bluuebunny/crossref_metadata_2025 huggingface dataset:
Precise genome editing of the Kozak sequence enables bidirectional and quantitative modulation of protein translation to anticipated levels without affecting transcription
Authors: Xie Jingke , Zhuang Zhenpeng , Gou Shixue , Zhang Quanjun , Wang Xia , Lan Ting , Lian Meng , Li Nan , Liang Yanhui , Ouyang Zhen , Ye Yinghua , Wu Han , Lai Liangxue , Wang Kepin
Published: August 2023

None of the existing approaches for regulating gene expression can bidirectionally and quantitatively fine-tune gene expression to desired levels. Here, on the basis of precise manipulations of the Kozak sequence, which has a remarkable influence on translation initiation, we proposed and validated a novel strategy to directly modify the upstream nucleotides of the translation initiation codon of a given gene to flexibly alter the gene translation level by using base editors and prime editors. When the three nucleotides upstream of the translation initiation codon (named KZ3, part of the Kozak sequence), which exhibits the most significant base preference of the Kozak sequence, were selected as the editing region to alter the translation levels of proteins, we confirmed that each of the 64 KZ3 variants had a different translation efficiency, but all had similar transcription levels. Using the ranked KZ3 variants with different translation efficiencies as predictors, base editor- and prime editor-mediated mutations of KZ3 in the local genome could bidirectionally and quantitatively fine-tune gene translation to the anticipated levels without affecting transcription in vitro and in vivo. Notably, this strategy can be extended to the whole Kozak sequence and applied to all protein-coding genes in all eukaryotes.
The Swi-Snf chromatin remodeling complex mediates gene repression through metabolic control
Authors: Church Michael C , Price Andrew , Li Hua , Workman Jerry L
Published: August 2023

In eukaryotes, ATP-dependent chromatin remodelers regulate gene expression in response to nutritional and metabolic stimuli. However, altered transcription of metabolic genes may have significant indirect consequences which are currently poorly understood. In this study, we use genetic and molecular approaches to uncover a role for the remodeler Swi-Snf as a critical regulator of metabolism. We find that snfΔ mutants display a cysteine-deficient phenotype, despite growth in nutrient-rich media. This correlates with widespread perturbations in sulfur metabolic gene transcription, including global redistribution of the sulfur-sensing transcription factor Met4. Our findings show how a chromatin remodeler can have a significant impact on a whole metabolic pathway by directly regulating an important gene subset and demonstrate an emerging role for chromatin remodeling complexes as decisive factors in metabolic control.
A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation
Authors: Yakhou Lounis , Azogui Anaelle , Gupta Nikhil , Richard Albert Julien , Miura Fumihito , Ferry Laure , Yamaguchi Kosuke , Battault Sarah , Therizols Pierre , Bonhomme Frédéric , Bethuel Elouan , Sarkar Arpita , Greenberg Maxim V C , Arimondo Paola B , Cristofari Gael , Kirsh Olivier , Ito Takashi , Defossez Pierre-Antoine
Published: August 2023

Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements and higher-order chromatin structures. Consequently, these chromatin marks are indispensable for mammalian development and alterations often lead to disease, such as cancer. Bivalent promoters are especially important during differentiation and development. Here we used a genetic screen to identify new regulators of a bivalent repressed gene. We identify BEND3 as a regulator of hundreds of bivalent promoters, some of which it represses, and some of which it activates. We show that BEND3 is recruited to a CpG-containg consensus site that is present in multiple copies in many bivalent promoters. Besides having direct effect on the promoters it binds, the loss of BEND3 leads to genome-wide gains of DNA methylation, which are especially marked at regions normally protected by the TET enzymes. DNA hydroxymethylation is reduced in Bend3 mutant cells, possibly as consequence of altered gene expression leading to diminished alpha-ketoglutarate production, thus lowering TET activity. Our results clarify the direct and indirect roles of an important chromatin regulator, BEND3, and, more broadly, they shed light on the regulation of bivalent promoters.
Arabidopsis membrane protein AMAR1 interaction with type III effector XopAM triggers a hypersensitive response
Authors: Xie Qingbiao , Wei Bingzheng , Zhan Zhaohong , He Qiguang , Wu Kejian , Chen Yu , Liu Shiyao , He Chaozu , Niu Xiaolei , Li Chunxia , Tang Chaorong , Tao Jun
Published: August 2023

The efficient infection of plants by the bacteria Xanthomonas campestris pv. campestris (Xcc) depends on its type III effectors (T3Es). Although the functions of AvrE family T3Es have been reported in some bacteria, the member XopAM in Xcc has not been studied. As XopAM has low sequence similarity to reported AvrE-T3Es and different reports have shown that these T3Es have different targets in hosts, we investigated the functions of XopAM in the Xcc–plant interaction. Deletion of xopAM from Xcc reduced its virulence in cruciferous crops but increased virulence in Arabidopsis (Arabidopsis thaliana) Col-0, indicating that XopAM may perform opposite functions depending on the host species. We further found that XopAM is a lipase that may target the cytomembrane and that this activity might be enhanced by its membrane-targeted protein XOPAM-ACTIVATED RESISTANCE 1 (AMAR1) in Arabidopsis Col-0. The binding of XopAM to AMAR1 induced an intense hypersensitive response that restricted Xcc proliferation. Our results showed that the roles of XopAM in Xcc infection are not the same as those of other AvrE-T3Es, indicating that the functions of this type of T3E have differentiated during long-term bacterium‒host interactions.
Ethical perspectives and police science: Using Social Contract Theory as an analytical framework for evaluating police legitimacy
Authors: Jonathan-Zamir Tal , Perry Gali , Willis James J
Published: August 2023

