bluuebunny/crossref_metadata_2025 huggingface dataset:
Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition
Authors: Gaela Venus Marie , Hsia Hsuan-Yu , Joseph Nithila A , Tzeng Wan-Yi , Ting Pin-Chao , Shen Yi-Ling , Tsai Chia-Tsen , Boudier Thomas , Chen Liuh-Yow
Published: May 2024

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.
Exploring effects of anesthesia on complexity, differentiation, and integrated information in rat EEG
Authors: Nilsen André Sevenius , Arena Alessandro , Storm Johan F
Published: May 2024

To investigate mechanisms underlying loss of consciousness, it is important to extend methods established in humans to rodents as well. Perturbational complexity index (PCI) is a promising metric of “capacity for consciousness” and is based on a perturbational approach that allows inferring a system’s capacity for causal integration and differentiation of information. These properties have been proposed as necessary for conscious systems. Measures based on spontaneous electroencephalography recordings, however, may be more practical for certain clinical purposes and may better reflect ongoing dynamics. Here, we compare PCI (using electrical stimulation for perturbing cortical activity) to several spontaneous electroencephalography-based measures of signal diversity and integrated information in rats undergoing propofol, sevoflurane, and ketamine anesthesia. We find that, along with PCI, the spontaneous electroencephalography-based measures, Lempel–Ziv complexity (LZ) and geometric integrated information (ΦG), were best able to distinguish between awake and propofol and sevoflurane anesthesia. However, PCI was anti-correlated with spontaneous measures of integrated information, which generally increased during propofol and sevoflurane anesthesia, contrary to expectations. Together with an observed divergence in network properties estimated from directed functional connectivity (current results) and effective connectivity (earlier results), the perturbation-based results seem to suggest that anesthesia disrupts global cortico-cortical information transfer, whereas spontaneous activity suggests the opposite. We speculate that these seemingly diverging results may be because of suppressed encoding specificity of information or driving subcortical projections from, e.g., the thalamus. We conclude that certain perturbation-based measures (PCI) and spontaneous measures (LZ and ΦG) may be complementary and mutually informative when studying altered states of consciousness.
Constraints on crustal compositional architecture across the North China–Altaids transition and implications for craton margin reworking
Authors: Ye Zhuo , Tan Xiaomiao , Gao Rui , Li Qiusheng , Zhang Hongshuang , Wu Xiaoyang , Li Wenhui , Li Yingkang
Published: May 2024

The phase of secular evolution of continents is manifested as the degree of compositional differentiation, modification and maturation of continental crusts, which is vital in understanding the mechanism of continental evolution but is difficult to quantify. Here we use integrated passive- and active-source seismic profiling to conduct joint analysis and inversion and derive Vs and Vp/Vs section models across the North China Craton (NCC) to southeastern Altaids boundary zone that bears a tectonic transition from a reworked ancient craton margin to a Phanerozoic accretionary orogen. We systematically exploited the imaged multiple physical properties as precise and delicate proxies to constrain the compositional architecture in the crust across this important tectonic transition subject to various crustal evolutional phases. Our Vs and Vp/Vs imaging, together with the existing isotopic data, characterizes the Yin Shan–Yan Shan belt as the northern NCC margin with layered homogeneous compositions that point to an evolved crust. However, the lower-crustal low-Vs/high-Vp/Vs signature that overlaps the shallowly dipping to horizontal reflective fabrics suggests that the crust of the northern NCC margin has undergone considerable reworking through lower-crustal-stretching-assisted melt migration and mixing since the late Paleozoic to Mesozoic eras. The process probably involved crust–mantle interaction and thus resulted in a compositionally modified ancient crustal basement. On the contrary, the southeastern Altaids domain manifests crustal complexity in compositions and structures inferred to be indicative of a juvenile crust of the Phanerozoic accretionary orogen. Our results provide deep physical-property constraints that shed new light on the crustal evolution of a complex craton margin.
A Cross-Country Study of Cigarette Affordability and Single-Stick Purchases Using Survey Data From African Countries
Authors: Filby Samantha
Published: May 2024

Introduction

Reducing cigarette affordability is paramount for reducing cigarette consumption. Measuring affordability requires data on cigarette prices. Unlike the commonly used retail price of a 20-pack of the most-sold cigarette domestically, survey-derived cigarette prices reflect differences arising from the brand variety and the types of packaging in which cigarettes are purchased.

