality: The Cardiovascular Disease Lifetime Risk Pooling Project (LRPP)
Authors: Ning Hongyan , Perak Amanda M. , Siddique Juned , Wilkins John T , Lloyd-Jones Donald M. , Allen Norrina B.
Published: August 2023

Background

The American Heart Association (AHA) recently launched updated cardiovascular health (CVH) metrics, termed Life’s Essential 8 (LE8). Compared to Life’s Simple 7 (LS7), the new approach added sleep health as an eighth metric and updated the remaining 7 metrics. Whether the updated LE8 score outperforms the original LS7 score in predicting cardiovascular disease (CVD) is not known. We examined the association of LE8 scores with CVD, subtype CVD events and all-cause mortality.

Methods

We pooled individual-level data from 6 contemporary US-based cohorts from the Cardiovascular Lifetime Risk Pooling Project (LRPP). Total LE8 score (0-100 points), LE8 score without sleep (0-100 points), as well as prior LS7 scores (0-14 points), were calculated separately. We used multivariable-adjusted Cox models to evaluate the association of LE8 with CVD, CVD subtypes, and all-cause mortality among younger, middle, and older aged adult participants. Reclassification was defined based on the concordant/discordant categories of LS7 and LE8 scores quartile rankings across age groups.

Results

Our sample consisted of 32,896 US adults (7836 [23.8%] Black; 14941 [45.4%] men) followed for 642,000 person-years; of whom 9,391 developed CVD events. Each 10-point higher overall LE8 score was associated with 23-40% lower CVD risk across age groups. Reclassification of CVH from LS7 to LE8 was related to heath behaviors as well as health factors and was significantly associated with CVD risk.

Conclusions

These findings support the improved utility of the LE8 algorithm for assessing overall cardiovascular health and future CVD risk.
Non-Stationary Dynamic Mode Decomposition
Authors: Ferré John , Rokem Ariel , Buffalo Elizabeth A. , Kutz J. Nathan , Fairhall Adrienne
Published: August 2023

Many physical processes display complex high-dimensional time-varying behavior, from global weather patterns to brain activity. An outstanding challenge is to express high dimensional data in terms of a dynamical model that reveals their spatiotemporal structure. Dynamic Mode Decomposition is a means to achieve this goal, allowing the identification of key spatiotemporal modes through the diagonalization of a finite dimensional approximation of the Koopman operator. However, DMD methods apply best to time-translationally invariant or stationary data, while in many typical cases, dynamics vary across time and conditions. To capture this temporal evolution, we developed a method, Non-Stationary Dynamic Mode Decomposition (NS-DMD), that generalizes DMD by fitting global modulations of drifting spatiotemporal modes. This method accurately predicts the temporal evolution of modes in simulations and recovers previously known results from simpler methods. To demonstrate its properties, the method is applied to multi-channel recordings from an awake behaving non-human primate performing a cognitive task.
Flicker and Ganzfeld induced visual hallucinations differ in frequency and content
Authors: Shenyan Oris , Lisi Matteo , Greenwood John A. , Skipper Jeremy I. , Dekker Tessa M.
Published: August 2023

Hallucinatory experiences, defined as perception in the absence of external stimuli, can occur in both pathological and non-pathological states and can be broadly phenomenologically divided into those of a simple and a complex nature. Non-pathological visual hallucinations can be induced experimentally using a variety of stimulation conditions. To assess whether these techniques drive a shared underlying hallucinatory mechanism, despite these differences, we compared two methods: flicker and perceptual deprivation (Ganzfeld). Specifically, we measured the frequency and complexity of the hallucinations produced by these techniques. We utilised button press, retrospective drawing, interviews, and questionnaires to quantify hallucinatory experience in 20 participants. With both experimental techniques, we found that simple hallucinations were more common than complex hallucinations. We also found that on average, flicker was more effective than Ganzfeld at eliciting a higher number of hallucinations, though Ganzfeld hallucinations were longer than flicker hallucinations. There was no interaction between experimental condition and hallucination complexity, suggesting that the increased bottom-up visual input in flicker increased both simple and complex hallucinations similarly. A correlation was observed between the total proportional time spent hallucinating in flicker and Ganzfeld, which was replicated in a retrospective questionnaire measure of experienced intensity, suggesting a shared hallucinatory mechanism between the two methodologies. We attribute these findings to a shared low-level core hallucinatory mechanism, such as excitability of visual cortex, which is amplified in flicker compared to Ganzfeld due to heightened bottom-up input.
Humans with Pulmonary Arterial Hypertension display a global hypermethylation signature that worsens in patients who have a mutation in the gene encoding the methylation eraser, Tet Methylcytosine Dioxygenase 2 (TET2)
Authors: Hindmarch Charles C.T , Potus François , Ruaa Al-Qazazi , Ring Brooke , Nichols William C , Rauh Michael J , Archer Stephen L
Published: August 2023

