bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic and Genotypic Adaptation of Escherichia coli to Thermal Stress is Contingent on Genetic Background
Authors: Batarseh Tiffany N , Batarseh Sarah N , Rodríguez-Verdugo Alejandra , Gaut Brandon S
Published: May 2023

Evolution can be contingent on history, but we do not yet have a clear understanding of the processes and dynamics that govern contingency. Here, we performed the second phase of a two-phase evolution experiment to investigate features of contingency. The first phase of the experiment was based on Escherichia coli clones that had evolved at the stressful temperature of 42.2 °C. The Phase 1 lines generally evolved through two adaptive pathways: mutations of rpoB, which encodes the beta subunit of RNA polymerase, or through rho, a transcriptional terminator. We hypothesized that epistatic interactions within the two pathways constrained their future adaptative potential, thus affecting patterns of historical contingency. Using ten different E. coli Founders representing both adaptive pathways, we performed a second phase of evolution at 19.0 °C to investigate how prior genetic divergence or adaptive pathway (rpoB vs. rho) affects evolutionary outcomes. We found that phenotype, as measured by relative fitness, was contingent on founder genotypes and pathways. This finding extended to genotypes, because E. coli from different Phase 1 histories evolved by adaptive mutations in distinct sets of genes. Our results suggest that evolution depends critically on genetic history, likely due to idiosyncratic epistatic interactions within and between evolutionary modules.
Position-dependent sequence motif preferences of SpCas9 are largely determined by scaffold-complementary spacer motifs
Authors: Huszár Krisztina , Welker Zsombor , Györgypál Zoltán , Tóth Eszter , Ligeti Zoltán , Kulcsár Péter István , Dancsó János , Tálas András , Krausz Sarah Laura , Varga Éva , Welker Ervin
Published: May 2023

Streptococcus pyogenes Cas9 (SpCas9) nuclease exhibits considerable position-dependent sequence preferences. The reason behind these preferences is not well understood and is difficult to rationalise, since the protein establishes interactions with the target-spacer duplex in a sequence-independent manner. We revealed here that intramolecular interactions within the single guide RNA (sgRNA), between the spacer and the scaffold, cause most of these preferences. By using in cellulo and in vitro SpCas9 activity assays with systematically designed spacer and scaffold sequences and by analysing activity data from a large SpCas9 sequence library, we show that some long (>8 nucleotides) spacer motifs, that are complementary to the RAR unit of the scaffold, interfere with sgRNA loading, and that some motifs of more than 4 nucleotides, that are complementary to the SL1 unit, inhibit DNA binding and cleavage. Furthermore, we show that intramolecular interactions are present in the majority of the inactive sgRNA sequences of the library, suggesting that they are the most important intrinsic determinants of the activity of the SpCas9 ribonucleoprotein complex. We also found that in pegRNAs, sequences at the 3′ extension of the sgRNA that are complementary to the SL2 unit are also inhibitory to prime editing, but not to the nuclease activity of SpCas9.
PAE viewer: a webserver for the interactive visualization of the predicted aligned error for multimer structure predictions and crosslinks
Authors: Elfmann Christoph , Stülke Jörg
Published: May 2023

The development of AlphaFold for protein structure prediction has opened a new era in structural biology. This is even more the case for AlphaFold-Multimer for the prediction of protein complexes. The interpretation of these predictions has become more important than ever, but it is difficult for the non-specialist. While an evaluation of the prediction quality is provided for monomeric protein predictions by the AlphaFold Protein Structure Database, such a tool is missing for predicted complex structures. Here, we present the PAE Viewer webserver (http://www.subtiwiki.uni-goettingen.de/v4/paeViewerDemo), an online tool for the integrated visualization of predicted protein complexes using a 3D structure display combined with an interactive representation of the Predicted Aligned Error (PAE). This metric allows an estimation of the quality of the prediction. Importantly, our webserver also allows the integration of experimental cross-linking data which helps to interpret the reliability of the structure predictions. With the PAE Viewer, the user obtains a unique online tool which for the first time allows the intuitive evaluation of the PAE for protein complex structure predictions with integrated crosslinks.
HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma
Authors: Wang Stacie S , Davenport Alexander J , Iliopoulos Melinda , Hughes-Parry Hannah E , Watson Katherine A , Arcucci Valeria , Mulazzani Matthias , Eisenstat David D , Hansford Jordan R , Cross Ryan S , Jenkins Misty R
Published: May 2023

Background

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer.

Methods

Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells.

Results

HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors.