Aims and Methods

This paper uses self-reported cigarette price data from the eight African countries that have implemented the Global Adult Tobacco Survey (GATS) to construct country-level Relative Income Prices. The relationship between cigarette affordability, cigarette smoking prevalence, and cigarette smoking intensity, is examined using logit models for smoking participation (N = 51 122) and generalized linear models for conditional cigarette demand (N = 2443). GATS data are also used to produce nationally representative estimates of the prevalence of single-stick cigarette purchases in the sampled countries.

Results

The estimated affordability elasticity of cigarette smoking participation is –0.245 (95% CI = –0.411 to –0.078). The estimated affordability elasticity of smoking intensity is –0.155 (95% CI = –0.286 to –0.023). Single-stick cigarette sales dominate all-markets. The proportion of smokers who reported buying cigarettes in the form of single sticks during their most recent cigarette purchase exceeds 90% in Kenya, Tanzania, and Uganda.

Conclusions

The results point to the need for governments in the countries sampled to increase excise taxes in a manner that renders cigarettes less affordable over time, and to enact and enforce legislation that prohibits the sale of single cigarettes. These findings highlight that measures to reduce both the demand and supply of cigarettes will be required to reduce their use in the region.

Implications

This study is the first to examine the prevalence of single-stick cigarette purchases, and the association between cigarette affordability and smoking outcomes, in the African setting, using data from the GATS. Findings provide local evidence for the countries sampled, which represent over half of sub-Saharan Africa’s adult population (aged 15 and older), on the importance of implementing excise tax increases that reduce cigarette affordability over time. They also highlight the need to enact and enforce legislation that prohibits the sale of single cigarettes.
The defectiveness of propaganda
Authors: Bonard Constant , Contesi Filippo , Marques Teresa
Published: May 2024

We argue that political propaganda is a negative phenomenon, against a recent strain of philosophical theorizing that argues that political propaganda can sometimes be neutral or even positive. After an exploration of the sense and connotation of the word ‘propaganda’ in ordinary use and in the scholarly literature, we discuss Ross's initial account of propaganda as an epistemically defective form of political communication. We claim that, with some refinements, it is an explanatorily useful analysis. We then assess two prominent attempts that aim at classifying legitimate cases of public communication as cases of propaganda, namely Ross's revision of her previous model and Stanley's influential account. We show that some of the cases in contention are problematic and that the arguments the authors offer for classifying other non-problematic cases as propaganda are inconclusive. We also argue that the idea of considering legitimate public communication as propaganda is unmotivated.
Labia minora hypertrophy: pathologizing diversity?
Authors: Perelmuter Sara
Published: May 2024

Introduction

Labia minora hypertrophy can be characterized by the labial tissue extending beyond the labia majora; however, the exact definition of hypertrophy is a matter of debate. While the prevalence of labia hypertrophy is very common among women, taboo/controversial attitudes and surgical interventions still dominate. The recognition and study of labia minora hypertrophy will increase our knowledge of this underrepresented anatomic diversity.

Objectives

To provide a report of the current literature on labia hypertrophy and discuss the definition, etiology, attitudes, management, and medicalization surrounding labia minora hypertrophy and the implications.

Methods

Comprehensive review of literature pertaining to labia minora hypertrophy.

Results

Labia minora appearance and measurements vary extensively, and hypertrophy is extremely prevalent in the population and largely nonpathologic. There remains a lack of standardized criteria to define labia hypertrophy. Attitudes surrounding labia hypertrophy differ globally, but in Western nations the overwhelming sentiment toward labia hypertrophy has largely been medicalized.