Epigenetic changes in gene expression due to DNA methylation are important physiologic and pathologic regulators of pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation or demethylation have been associated with the development and progression of pulmonary arterial hypertension (PAH). However, the DNA methylome signature of human PAH and its consequences on the PAH transcriptome are unknown. Reduced Representation Bisulfite Sequencing (RRBS) was used for epigenome-wide mapping of DNA methylation in whole peripheral blood of 10 healthy people and 20 age/sex matched PAH patients. RNA deep sequencing was performed in parallel on the same samples. We used whole-exome sequencing to identify two PAH cohorts, one free of mutations in the genes know to be associated with PAH patients and the second had mutations ofTET2, a newly identified PAH gene that encodes an enzyme that mediates DNA demethylation. We report an increased in global DNA methylation in the blood of PAH patients compared to healthy controls. Patients carrying theTET2mutation had a further increase in DNA compared to mutation free PAH patients. We identified 1,069 unique Differentially Methylated Regions (DMR) in the blood of PAH patients with a TET2 mutation. When organized into functional groups, we observed an enrichment of genes involved in ‘immune’, ‘cell differentiation’, or ‘metabolic’. When we compared these genes to publicly available data from an independent study on blood from PAH patients compared to controls, we identified 218 mRNA transcripts that align with our data (e.g. are hypermethylated blood genes that are downregulated in PAH blood), and functional analysis of these genes reveals common enriched terms in ‘immune’, ‘cell differentiation’, or ‘metabolic’ function. We characterized DNA methylation changes associated with TET2 mutation in the blood of patients with PAH compared to controls. This data demonstrates that epigenetic regulation of genes by methylation is involved in altered immune function, cell differentiation and metabolism in PAH.
A sex-stratified analysis of the genetic architecture of human brain anatomy
Authors: Shafee Rebecca , Moraczewski Dustin , Liu Siyuan , Mallard Travis , Thomas Adam , Raznahan Armin
Published: August 2023

Large biobanks have dramatically advanced our understanding of genetic influences on human brain anatomy. However, most studies have combined rather than compared males and females - despite theoretical grounds for potential sex differences. By systematically screening for sex differences in the common genetic architecture of > 1000 neuroanatomical phenotypes in the UK Biobank, we establish a general concordance between males and females in heritability estimates, genetic correlations and variant-level effects. Notable exceptions include: higher mean h2in females for regional volume and surface area phenotypes; between-sex genetic correlations that are significantly below 1 in the insula and parietal cortex; and, a male-specific effect common variant mapping toRBFOX1 -a gene linked to multiple male-biased neuropsychiatric disorders. This work suggests that common variant influences on human brain anatomy are largely consistent between males and females, with a few exceptions that will guide future research as biobanks continue to grow in size.
WASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Authors: Ante-Testard Pearl Anne , Rerolle Francois , Nguyen Anna T. , Ashraf Sania , Parvez Sarker Masud , Naser Abu Mohammed , Benmarhnia Tarik , Rahman Mahbubur , Luby Stephen P. , Benjamin-Chung Jade , Arnold Benjamin F.
Published: August 2023