Conclusions

HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.
Concomitant Treatment of Tuberculosis and Hepatitis C Virus in Coinfected Patients Using Serum Drug Concentration Monitoring
Authors: Ashkin Alex , Alexis Afe , Ninneman Megan , Tresgallo Rene Rico , Ashkin David , Peloquin Charles A
Published: May 2023

Background

Concern for drug-drug interactions leading to treatment failure and drug-resistant strains have discouraged clinicians from attempting concomitant treatment of hepatitis C virus (HCV) and tuberculosis (TB). Increased metabolism of direct-acting antivirals (DAAs) by rifamycins has hindered concurrent use. Development of an assay for ledipasvir and sofosbuvir (LDV/SOF) serum concentrations for therapeutic drug monitoring (TDM) can ensure adequate therapy. We present the first cases of concomitant therapy of active TB and HCV with rifamycin-containing regimens and DAAs using TDM.

Methods

Using TDM, we aim to determine whether concomitant therapy with rifamycin-containing regimens and DAAs is safe and effective for patients coinfected with TB and HCV. Five individuals with TB and HCV who experienced transaminitis before or during TB therapy were concomitantly treated with rifamycin-containing regimens and LDV/SOF. Therapeutic drug monitoring was performed for LDV, SOF, and rifabutin during therapy. Baseline laboratory tests and serial liver enzymes were performed. Hepatitis C virus viral load and mycobacterial sputum cultures were obtained upon completion of therapy to determine efficacy of therapy.

Results

All patients were found to have nondetectable HCV viral loads and negative mycobacterial sputum cultures upon completion of therapy. No clinically significant adverse effects were reported.

Conclusions

These cases illustrate concomitant use of LDV/SOF and rifabutin in patients with HCV/TB coinfection. Utilizing serum drug concentration monitoring to guide dosing, correction of transaminitis were achieved, which allowed the use rifamycin-containing TB therapy. These findings suggest that concomitant therapy of TB/HCV is possible, safe, and effective.
Thermoelectricity in Ag/Cu-based complex crystal structure minerals with inherent low thermal conductivity
Authors: Rana Kewal Singh , Soni Ajay
Published: May 2023

Inherently poor lattice thermal conductivity (κL) is highly desired for applications like thermoelectricity, thermal management in electronics, thermal barrier coatings and refractories. Recently, complex crystalline materials have drawn serious scientific attention because of various interesting underlying physical phenomena which explain the unique thermal properties. In this review, we have discussed various interesting concepts and their consequences leading to ultralow κL in complex bulk chalcogenide minerals having multiple scattering channels for heat-carrying phonons. The primary focus of this review is on the Ag- and Cu-based large unit cell structures with low heat capacity and liquid-like superionic conduction of cations. The Ag/Cu sublattice of these materials that followed the phonon-liquid electron-crystal concept strongly reduces the transportation of phonons and enhances the scattering process. The presence of a large number of atoms in the unit cell results in low acoustic phonons cut-off frequency, robust acoustic–optical phonons scattering, poor sound velocity and strong crystal anharmonicity inside the crystalline lattice.
The National Negro Business League and the Economic Life of Black Entrepreneurs
Authors: Regev Ronny
Published: May 2023

This article uses the records of the National Negro Business League (NNBL) to examine the economic life and experiences of African American entrepreneurs between 1900 and 1920. Often referred to as the ‘golden age’ of Black business, this era saw the proliferation of African American owned businesses, despite the increase in discrimination and racial persecution that had characterized the United States since the turn of the century. Far from merely a platform to reaffirm the ideology of its founder Booker T. Washington, the League enabled a diverse group of business owners, entrepreneurs and professional men and women to exchange ideas and help one another navigate the segregated and uneven infrastructures of American capitalism. The protocols of the League’s annual conventions offer a window into the world of Black proprietors and shopkeepers. Specifically, the personal accounts delivered at these events reveal the experimental commercial sphere that existed next to the well-established trade and business institutions of corporate capitalism. They also demonstrate that the members of the NNBL were a progressive force: they confounded gender norms by carving a place for women within the formal Black business establishment and they diversified the economic playing field by charting alternative narratives of business success.
Inhaled nitric oxide use in newborns
Authors: Mitra Souvik , Altit Gabriel
Published: May 2023

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, is used as a therapeutic modality in infants with hypoxemic respiratory failure (HRF) associated with persistent pulmonary hypertension of the newborn (PPHN). iNO should ideally be initiated following echocardiographic confirmation of PPHN. Use of iNO is recommended in late preterm and term infants who develop HRF despite optimal oxygenation and ventilation strategies. However, routine iNO use in preterm infants on respiratory support is not recommended. iNO may be considered as a rescue modality in preterm infants with early-onset HRF when associated with prolonged rupture of membranes or oligohydramnios, or late-onset HRF in the context of bronchopulmonary dysplasia-associated pulmonary hypertension (PH) with severe right ventricular failure. A trial of iNO may also be considered for infants with congenital diaphragmatic hernia with persistent HRF despite optimal lung recruitment, and with echocardiographic evidence of supra-systemic PH and adequate left ventricular function.
Current recommendations for management of paediatric diabetic ketoacidosis
Authors: Gripp Karen E , Trottier Evelyne D , Thakore Sidd , Sniderman Jonathan , Lawrence Sarah
Published: May 2023