Conclusion

Negative attitudes and unnecessary medicalization of nonpathologic instances of labia hypertrophy is unjustifiable and comes with potential risks. There remains an impending need to demedicalize nonpathologic elongated labia, educate the public on diverse genital appearance, and improve understanding of the long-term outcomes and risks of genital cosmetic surgery.
Inhibition of NLRP3 inflammasome by MCC950 under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in Müller glia
Authors: Gao Shuang , Li Na , Lin Zhongjing , Zhong Yisheng , Wang Yanuo , Shen Xi
Published: May 2024

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen‐induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP‐GFP‐LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK‐1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK‐1 pathway significantly interfered with the MCC950‐induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK‐1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK‐1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.
DDX58 variant triggers IFN‐β‐induced autophagy in trabecular meshwork and influences intraocular pressure
Authors: Huang Xinting , Zhou Xiaoyu , Zhang Feng , Wang Xiaobo , Duan Xuanchu , Liu Ke
Published: May 2024

Singleton–Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN‐stimulated gene expression and high IFN‐β‐based type‐I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN‐β on TM cells. Our study is the first to demonstrate that IFN‐β significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN‐β remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN‐β‐induced autophagy in TM cells, we performed microarray analysis in IFN‐β‐treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN‐β‐induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN‐β. Our findings suggest that DDX58 mutation leads to the overproduction of IFN‐β, which elevates IOP by modulating autophagy through RSAD2 in TM cells.
c‐Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy
Authors: Liang Lulu , He Mengfei , Zhou Panpan , Pan Shaokang , Chen Jingfang , Lv Linxiao , Hu Mingyang , Zhou Sijie , Liu Dongwei , Liu Zhangsuo
Published: May 2024

The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography‐mass spectrometry (LC–MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c‐Cbl binds to podocin, and the regulation of c‐Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c‐Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.
Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department
Authors: Bolanaki Myrto , Winning Johannes , Slagman Anna , Lehmann Thomas , Kiehntopf Michael , Stacke Angelika , Neumann Caroline , Reinhart Konrad , Möckel Martin , Bauer Michael
Published: May 2024

Objectives:

Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool.

Design:

In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission.

Setting:

Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin).

Patients:

One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1.

Interventions:

None.

Measurements and Main Results:

The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79–0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively.

Conclusions:

Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.
Understanding Perioperative Acute Myocardial Ischemia Following Coronary Artery Bypass Grafting
Authors: Kompella Ritika , Patail Haris , Sharma Tanya , Haidry Syed Abbas , Frishman William , Aronow Wilbert S.
Published: May 2024

Surgical revascularization and coronary artery bypass grafting are often pursued as treatment for obstructive coronary artery disease. Despite trends of increased referrals for complex percutaneous coronary intervention, surgical revascularization often remains the standard of care for patients with multivessel or complex coronary artery disease. Myocardial ischemia during the perioperative and postoperative periods during coronary artery bypass grafting remains a challenge. Nuanced consideration is necessary to decide on interventions that include conservative management and percutaneous or repeat surgical revascularization.
Histologic Hitchhikers: A Review of Common Exogenous Artifacts Encountered During Mohs Micrographic Surgery
Authors: Lam Charlene , Shamloul Norhan , Samaan Christen , Ken Kimberly , Ioffreda Michael
Published: May 2024

BACKGROUND

Exogenous artifacts can interfere with accurate histologic tissue evaluation on frozen sections during Mohs micrographic surgery (MMS). Mohs surgeons should be aware of these anomalies to avoid potential misdiagnoses.

OBJECTIVE

To review exogenous artifacts encountered in frozen tissue pathology during MMS.

METHODS

A literature search was conducted in PubMed to identify studies reporting on exogenous artifacts encountered during MMS and a list of previously described exogenous artifacts was compiled. A retrospective examination of frozen histology slides from recent Mohs cases at the authors' institution was performed to obtain illustrative examples of these artifacts, supplemented by formalin-fixed paraffin-embedded samples when frozen examples could not be found.

RESULTS

Exogenous artifacts represent foreign bodies that have been externally introduced into the skin or artifacts resulting from other external factors. If frozen section evaluation is inaccurate, overdiagnosis can occur during MMS, resulting in unnecessary layers, larger margins, and more complex reconstructions. These exogenous tissue changes can mimic inflammatory processes and melanocytic or keratinocyte malignancies on histology.