Many diarrhea-causing pathogens are climate-sensitive, and the poorest populations are often most vulnerable to climate-related transmission. Household Water, Sanitation, and Handwashing (WASH) interventions constitute one potential effective strategy to reduce diarrhea among children, especially among low-income households. Here, capitalizing on a cluster randomized trial population (360 clusters, 8,440 measurements among children < 3 years) in rural Bangladesh, one of the world’s most climate-sensitive regions regarding precipitation regimes, we show that improved WASH substantially reduces diarrhea risk with largest benefits among poorest children and during the monsoon season. We extrapolated trial results to rural Bangladesh regions using high-resolution geospatial layers to identify areas most likely to benefit. We estimated that a similar intervention at scale could prevent 734 cases per 1,000 children per month during the seasonal monsoon, with marked heterogeneity by region. The analysis demonstrates how to extend large-scale trials to inform WASH strategies among climate-sensitive and low-income populations.
Evidence that metastases arisede novoas new cancers from cells of target organs
Authors: Raghuram Gorantla V. , Pal Kavita , Shende Soniya , Khare Naveen Kumar , Jadhav Vishalkumar , Shinde Sushma , Prasad Ratnam , Wani Harshada , Mittra Indraneel
Published: August 2023

Introduction

Based on our earlier finding that cell-free chromatin particles (cfChPs) released from dying cancer cells are potentially oncogenic, we hypothesised that metastases arise as new cancers from the cells of target organs transformed by cfChPs released from dying cancer cells.

Methods

We fluorescently dually-labelled MDA-MB-231 human breast cancer cells and A-375 human melanoma cells in their DNA with BrdU and in their histones with CellLight® Histone 2BGFP. One hundred thousand dually-labelled cells were intravenously injected into SCID mice. In other experiments unlabelled cells were injected for detection of lung metastasis. Also intravenously injected were 700 ng of purified cfChPs isolated from radiation-killed MDA-MB-231 cells.

Results

We observed that the fluorescently dually-labelled MDA-MB-231 and A-375 cells died upon reaching the lungs and released dually-labelled fluorescent chromatin particles that accumulated in the nuclei of lung cells at 48 h. Injection of unlabelled cfChPs led to the activation of 10 hallmarks of cancer and immune checkpoints in lung cells at 72 h, suggesting that the lung cells had rapidly transformed into incipient cancer cells. Fluorescentin situhybridisation analysis of lung metastases that subsequently developed using mouse and human specific DNA probes revealed that the tumour cells contained both mouse and human DNA in almost equal proportions. Similarly, immune-fluorescence analysis using species specific mAbs revealed that the tumour cells co-expressed mouse and human specific proteins. Metaphase preparations and single-cell clones developed from cell cultures of lung metastases were found to contain chimeric chromosomes containing both mouse and human DNA, and the cells to co-express both human- and mouse-specific proteins. The Intravenously injected purified cfChPs isolated from radiation-killed MDA-MB-231 cells also induced lung metastasis which predominantly contained mouse DNA strongly suggesting that the metastatic tumours had arisen from the mouse lung cells.

Conclusion

These results provide strong evidence that cfChPs released from dying cancer cells integrate into genomes of target lung cells to transform them into new cancers that masquerade as metastasis. They support our hypothesis that metastases arise from the cells of target organs and not from those of the primary tumour. These findings have implications for the principles of cancer therapy.
Multiplexed Digital Characterisation of Misfolded Protein Oligomers via Solid-State Nanopores
Authors: Sandler Sarah E. , Horne Robert I. , Rocchetti Sara , Novak Robert , Hsu Nai-Shu , Cruz Marta Castellana , Brotzakis Z. Faidon , Gregory Rebecca C. , Chia Sean , Bernardes Gonçalo J. L. , Keyser Ulrich F. , Vendruscolo Michele
Published: August 2023

Misfolded protein oligomers are of central importance in both the detection and treatment of Alzheimer’s and Parkinson’s diseases. However, accurate high-throughput methods to identify and quantify oligomer populations are currently lacking. We present here a single-molecule approach for the detection of oligomeric species. The approach is based on the use of solid state nanopores and multiplexed DNA barcoding to identify and characterise oligomers from multiple samples. We study α-synuclein oligomers in the presence of several small molecule inhibitors of α-synuclein aggregation, as an illustration of the applicability of this method to assist the development of diagnostic and therapeutic methods for Parkinson’s disease.
Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer
Authors: Oliphant Michael UJ , Akshinthala Dipikaa , Muthuswamy Senthil K
Published: August 2023

Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to better understand drug resistance and disease progression. However, the establishment and long-term maintenance of ER expression, function, and response in vitro remains a significant challenge. Here, we report the development of an ER+ breast tumor organoid medium (BTOM-ER) that conserves ER expression, estrogen responsiveness, and dependence, as well as sensitivity to endocrine therapy of ER+ patient-derived xenograft organoids (PDXO). Our findings demonstrate the utility of subtype-specific culture conditions that better mimic the characteristics of the breast epithelial biology and microenvironment, providing a powerful platform for investigating therapy response and disease progression of ER+ breast cancer.
Chromosome-Level Genome Assembly of Navel orange cv. Gannanzao (Citrus sinensisOsbeck cv. Gannanzao)
Authors: Xiong Zhiwei , Yin Hui , Wang Nian , Gao Yuxia
Published: August 2023

Navel orange cv. Gannanzao is a variant of the navel orange cv. Newhall (C. sinensisOsbeck cv. Newhall) that exhibits an earlier maturation, making it commercially valuable. However, the underlying mechanism underneath its early maturation remains unknown. To address this question, we conducted genome sequencing and de novo assembly of navel orange cv. Gannanzao. The assembled genome sequence is 334.57 Mb in length with a GC content of 31.48%. It comprises 318 contigs (N50 = 3.23 Mb) and 187 scaffolds (N50 = 31.86 Mb). The BUSCO test demonstrates 94.6% completeness. The annotation revealed 23,037 gene models, 164.95 Mb of repetitive sequences, and 2,554 ncRNA. Comparative analysis identified 323 fruit ripening-related genes in navel orange cv. Gannanzao genome, while navel orange cv. Newhall genome contained 345 such genes. These genes were organized into 320 orthologous gene families, with 30.3% of them exhibiting differences in gene copy numbers between the two genomes. Additionally, we identified 15 fruit ripening-related genes that have undergone adaptive evolution, suggesting their potential role in advancing fruit maturation in navel orange cv. Gannanzao. Whole genome sequencing and annotation of navel orange cv. Gannanzao provides a valuable resource to unravel the early maturation mechanism of citrus and enriches the genomic resources for citrus research.
Complete Suspension Differentiation of Human Pluripotent Stem Cells into Pancreatic Islets Using Vertical Wheel®Bioreactors
Authors: Dadheech Nidheesh , Bermúdez de León Mario , Cuesta-Gomez Nerea , Jasra Ila Tewari , Pawlick Rena , Marfil-Garza Braulio , Verhoeff Kevin , Sapkota Sandhya , Razavy Haide , Anwar Perveen , Lyon James , MacDonald Patrick , Gorman Doug O’ , Jickling Glen , Shapiro AM James
Published: August 2023

Advanced protocols to produce human pluripotent stem cell (SC)-derived islets show promise in functional, metabolic, and transcriptional maturation of cell therapy product to treat diabetes. Available protocols are either developed as complete planar (2D) or, in later stages, combined with suspension cultures (3D). Despite marked progress, both approaches have clear limitations for scalability, cell loss and batch to batch heterogeneity during differentiation. Using a Vertical Wheel®bioreactor system, we present a highly efficient and scalable complete suspension protocol across all stages for directed differentiation of human pluripotent stem cells into functional pancreatic islets. Here, we generate homogeneous, metabolically functional, and transcriptionally enriched SC-islets and compared against adult donor islets. Generated SC-islets showed enriched endocrine cell composition (∼63% CPEP+NKX6.1+ISL1+) and displayed functional maturity for glucose stimulated insulin secretion (∼5-fold) duringin vitroand post transplantation. Comprehensive stage-specific single-cell mass flow cytometry characterization with dimensional reduction analysis at stage-4 and -6 confirmed optimal maturation was achieved without heterogeneity. Notably, by 16-weeks transplantation follow-up, normal glycemic homeostasis was restored, and glucose responsive human c-peptide secretion response (2-fold) was achieved. Four months post engraftment, graft-harvested single cells displayed islet hormonal cell composition with flow cytometry, improved functional maturity byin vivoglucose-stimulated insulin secretion (GSIS) and enhanced transcriptional landscape with real-time expression that closely resembled patterns comparable to adult human islets. Our comprehensive evaluation of a complete suspension method applied across all stages using Vertical Wheel®bioreactors for SC-islets generation highlight progressive molecular and functional maturation of islets while reducing potential cell loss and cellular heterogeneity. Such a system could potentially be scaled to deliver clinical grade SC-islet products in a closed good manufacturing practice type environment.

One Sentence Summary

This study describes all-stages complete suspension protocol for SC-islets generation.