Treatment of paediatric diabetic ketoacidosis (DKA) includes careful attention to fluids and electrolytes to minimize the risk of complications such as cerebral injury (CI), which is associated with high morbidity and mortality. The incidence of cerebral edema in paediatric DKA has not decreased despite the use of fluid-limiting protocols based on restricting early fluid resuscitation. New evidence suggests that early isotonic fluid therapy does not confer additional risk and may improve outcomes in some patients. Protocols and clinical practice guidelines are being adjusted, with a particular focus on recommendations for initial and ongoing fluids and electrolyte monitoring and replacement. Initial isotonic fluid resuscitation is now recommended for all patients in the first 20 to 30 minutes after presentation, followed by repletion of volume deficit over 36 hours in association with an insulin infusion, electrolyte supplementation, and careful monitoring for and management of potential CI.
Never a Dull Moment: Entropy Risk in Commodity Markets
Authors: Chabi-Yo Fousseni , Doshi Hitesh , Zurita Virgilio
Published: May 2023

We develop a new approach to determine investors’ risk compensations for all distributional moments of a security. Using the concept of entropy, which is a summary of all moments of a risky security, we derive the relationship between expected returns and their compensation for entropy risk. Entropy risk premium (ERP), which is entropy under the physical minus the risk-neutral measure, indicates the hedging cost against changes in risks associated with all moments of the return’s distribution. Applying our model to the commodity markets, we find that ERP carries economically significant information for the cross-section of returns that is different from individual or combined moments.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Swiss foundations caught between compliance, control and complaints
Authors: Studen Goran
Published: May 2023

Swiss foundations are subject to a wide range of legal and regulatory requirements, including anti-money laundering (AML) and know-your-customer (KYC) rules. These rules and regulations aim to prevent illicit activities such as money laundering, terrorist financing, and tax evasion. However, Swiss foundations often face a difficult balancing act between complying with these rules, avoiding complacency, and managing complaints from stakeholders. This article explores the challenges faced by Swiss foundations in managing these competing priorities.
Fifty Years of Fungicide Development, Deployment, and Future Use
Authors: Beckerman J. , Palmer C. , Tedford E. , Ypema H.
Published: May 2023

Plant disease management has not significantly changed in the past 50 years, even as great strides have been made in the understanding of fungal biology and the etiology of plant disease. Issues of climate change, supply chain failures, war, political instability, and exotic invasives have created even more serious implications for world food and fiber security, and the stability of managed ecosystems, underscoring the urgency for reducing plant disease-related losses. Fungicides serve as the primary example of successful, widespread technology transfer, playing a central role in crop protection, reducing losses to both yield and postharvest spoilage. The crop protection industry has continued to improve upon previous fungicide chemistries, replacing active ingredients lost to resistance and newly understood environmental and human health risks, under an increasingly stricter regulatory environment. Despite decades of advances, plant disease management continues to be a constant challenge that will require an integrated approach, and fungicides will continue to be an essential part of this effort.
Clinical and Physician Factors Associated With Failed Operative Vaginal Delivery
Authors: Panelli Danielle M. , Leonard Stephanie A. , Joudi Noor , Judy Amy E. , Bianco Katherine , Gilbert William M. , Main Elliott K. , El-Sayed Yasser Y. , Lyell Deirdre J.
Published: May 2023

OBJECTIVE:

To examine clinical and physician factors associated with failed operative vaginal delivery among individuals with nulliparous, term, singleton, vertex (NTSV) births.

METHODS:

This was a retrospective cohort study of individuals with NTSV live births with an attempted operative vaginal delivery by a physician between 2016 and 2020 in California. The primary outcome was cesarean birth after failed operative vaginal delivery, identified using linked diagnosis codes, birth certificates, and physician licensing board data stratified by device type (vacuum or forceps). Clinical and physician-level exposures were selected a priori, defined using validated indices, and compared between successful and failed operative vaginal delivery attempts. Physician experience with operative vaginal delivery was estimated by calculating the number of operative vaginal delivery attempts made per physician during the study period. Multivariable mixed effects Poisson regression models with robust standard errors were used to estimate risk ratios of failed operative vaginal delivery for each exposure, adjusted for potential confounders.