CONCLUSION

Exogenous artifacts are common findings during margin assessment in Mohs micrographic surgery. The resulting histological findings can be confusing but correlating them with the clinical and surgical history often reassures surgeons. Recognizing these artifacts facilitates accurate diagnosis and promotes optimal patient care.
Lessons Learned—A Case for Required Student Services 1:1 Orientation
Authors: Hoffmann Chelsey , Griffey Stacy
Published: May 2024

Introduction

Both faculty and student learners associated with physician assistant/associate (PA) programs continue to suffer from the effects of the ongoing mental health crisis. Furthermore, student learners may have other personal needs impacting their potential success in PA school (ie, financial, academic, or other). A proactive approach to supporting student learners early in their PA educational journey is warranted.

Methods

Required 1:1 face-to-face orientations between incoming PA students and a representative from the Office of Wellness and Academic Support (OWAS) were implemented during the first week of PA program orientation. Students were allowed time and space to privately share their individual experiences and concerns as they entered PA school. In addition, the student services representative from OWAS was able to provide customized education on the variety of resources available for students.

Results

The student services representative from OWAS established personal relationships with each of the incoming PA students. Multiple follow-up appointments and referrals were made to various service lines including tutoring, learner accommodations, and mental health counseling.

Discussion

The implementation of required 1:1 face-to-face orientations between incoming PA students and student services during the first week of PA program orientation was highly effective. The primary lesson learned is that a simple, preventative, proactive approach can be extremely impactful if we are willing to view the challenges of student learners in PA education through a different lens.
Infected Thrombosis Leading to Veno-Venous Extracorporeal Membrane Oxygenation Dysfunction in Chronic Thromboembolic Pulmonary Hypertension
Authors: Grate Jeremy C. , Reynolds Tyler S. , Gordon Adam C. , Dave Sagar B.
Published: May 2024

Nosocomial infections and thrombosis are frequent complications during extracorporeal membrane oxygenation (ECMO). Preventative measures and close monitoring for early recognition of these complications are imperative in patients supported with ECMO. We report the case of a 41 year old female on veno-venous ECMO awaiting surgical thrombectomy for chronic thromboembolic pulmonary hypertension that developed profound bacteremia leading to gross purulence and thrombosis of the membrane oxygenator. Recannulation in addition to targeted antibiotics, frequent cultures, imaging, and surgery were diagnostic and therapeutic interventions that led to ultimate resolution.
Molecular Imaging and Therapy of Differentiated Thyroid Carcinoma in Adults
Authors: Mulugeta Philipose Getachew , Chi Anthony W. , Anderson Thomas Michael
Published: May 2024

Differentiated thyroid carcinoma (DTC) has been increasing in incidence in the United States over the last several decades, although mortality rates have remained low. Radioactive iodine therapy (RAI-T) has been a mainstay of treatment for DTC since the 1940s. Imaging of DTC before and after RAI-T primarily focuses on molecular imaging of the sodium iodide symporter. The expanding understanding of the molecular profile of DTC has increased available treatment options. Incorporation of risk stratification to treatment approaches has led to deintensification of both surgical and nonsurgical treatments, leading to decreased morbidity without compromising disease control.
Postcardiac Arrest Care Delivery in Pediatric Intensive Care Units: A Plan and Call to Action
Authors: Barreto Jessica A. , Wenger Jesse , Dewan Maya , Topjian Alexis , Roberts Joan ,   for the pediatric Resuscitation Quality (pediRES-Q) Collaborative Investigators
Published: May 2024

Background:

Despite national pediatric postcardiac arrest care (PCAC) guidelines to improve neurological outcomes and survival, there are limited studies describing PCAC delivery in pediatric institutions. This study aimed to describe PCAC delivery in centers belonging to a resuscitation quality collaborative.

Methods:

An institutional review board-approved REDCap survey was distributed electronically to the lead resuscitation investigator at each institution in the international Pediatric Resuscitation Quality Improvement Collaborative. Data were summarized using descriptive statistics. A chi-square test was used to compare categorical data.