RESULTS:

Of 47,973 eligible operative vaginal delivery attempts, 93.2% used vacuum and 6.8% used forceps. Of all operative vaginal delivery attempts, 1,820 (3.8%) failed; the success rate was 97.3% for vacuum attempts and 82.4% for forceps attempts. Failed operative vaginal deliveries were more likely with older patient age, higher body mass index, obstructed labor, and neonatal birth weight more than 4,000 g. Between 2016 and 2020, physicians who attempted more operative vaginal deliveries were less likely to fail. When vacuum attempts were successful, physicians who conducted them had a median of 45 vacuum attempts during the study period, compared with 27 attempts when vacuum attempts were unsuccessful (adjusted risk ratio [aRR] 0.95, 95% CI 0.93–0.96). When forceps attempts were successful, physicians who conducted them had a median of 19 forceps attempts, compared with 11 attempts when forceps attempts were unsuccessful (aRR 0.76, 95% CI 0.64–0.91).

CONCLUSION:

In this large, contemporary cohort with NTSV births, several clinical factors were associated with operative vaginal delivery failure. Physician experience was associated with operative vaginal delivery success, more notably for forceps attempts. These results may provide guidance for physician training in maintenance of operative vaginal delivery skills.
Keeping It Legal: Empowering Physicians and Trainees Through the Creation of State-specific Legal Primers
Authors: Subbarao Shalini , Latimer Katherine , Davis Carolyn , Marko Emily
Published: May 2023

OBJECTIVE:

State policies on obstetrics and gynecology issues vary widely across the nation and dramatically affect the care physicians can offer depending on where they practice. A 2020 study demonstrates that many obstetrics and gynecology residents surveyed across the United States felt that their exposure to medical–legal topics was limited. The purpose of this initiative was to create legal primers on state-specific laws regarding obstetric and gynecologic care and evaluate their educational utility for residents and attendings across specialties.

PROJECT SUMMARY:

Ten primers with relevant Virginia state laws and their clinical relevance were created on the following topics: adolescent rights, emergency contraception, expedited partner therapy, mandatory reporting situations, close-in-age exemptions, medical students performing pelvic examinations, abortion, transgender rights, and paternity rights. The primers were presented to residents and attendings in obstetrics and gynecology, family medicine, and emergency medicine. Knowledge pretests and posttests were administered, with an opinion survey on comfort level of topics to assess usefulness of the primers.

OUTCOME:

A total of 49 participants from obstetrics and gynecology and emergency medicine participated in the project. Participants from family medicine were presented the primers before data collection. The mean change in pretest–posttest scores was 3.6 of 10 (SD 1.8, P<.001). A total of 97.9% of participants found the primers very helpful or somewhat helpful. Participants reported an increased comfort level on all 10 topics after participating. Anecdotally, many residents and attendings referenced the primers afterward in clinical situations to guide their practice.

RELEVANCE TO PHYSICIANS IN PRACTICE:

State-specific legal primers are useful learning tools for understanding the nuances of laws regarding obstetric and gynecologic care. These primers can be used as quick resources for providers in difficult clinical situations. They can also be modified to reflect other state laws to reach a wider audience.
Interpregnancy Interval After Stillbirth and Adverse Perinatal Outcomes
Authors: Gibbins Karen J. , Garg Bharti , Caughey Aaron B.
Published: May 2023

We used a retrospective cohort of 5,581 individuals to examine the association between interpregnancy interval (IPI) after stillbirth and pregnancy outcomes of preterm birth, preeclampsia, small for gestational age, recurrent stillbirth, infant death, and neonatal intensive care unit admission in the subsequent pregnancy. The IPI was divided in six categories, with 18–23 months as referent. Association between IPI category and adverse outcomes was determined with logistic regression models adjusted for maternal race and ethnicity, age, education, insurance, and gestational age at preceding stillbirth. Adverse perinatal outcome was common in pregnancies after stillbirth, with 26.7% of individuals delivering preterm. None of the IPI categories were associated with increased risk of adverse perinatal outcomes, including the shortest category (IPI less than 3 months). This finding is meaningful for bereaved parents who desire to conceive shortly after stillbirth.
Gilteritinib-induced severe immune-related enteritis: a possible case report
Authors: Luo Pan , Qiu Huiying , Yang Yushan , Wu Jiaqi , Song Xianmin , Fan Guorong , Liu Gaolin , Gao Junwei
Published: May 2023

Gilteritinib is currently approved in China for relapsed/refractory FLT3-mutated acute myeloid leukemia, and it is very important to monitor and report its adverse drug reaction (ADR) after post-marketing. This case report describes a patient who was diagnosed with acute myeloid leukemia harboring FLT3 mutations and developed a severe suspected immune-related enteritis during treatment with gilteritinib for maintenance therapy following allo-hematopoietic stem cell transplantation. According to the Naranjo probability scale, gilteritinib was defined as a ‘possible’ cause of ADR. Another suspicious inducement, graft-versus-host disease, can not be eluted and might represent a limitation in this case. To the best of our knowledge, this is the first report on gilteritinib-induced severe enteritis and will help physicians to keep vigilant, and detect and deal with time for possible ADR.
Development of a Communication Skills Training to Enhance Effective Team Communication in Oncology
Authors: Parker Patricia A. , Staley Jessica , Rosa William E. , Weiner Richard , Banerjee Smita C.
Published: May 2023

Introduction:

Effective communication among members of health care teams is essential to provide quality and patient-centered care, yet many people identify this as a challenge. We developed, implemented, and conducted a preliminary evaluation of a training to enhance communication within oncology teams.

Methods:

This training identifies key strategies, communication skills, and process tasks recommended to achieve the goal of using a collaborative approach to navigate communication interactions across members of the hospital team to enhance patient care outcomes and increase team effectiveness. Forty-six advanced practice providers (APPs) participated and completed an evaluation of the module.

Results:

Eighty-three percent of participants identified as female and 61% were White. Eighty-three percent of participants were nurse practitioners and 17% were physician assistants. The module was highly rated. Participants responded that they were satisfied (“agree” or “strongly agree”) on 16 of 17 evaluation items (80% or higher).

Discussion:

APPs were satisfied with the course and found many aspects useful in learning and practicing skills to improve their communication with other team members to enhance their care of patients. Training with this module and other communication approaches are needed for health care professionals of all types to encourage more consistent and meaningful communication with their colleagues to improve patient care.
Regional Workshops to Disseminate Decision Guide to Reduce Potentially Preventable Hospital Transfers: Application of the Diffusion of Innovation Model
Authors: Tappen Ruth M. , Sopcheck Janet , Southard Karen , Hain Debra , Suriaga Armiel
Published: May 2023

Introduction:

Medically unnecessary, potentially preventable transfers of nursing home (NH) residents to acute care poses multiple risks for residents. Family and resident insistence on these preventable transfers has not been thoroughly addressed in transfer reduction programs.

Methods:

The Diffusion of Innovation model guided dissemination of an evidence-based patient decision guide that addressed resident and family insistence on hospital transfer. Twenty workshops were held across eight states of Centers for Medicare and Medicaid Services Region IV. All Medicare-certified NHs in Region IV received emailed invitations to the workshops in their states. Quantitative and qualitative data were collected on workshop attendees, the facilities they represented, and response to the workshop including adoption of the Guide and its effect on hospital readmissions.

Results:

Altogether, 1124 facility representatives and affiliated professionals attended the workshops. NH administrators rated the program 4.4 out of 5. Of those who responded, 71% said that they were using the Guide as a result of the workshop; 89% of these said that it was helpful, especially to initiate difficult conversations about end-of-life care and to discuss the care a contemporary NH can provide. Readmission rates dropped 30% in the NHs that reported their results.

Discussion:

The use of the Diffusion of Innovation model was effective in delivering information to a large number of facilities in sufficient detail to implement the Decision Guide. However, the workshop format provided little opportunity to respond to concerns that arose after the workshops, to diffuse the innovation further, or to build sustainability.
Increased accuracy in identifying NAFLD with advanced fibrosis and cirrhosis: independent validation of the Agile 3+ and 4 scores
Authors: Noureddin Mazen , Mena Edward , Vuppalanchi Raj , Samala Niharika , Wong Micaela , Pacheco Fabiana , Polanco Prido , Sakkal Celine , Antaramian Ani , Chang Devon , Noureddin Nabil , Kohli Anita , Harrison Stephen A. , Gawrieh Samer , Alkhouri Naim , Truong Emily
Published: May 2023

Background and Aims:

We explored 2 novel scores, Agile 3+ and 4, to identify advanced fibrosis (≥F3) and cirrhosis (F4), respectively, in NAFLD and compared their diagnostic performances to liver stiffness measurement (LSM) by vibration-controlled transient elastography and fibrosis-4 index (FIB-4) (for Agile 3+).

Approach and Results:

This multicenter study included 548 NAFLD patients with laboratory testing, liver biopsy, and vibration-controlled transient elastography within 6 months. Agile 3+ and 4 were applied and compared with FIB-4 or LSM alone. Goodness of fit was evaluated using a calibration plot and discrimination using area under the receiver operating curve. Area under the receiver operating curves was compared using the Delong test. Dual cutoff approaches were applied to rule out and rule in ≥F3 and F4. Median (interquartile range) age was 58 (15) years. Median body mass index was 33.3 (8.5) kg/m2. Fifty-three percent had type 2 diabetes, 20% had F3, and 26% had F4. Agile 3+ demonstrated an area under the receiver operating curve of 0.85 (0.81; 0.88) similar to that of LSM [0.83 (0.79; 0.86), p=0.142] but significantly higher than that of FIB-4 [0.77 (0.73; 0.81), p<0.0001). Agile 4’s area under the receiver operating curve [0.85 (0.81; 0.88)] was similar to that of LSM [0.85 (0.81; 0.88), p=0.065). However, the percentage of patients with indeterminate results was significantly lower with Agile scores compared with FIB-4 and LSM (Agile 3+: 14% vs. FIB-4: 31% vs. LSM: 13%, p<0.001; Agile 4: 23% vs. LSM: 38%, p<0.001).