Results:

Twenty-four of 47 centers (51%) completed the survey. Most respondents (58%) belonged to large centers (>1,000 annual pediatric intensive care unit admissions). Sixty-seven percent of centers reported no specific process to initiate PCAC with the other third employing order sets, paper forms, or institutional guidelines. Common PCAC targets included temperature (96%), age-based blood pressure (88%), and glucose (75%). Most PCAC included electroencephalogram (75%), but neuroimaging was only included at 46% of centers. Duration of PCAC was either tailored to clinical improvement and neurological examination (54%) or time-based (45%). Only 25% of centers reported having a mechanism for evaluating PCAC adherence. Common barriers to effective PCAC implementation included lack of time and limited training opportunities.

Conclusions:

There is wide variation in PCAC delivery among surveyed pediatric institutions despite national guidelines to standardize and implement PCAC.
Synergizing Safety: A Customized Approach to Curtailing Unplanned Extubations through Shared Decision-making in the NICU
Authors: Krishnan Parvathy , Jawale Nilima , Sodikoff Adam , Malfa Susan R. , McCarthy Kathleen , Strickrodt Lisa M. , D’Agrosa Diana , Pickard Alexandra , Parton Lance A. , Singh Meenakshi
Published: May 2024

Background:

Unplanned Extubation (UE) remains an important patient safety issue in the Neonatal Intensive Care Unit. Our SMART AIM was to decrease the rate of UE by 10% from the baseline from January to December 2022 by emphasizing collaboration among healthcare professionals and through the use of shared decision-making.

Methods:

We established an interdisciplinary Quality Improvement team composed of nurses, respiratory therapists, and physicians (MDs). The definition of UE was standardized. UE was audited using an apparent cause analysis form to discern associated causes and pinpoint areas for improvement. Interventions were implemented in a step-by-step fashion and reviewed monthly using the model for improvement. A shared decision-making approach fostered collaborative problem-solving.

Results:

Our baseline UE rate was 2.3 per 100 ventilator days. Retaping, general bedside care, and position change accounted for over 50% of the UE events in 2022. The rate of UE was reduced by 48% by the end of December 2022. We achieved special-cause variation by the end of March 2023.

Conclusions:

The sole education of medical and nursing providers about various approaches to decreasing unnecessary retaping was ineffective in reducing UE rates. Shared decision-making incorporating inputs from nurses, respiratory therapists, and MDs led to a substantial reduction in the UE rate and underscores the potential of systematic evaluation of risk factors combined with collaborative best practices.
Perinatal Use and Discontinuation of Disease-Modifying Antirheumatic Drugs
Authors: Rebić Nevena , De Vera Mary A. , Gupta Amit , Amiri Neda
Published: May 2024

Background

Managing rheumatic disease activity using pregnancy-compatible medications is essential for reducing adverse maternal and fetal outcomes. We characterized medication use and discontinuation before, during, and after pregnancy, among female patients with rheumatic diseases attending a targeted pregnancy and rheumatic diseases clinic.

Methods

We conducted a cross-sectional medical record review of female patients with rheumatic diseases at a Canadian clinic between January 2017 and July 2020. Patients were categorized by pregnancy stage at their latest clinic visit: (1) preconception; (2) pregnant; (3) postpartum. We assessed use of conventional, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), prednisone, and nonsteroidal anti-inflammatory drugs across 6 perinatal windows: 24 and 12 months preconception, each pregnancy trimester, and 3 months postpartum. We reported adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for medication discontinuation in the first trimester and subsequent disease flare.

Results

Of 230 included patients, 85 (37.0%), 12 (5.2%), and 133 (57.8%) were preconception, pregnant, and postpartum, respectively. Approximately half experienced at least 1 disease flare during each pregnancy stage (56.4% preconception, 58.1% during pregnancy, and 53.7% postpartum). Most used at least 1 DMARD throughout the perinatal period (82.6% preconception, 55.6% during pregnancy, and 45.1% postpartum). Overall, 25.5% discontinued at least 1 DMARD in the first trimester. DMARD discontinuation was associated with disease flare during pregnancy (aOR, 1.49; 95% CI, 0.55–4.03; p = 0.87) and postpartum (aOR, 3.09; 95% CI, 0.83–11.47; p = 0.09).