Conclusions:

Agile 3+ and 4 are novel vibration-controlled transient elastography–based noninvasive scores that increase accuracy in the identification of advanced fibrosis and cirrhosis respectively and are ideal for clinical use due to a lower percentage of indeterminant outputs compared with FIB-4 or LSM alone.
Bile exosomal miR-182/183-5p increases cholangiocarcinoma stemness and progression by targeting HPGD and increasing PGE2 generation
Authors: Shu Lizhuang , Li Xingyong , Liu Zengli , Li Kangshuai , Shi Anda , Tang Yongchang , Zhao Liming , Huang Lingling , Zhang Zhiyue , Zhang Dong , Huang Shaohui , Lian Shuo , Sheng Guoli , Yan Zhangdi , Zhang Zongli , Xu Yunfei
Published: May 2023

Background & Aims:

Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components.

Approach & Results:

Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis.

Conclusions:

CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.
Dietary cholesterol in alcohol-associated liver disease
Authors: Jia Lin
Published: May 2023

There is an increasing prevalence of alcohol-associated liver disease (ALD) worldwide. In addition to excessive alcohol consumption, other nutritional factors have been shown to affect the initiation and progression of ALD. The emerging role of cholesterol in exacerbating ALD has been reported recently and the underlying mechanisms are discussed. In addition, the interplay between dietary cholesterol and alcohol on cholesterol metabolism is reviewed. Furthermore, we highlight the therapeutic potential of cholesterol-lowering drugs in managing the onset and severity of ALD. Finally, we suggest the future mechanistic investigation of the effect of cholesterol on insulin resistance and intestinal inflammation in the exacerbation of alcohol-induced cellular and systemic dysfunction.
Prescription Opioid Misuse in Older Adult Surgical Patients
Authors: Dahlem Chin Hwa , Schepis Ty S. , McCabe Sean Esteban , Rank Aaron L. , Kcomt Luisa , McCabe Vita V. , Voepel-Lewis Terri
Published: May 2023

The United States and many other developed nations are in the midst of an opioid crisis, with consequent pressure on prescribers to limit opioid prescribing and reduce prescription opioid misuse. This review addresses prescription opioid misuse for older adult surgical populations. We outline the epidemiology and risk factors for persistent opioid use and misuse in older adults undergoing surgery. We also address screening tools and prescription opioid misuse prevention among vulnerable older adult surgical patients (e.g., older adults with a history of an opioid use disorder), followed by clinical management and patient education recommendations. A significant plurality of older adults engaged in prescription opioid misuse obtain opioid medication for misuse from health providers. Thus, nurses can play a critical role in identifying those older adults at a higher risk for misuse and deliver quality care while balancing the need for adequate pain management against the risk for prescription opioid misuse.
Effective Nursing Recovery-Oriented Interventions for Individuals With Substance Use Disorder
Authors: Tamayo Niall , Lane Annette
Published: May 2023

Nurses support the recovery of individuals with substance use disorder. How they support individuals, however, may impact the effectiveness of their work. For example, there are various paradigms of recovery that alter interventions. In addition, negative attitudes adopted by clinicians discourage individuals who use substances from accessing healthcare services, experiencing further health deterioration. Alternatively, nurses can enact interventions that promote positive experiences, further supporting the recovery of individuals. Hence, it is beneficial to increase nurses' awareness of effective interventions that promote recovery. The purpose of this literature review is to examine effective nursing interventions that promoted recovery of those with substance use disorders from the perspective of nurses and individuals who received nursing care. The review identified that effective interventions were based on three major themes: person-centered care, empowerment, and maintaining supports and capability enhancement. In addition, literature revealed that some interventions were perceived to be more effective; this depended on whose viewpoint was examined—nurses or individuals with substance use disorders. Finally, there are interventions based on spirituality, culture, advocacy, and self-disclosure that are often disregarded but may be effective. Nurses should utilize the more prominent interventions as they offer the most benefit and integrate interventions that are often overlooked.
Implementing a Screening and Brief Intervention Protocol for Excessive Alcohol Use in a Trauma Center
Authors: Harry Melissa L. , Lake Erica , Woehrle Theo A. , Heger Anna Mae C. , Vogel Linda E.
Published: May 2023

Objective

The aim of this healthcare improvement project was to evaluate healthcare provider use of screening and brief interventions (SBIs) for patients screening positive for alcohol at an upper Midwestern adult trauma center transitioning from Level II to Level I.