Conclusions

Patients receiving care at a pregnancy and rheumatic disease clinic show perinatal medication use patterns consistent with recent recommendations and clinical guidelines.
Not All Days Were Created Equal—Better Day Orientation Following the Weekend on Mini-Mental State Examination (MMSE)
Authors: Shefet Daphna , Lurie Ido
Published: May 2024

Objective:

The aim of this study was to test whether patients are better oriented to the day on the first working day following the weekend (in Israel—Sunday), compared with other weekdays, on the Mini-Mental Score Examination (MMSE).

Methods:

All MMSE scores from November 2016 until December 2022 in our mental health center’s computerized system were collected. The proportion of correct answers to orientation to the day was compared between weekdays.

Results:

The cohort consisted of 2049 MMSEs taken by 1376 patients [average age 80.3 (SD=9.3), 56.4% female]. The difference between the proportion of correct and incorrect answers was statistically significant between the days, of which Sundays showed a larger difference (53.4%) compared with the other days (χ2=20.77, P<0.001, Cramer V=0.104). A statistically significant odds ratio (OR) for providing a correct response was found for Sundays (OR=1.55, P=0.001) and, to a lesser extent, on Thursdays (OR=1.29, P=0.01). The difference between Sundays and other weekdays disappears as the total MMSE decreases.

Conclusion:

Day orientation on the MMSE may be better on the first day following the weekend, especially in early cognitive decline.

Clinical Implications:

The weekday in which the MMSE is performed may influence its results.
Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases
Authors: Levintov Lev , Gorai Biswajit , Vashisth Harish
Published: May 2024

The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R) are homodimeric transmembrane glycoproteins that transduce signals across the membrane on binding of extracellular peptide ligands. The structures of IR/IGF1R fragments in apo and liganded states have revealed that the extracellular subunits of these receptors adopt Λ-shaped configurations to which are connected the intracellular tyrosine kinase (TK) domains. The binding of peptide ligands induces structural transitions in the extracellular subunits leading to potential dimerization of transmembrane domains (TMDs) and autophosphorylation in TKs. However, the activation mechanisms of IR/IGF1R, especially the role of TMDs in coordinating signal-inducing structural transitions, remain poorly understood, in part due to the lack of structures of full-length receptors in apo or liganded states. While atomistic simulations of IR/IGF1R TMDs showed that these domains can dimerize in single component membranes, spontaneous unbiased dimerization in a plasma membrane having physiologically representative lipid composition has not been observed. We address this limitation by employing coarsegrained (CG) molecular dynamics simulations to probe the dimerization propensity of IR/IGF1R TMDs. We observed that TMDs in both receptors spontaneously dimerized independent of their initial orientations in their dissociated states, signifying their natural propensity for dimerization. In the dimeric state, IR TMDs predominantly adopted X-shaped configurations with asymmetric helical packing and significant tilt relative to the membrane normal, while IGF1R TMDs adopted symmetric V-shaped or parallel configurations with either no tilt or a small tilt relative to the membrane normal. Our results suggest that IR/IGF1R TMDs spontaneously dimerize and adopt distinct dimerized configurations.

TOC Graphic
A Single Dose of Inactivated Influenza Virus Vaccine Expressing COBRA Hemagglutinin Elicits Broadly-Reactive and Long-Lasting Protection
Authors: Shi Hua , Zhang Xiaojian , Ross Ted M.
Published: May 2024

Influenza virus infections present a pervasive global health concern resulting in millions of hospitalizations and thousands of fatalities annually. To address the influenza antigenic variation, the computationally optimized broadly reactive antigen (COBRA) methodology was used to design influenza hemagglutinin (HA) or neuraminidase (NA) for universal influenza vaccine candidates. In this study, whole inactivated virus (WIV) or split inactivated virus (SIV) vaccine formulations expressing either the H1 COBRA HA or H3 COBRA HA were formulated with or without an adjuvant and tested in ferrets with pre-existing anti-influenza immunity. A single dose of the COBRA-WIV vaccine elicited a robust and broadly reactive antibody response against H1N1 and H3N2 influenza viruses. In contrast, the COBRA-SIV elicited antibodies that recognized fewer viruses, but with R-DOATP, its specificity was expanded. Vaccinated ferrets were protected against morbidity and mortality following challenge with A/California/07/2009 at 14 weeks post-vaccination with reduced viral shedding post-infection compared to the naïve mock-vaccinated ferrets. However, the COBRA-IIVs did not block the viral transmission to naïve ferrets. The contact infection induced less severe disease and delayed viral shedding than direct infection. Overall, the COBRA HA WIV or the COBRA HA SIV plus R-DOTAP elicited broadly reactive antibodies with long-term protection against viral challenge and reduced viral transmission following a single dose of vaccine in ferrets pre-immune to historical H1N1 and H3N2 influenza viruses.

IMPORTANCE

A next-generation influenza virus vaccine aims to provide broadly reactive protection against various drifted influenza strains. COBRA HA-based vaccines elicit broadly-reactive antibodies following two or three vaccinations. However, people are administered a single vaccination of current commercial influenza virus vaccines. In this study, ferrets with pre-existing anti-influenza immunity were administered a single shot COBRA-WIV that elicited long-lasting, broadly-reactive antibodies that protected ferrets against pdmH1N1 viral challenge. This is the first study describing the immune responses elicited by COBRA-IIV vaccines in ferrets that protected ferrets 14 weeks post-vaccination.
Measuring autofluorescence spectral signatures for detecting antibiotic-resistant bacteria using Thermofisher’s Bigfoot spectral flow cytometer
Authors: Iyengar Sharath Narayana , Patsekin Valery , Rajwa Bartek , Bae Euiwon , Dowden Brianna , Ragheb Kathy , Robinson J Paul
Published: May 2024

Application of flow cytometry to microbiology has been limited due to inadequate availability of bacterial-specific stains, expensive antibody-based fluorophores, ineffective stain cell permeability and challenges in differentiating bacterial cells from cell debris due to their similarity and their small size. In addition, staining cells demands multiple washing steps which limits the sensitivity of detection due to the cell volume that is up to two orders smaller than typical eukaryotic cells. Further, most flow cytometers are not equipped to handle pathogenic organisms. Autofluorescence-based detection of cells can be a useful method for bacterial detection as multiple washing steps can be avoided and it also reduces the time and cost of using stains. Multiple studies have shown that the autofluorescence in bacterial cells are mainly linked to specific proteins, enzymes, or enzyme cofactors such as Flavin Adenine Dinucleotide (FAD) and Nicotinamide Adenine Dinucleotide (NAD) which are involved in bacterial metabolism. In this report, we present a novel method for differentiation between clinically isolated antibiotic resistant and non-resistant bacteria by utilizing their autofluorescence spectral signatures. We utilized a spectral cytometer known as Bigfoot which is equipped with an integrated biosafety cabinet allowing easy handling of pathogenic organisms unlike any other flow cytometers. Bigfoot also has 9 lasers and 54 fluorescence detectors which we utilize to capture the bacterial spectral autofluorescence signatures. As a proof of principle, we initially stressed different types of bacteria (E.coli and Salmonella sp.)using gentamicin antibiotics by collecting spectral autofluorescence over different time points. The spectral signatures were compared with the non-stressed bacteria. We observed that the stressed bacteria showed an increase in autofluorescence at distinct excitation (Ultraviolet, Violet, and blue color) and emission wavelengths whereas the non-stressed did not. The same experiments were repeated to compare the autofluorescence signatures between Methicillin-resistant and methicillin susceptiblestaphylococcus aureus(MRSA and MSSA) which were stressed with oxacillin antibiotics. MSSA showed an increase in autofluorescence between 4 – 6 h after exposure to oxacillin. MRSA on the other hand showed no increase in autofluorescence and the autofluorescence between stressed and non-stressed MRSA had similar signatures. This demonstrated that the antibiotic resistant or susceptible strain can be detected by observing the change in autofluorescence signature at specific wavelengths in a few hours. This label-free, quantitative, and resistant-specific autofluorescence spectral signatures from the Bigfoot spectral flow cytometer could potentially be utilized for rapid detection of antibioticresistant strain.
Mechanophysiology of endometriosis: a non-dimensional physiomarker to detect retrograde flow
Authors: Elisha Guy , Patankar Neelesh A.
Published: May 2024