Method

Trauma registry data for 2,112 adult patients with trauma who screened positive for alcohol were compared between three periods: pre-formal-SBI protocol (January 1, 2010, to November 29, 2011); first post-SBI protocol (February 6, 2012, to April 17, 2016) after protocol implementation, healthcare provider training, and documentation changes; and second post-SBI protocol (June 1, 2016, to June, 30, 2019) after additional training and process improvements. Data analysis included descriptive statistics and logistic regression for comparisons over time and between admitting services.

Results

For the trauma admitting service, SBI rates increased from 32% to 90% over time, compared with 18%–51% for other admitting services combined. Trauma-service-admitted patients screening positive for alcohol had higher odds of receiving a brief intervention than other admitting services in each period in adjusted models: pre-SBI (OR = 1.99, 95% CI [1.15, 3.43], p = .014), first post-SBI (OR = 2.89, 95% CI [2.04, 4.11], p < .001), and second post-SBI (OR = 11.40, 95% CI [6.27, 20.75], p < .001) protocol periods. Within trauma service admissions, first post-SBI protocol (OR = 2.15, 95% CI [1.64, 2.82], p < .001) and second post-SBI protocol (OR = 21.56, 95% CI [14.61, 31.81], p < .001) periods had higher rates and odds of receiving an SBI than the pre-SBI protocol period.

Conclusion

The number of SBIs completed with alcohol-positive adult patients with trauma significantly increased over time through SBI protocol implementation, healthcare provider training, and process improvements, suggesting other admitting services with lower SBI rates could adopt similar approaches.
An Integrative Review of Programs for Managing Nurses' Substance Use Disorder in the Workplace
Authors: Luurila Katrimaija , Kangasniemi Mari , Häggman-Laitila Arja
Published: May 2023

Background

Nurses' substance use disorder (SUD) endangers patient safety and decreases nurses' work ability and health. To better understand the methods, treatments, and benefits of the programs used to monitor nurses with SUD and promote their recovery, a systematic review of international research is needed.

Aim

The aim was to gather, evaluate, and summarize empirical research on programs for managing nurses with SUD.

Design

An integrative review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis instructions.

Method

Systematic searches were conducted in the CINAHL, PsycInfo, PubMed, Scopus, and Web of Science databases between 2006 and 2020, complemented with manual searches. Articles were selected based on inclusion, exclusion, and method-specific evaluation criteria. The data were analyzed narratively.

Results

The review identified 12 studies of which nine focused on recovery and monitoring programs for nurses with SUD or other impairment and three concerned training programs for nurse supervisors or worksite monitors. The programs were described in terms of their target groups, goals, and theoretical basis. The programs' methods and benefits were described together with challenges in their implementation.

Conclusion

There has been little research on programs for nurses with SUD, the programs that exist are heterogenous, and the evidence available in this field is weak. Further research and developmental work are needed on preventive and early detection programs as well as rehabilitative programs and programs supporting reentry to workplaces. In addition, programs should not be restricted to nurses and their supervisors; colleagues and work communities should also be involved.
Congenital myasthenic syndrome due to a genetic mutation
Authors: Tsalta-Mladenov Mihael , Levkova Mariya , Georgieva Darina , Andonova Silva
Published: May 2023

Congenital myasthenic syndrome (CMS) is a group of rare genetic disorders that mimics the symptoms of myasthenia gravis, but it is due to a genetic defect. We present a case of a male CMS patient, and the course of the disease through the years. The patient initially presented with generalized muscle weakness and difficulty swallowing. During the follow-up, he developed difficulty in chewing, bilateral external ophthalmoparesis with an almost full block of eye movements and bulbar syndrome. The case illustrates both the clinical heterogeneity and the progressive worsening of the symptoms of the disease over the years. The optimal treatment for CMS is based on the molecular defect and its localization in the neuromuscular junction. In our case, treatment with pyridostigmine resulted in good long-term control of symptoms. As a result of the patient's good compliance with treatment, he was not admitted to hospital because of respiratory distress. The lack of a unified protocol for the treatment of CMS highlights the need for a more personalized approach when dealing with patients with rare diseases.
Association between the diagnostic classification of newly diagnosed coronary artery disease and future heart failure development
Authors: Williams Brent A. , Voyce Stephen , Blankenship James C. , Chang Alexander R.
Published: May 2023

Objective

The first clinical manifestation of coronary artery disease (CAD) varies widely from unheralded myocardial infarction (MI) to mild, incidentally detected disease. The primary objective of this study was to quantify the association between different initial CAD diagnostic classifications and future heart failure.

Methods

This retrospective study incorporated the electronic health record of a single integrated health care system. Newly diagnosed CAD was classified into a mutually exclusive hierarchy as MI, CAD with coronary artery bypass graft (CABG), CAD with percutaneous coronary intervention, CAD only, unstable angina, and stable angina. An acute CAD presentation was defined when the diagnosis was associated with a hospital admission. New heart failure was identified after the CAD diagnosis.