Endometriosis affects a significant portion of fertile-age women, often leading to infertility and a substantial decline in quality of life. Despite its prevalence, current diagnostic methods are limited, focusing on assessing the presence or absence of endometrial lesion, rather than the origin of the disorder. Thus, resulting in underdiagnosis. A potential mechanics-based metric for diagnosing endometriosis is proposed here by leveraging the retrograde menstruation hypothesis. By examining the interplay between uterine and fallopian tube peristalses, a non-dimensional physiomarker is introduced to signify the onset of retrograde flow. The analysis reveals that increased uterine contractile activity, coupled with decreased fallopian tube contractile activity, correlates with retrograde flow, suggesting a predisposition to endometriosis. This mechanophysiology-based approach offers a promising avenue for origin based diagnosis, with the proposed non-dimensional physiomarker – the endometriosis number – serving as a potential indicator of endometrial cell migration and the onset of endometriosis.
Oral Exposure to Benzalkonium Chlorides in Male and Female Mice Reveals Sex-Dependent Alteration of the Gut Microbiome and Bile Acid Profile
Authors: Lopez Vanessa A. , Lim Joe L. , Seguin Ryan P. , Dempsey Joseph L. , Kunzman Gabrielle , Cui Julia Y. , Xu Libin
Published: May 2024

Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 µg/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.
AdipocytemicroRNA-802promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity
Authors: Yang Yue , Huang Bin , Qin Yimeng , Wang Danwei , Jin Yinuo , Su Linmin , Pan Yi , Zhang Yanfeng , Shen Yumeng , Hu Wenjun , Cao Zhengyu , Jin Liang , Zhang Fangfang
Published: May 2024

Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found thatmicroRNA-802(miR-802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend ofmiR-802preceded the accumulation of macrophages. Adipose tissue-specific knockout ofmiR-802lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression ofmiR-802in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically,miR-802activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokine and SREBP1, which translated into strong recruitment and M1-like polarization of macrophages. Our findings indicate thatmiR-802endows adipose tissue with the ability to recruit and polarize macrophages, which underscoresmiR-802as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.
Shared genetics between breast cancer and its predisposing diseases identify novel breast cancer treatment candidates
Authors: Lalagkas Panagiotis N. , Melamed Rachel D.
Published: May 2024

Breast cancer is a major public health issue. Current treatment options, while effective, have severe side effects. FDA-approved drugs have known safety and pharmacological profiles and some, such as metformin, have been tested in clinical trials for repurposing for breast cancer. However, clinical trials are slow and expensive, which creates the need for innovative approaches to accelerate drug repurposing for breast cancer. We have previously shown that genes associated with Mendelian diseases that predispose patients to certain cancers are enriched for successful drug targets, due to their pleiotropic effects. Here, we extend our approach to exploit clinical associations between breast cancer and its predisposing diseases for drug repurposing. We hypothesize that pleiotropic genes shared between breast cancer and its predisposing diseases can help us discover new uses for drugs currently approved only for the predisposing diseases. To test our hypothesis, we compile a list of six traits known to increase breast cancer risk (predisposing diseases). Using GWAS summary statistics and local genetic correlation analysis, we find 84 genomic loci harboring mutations with positively correlated effects between breast cancer and each predisposing disease. These loci contain 194 protein-coding genes (shared genes). Using a network biology approach and canonical pathways, for each disease pair, we connect drugs already indicated for the predisposing disease to its shared biology with breast cancer and identify drug repurposing candidates for breast cancer. Finally, we show that our list of candidate drugs is enriched for currently investigated and indicated drugs for breast cancer (OR=9.28, p=7.99e-03). Our findings suggest a novel way to accelerate drug repurposing for complex diseases by leveraging shared genetics.