Results

Among 28 693 newly diagnosed CAD patients, initial presentation was acute in 47% and manifested as MI in 26%. Within 30 days of CAD diagnosis, MI [hazard ratio (HR) = 5.1; 95% confidence interval: 4.1–6.5] and unstable angina (3.2; 2.4–4.4) classifications were associated with the highest heart failure risk (compared to stable angina), as was acute presentation (2.9; 2.7–3.2). Among stable, heart failure-free CAD patients followed on average 7.4 years, initial MI (adjusted HR = 1.6; 1.4–1.7) and CAD with CABG (1.5; 1.2–1.8) were associated with higher long-term heart failure risk, but an initial acute presentation was not (1.0; 0.9–1.0).

Conclusion

Nearly 50% of initial CAD diagnoses are associated with hospitalization, and these patients are at high risk of early heart failure. Among stable CAD patients, MI remained the diagnostic classification associated with the highest long-term heart failure risk, however, having an initial acute CAD presentation was not associated with long-term heart failure.
Posttraumatic osteoarthritis: from basic science to clinical implications
Authors: Haller Justin M. , van der Meulen Marjolein C H. , Olson Steven , Anderson Donald , Marsh J. Lawrence , Working Zachary
Published: May 2023

Posttraumatic osteoarthritis (PTOA) is a subset of osteoarthritis that occurs after joint injury and is associated with degradation of articular cartilage and subchondral bone. As compared with primary osteoarthritis, PTOA occurs in a time window initiated by a traumatic event resulting in damage to layers of joint structure and alterations in joint shape. As techniques in open reduction and internal fixation continue to mature, our success in preventing posttraumatic osteoarthritis has not kept pace. Advances in research in the subchondral bone, inflammatory response, and joint mechanics continue to open our understanding of this posttraumatic process. In addition, there are possibilities emerging as biological agents to therapeutically alter the progression of PTOA.
COMBINATION THERAPY WITH A SENSE OLIGONUCLEOTIDE TO INDUCIBLE NITRIC OXIDE SYNTHASE MRNA AND HUMAN SOLUBLE THROMBOMODULIN IMPROVES SURVIVAL OF SEPSIS MODEL RATS AFTER PARTIAL HEPATECTOMY
Authors: Nakatake Richi , Okuyama Tetsuya , Kotsuka Masaya , Ishizaki Morihiko , Kitade Hiroaki , Yoshizawa Katsuhiko , Tolba Rene H. , Nishizawa Mikio , Sekimoto Mitsugu
Published: May 2023

Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded “sense oligonucleotide” (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis.
A COMPARATIVE ANALYSIS TO DETERMINE THE OPTIMUM HISTONE DEACETYLASE INHIBITORS AND ADMINISTRATION ROUTE FOR IMPROVING SURVIVAL AND ORGAN INJURY IN RATS AFTER HEMORRHAGIC SHOCK
Authors: Niu Kunwei , Yang Long , Song Wenjie , Liu Zhengcai , Yuan Juzheng , Zhang Hong , Zhang Wenjie , Wang Jianlin , Tao Kaishan
Published: May 2023

Objective: Histone deacetylase inhibitors (HDACIs) have been reported to improve survival in rats with hemorrhagic shock (HS). However, no consensus exists on the most effective HDACIs and their administration routes. We herein aimed to determine the optimal HDACIs and administration route in rats with HS. Methods: Survival analysis: In experiment I, male Sprague-Dawley rats were subjected to HS (mean arterial pressure [MAP] was maintained at 30–40 mm Hg for 20 min), and intravenously injected with the following agents (n = 8 per group): (1) no treatment, (2) vehicle (VEH), (3) entinostat (MS-275), (4) [N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide] (LMK-235), (5) tubastatin A, (6) trichostatin A (TSA), and (7) sirtinol. In experiment II, rats were intraperitoneally injected with TSA. Mechanism research: In experiments I and II, rats were observed for 3 h, after which blood samples and liver, heart, and lung tissues were harvested. Results: In experiment I, 75% rats in the VEH group but only 25% rats in the LMK-235 and sirtinol groups died within ≤5 h of treatment, whereas the survival of rats in the MS-275, tubastatin A, and TSA groups was significantly prolonged. MS-275, LMK-235, tubastatin A, and TSA significantly reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels. In experiment II, the survival was longer after i.v. TSA treatment than after i.p. TSA treatment, and the IL-6 levels in the heart were significantly lower in rat who received i.p. TSA treatment than in those who received i.v. TSA treatment. Conclusions: The i.v. effect was superior to the i.p. effect, while nonselective and isoform-specific classes I and IIb HDACIs had similar effects.