It has recently been argued that ethical/moral considerations could be better integrated into the science of policing. The present study picks up the gauntlet and examines if a central normative theory of government authority—Social Contract Theory—can contribute to our understanding of police legitimacy. Building on five constraints on police authority derived from Social Contract Theory, the present study examines the relationship between citizen views of police compliance with the social contract while enforcing COVID-19 regulations, and of police legitimacy. A community survey carried out in Israel reveals that public evaluations of the appropriate balance between liberty, safety, and police authority, have a significant, independent correlation with legitimacy, surpassed only by views of procedural justice. These findings have implications for the theory, practice, and future study of police legitimacy, but more generally demonstrate the utility of theoretical–philosophical theories and concepts concerned with ethics for contemporary research questions in policing.
Dealing with the challenges of legitimacy, values, and politics in policy advice
Authors: Capano Giliberto , Howlett Michael , Pal Leslie A , Ramesh M
Published: August 2023

Policy advice has been the subject of ongoing research in the policy sciences as it raises fundamental issues about what constitutes policy knowledge, expertise, and their effects on policymaking. This introduction reviews the existing literature on the subject and introduces the themes motivating the articles in the issue. It highlights the need to consider several key subjects in the topic in the contemporary era: namely the challenge of legitimacy, that of values, and the challenge of politics. The papers in the issue shed light on the ongoing delegitimization of conventional knowledge providers, the problem of the normative basis of experts’ advice, the increasing politicization of expertise in policymaking, and the relevance of political context in influencing not only the role of experts but also whether or not their advice is accepted and implemented. It is argued that these modern challenges, when not addressed, reinforce trends toward the inclusion of antidemocratic values and uninformed ideas in contemporary policymaking.
Glasgow Coma Scale on admission as predictor of neurological sequelae at discharge and acute respiratory failure in patients with heatstroke
Authors: Chen Lan , Lu Liyun , Fang Yuan , Ren Jingnan , Yang Xiaoling , Gong Zhumei , Zhang Yuping , Feng Xiuqin
Published: August 2023

Background

Transient neuronal dysfunction may occur in most brain regions with heatstroke (HS). This study aimed to explore the prognostic significance of initial Glasgow Coma Scale (GCS) scores in HS.

Methods

Retrospective data regarding HS were obtained from six hospitals. The primary outcome was neurological sequelae at discharge. Secondary outcomes included acute respiratory failure (ARF) and intensive care unit (ICU) admission. Logistic regression models and random forest imputation were used to assess the independent association between GCS score and outcomes. Interaction and stratified analyses of body temperature (BT) at 0.5 hours were also conducted. Receiver operating characteristic curves and decision curve analysis were used to estimate prognostic values.

Results

Of 206 patients, 44 (21.36%) had neurological sequelae at discharge. The mean ± standard deviation initial GCS score was 8.17 ± 4.05. After adjustment for confounders, GCS, as a continuous variable, was significantly related to neurological sequelae at discharge [odds ratio (OR): 0.65; 95% confidence interval (CI): 0.50–0.85; P = 0.002], ARF (OR: 0.76; 95% CI: 0.66–0.87; P = 0.001), and ICU admission (OR: 0.68; 95% CI: 0.53–0.87; P = 0.003). These relationships were consistent in the random forest imputation cohort. The OR between GCS and neurological sequelae at discharge was much lower (P = 0.048) in participants with BT at 0.5 hours ≤39°C than in those with BT at 0.5 hours >39°C. The GCS and National Early Warning Score (NEWS) had similar prognostic ability for all outcomes, whereas the net benefits were greater with the GCS compared with the NEWS.

Conclusions

Initial GCS score was an independent prognostic factor for neurological sequelae at discharge in HS. Rapid cooling played a positive role in this relationship.

Key messages What is already known on this topic Brain damage caused by heatstroke (HS) can be transient or result in irreversible injury. Early recognition of those at risk of death or developing neurological complications is very important for improving the outcomes of HS. What this study adds Initial Glasgow Coma Scale (GCS) score was an independent prognostic factor for neurological sequelae at discharge, acute respiratory failure, and intensive care unit (ICU) admission in HS. Rapid cooling played a positive role in this relationship. How this study might affect research, practice, or policy The GCS upon emergency department admission can be a useful predictor of prognosis in patients with HS.
Necessarily Veridical Hallucinations: A New Problem for the Uninstantiated Property View
Authors: Gow Laura
Published: August 2023

Philosophers of perception have a notoriously difficult time trying to account for hallucinatory experiences. One surprisingly quite popular move, and one that cross-cuts the representationalism/relationalism divide, is to say that hallucinations involve an awareness of uninstantiated properties. In this paper, I provide a new argument against this view. Not only are its proponents forced to classify many hallucinations as veridical, such experiences turn out to be necessarily veridical. In addition, I show that representationalists who endorse the uninstantiated property view must reject the common fundamental kind claim and adopt disjunctivism, and naïve realists/relationalists must radically modify their disjunctivism: The distinction between ‘veridical’ and ‘hallucinatory’ will no longer track a metaphysical distinction between the relevant experiences.
Direct optogenetic activation of upper airway muscles in an acute model of upper airway hypotonia mimicking sleep onset
Authors: Knapman Fiona L , Cohen E Myfanwy , Kulaga Tom , Lovell Nigel , Lisowski Leszek , McMullan Simon , Burke Peter G R , Bilston Lynne E
Published: August 2023

Study Objectives

Obstructive sleep apnea (OSA), where the upper airway collapses repeatedly during sleep due to inadequate dilator muscle tone, is challenging to treat as current therapies are poorly tolerated or have variable and unpredictable efficacy. We propose a novel, optogenetics-based therapy, that stimulates upper airway dilator muscle contractions in response to light. To determine the feasibility of a novel optogenetics-based OSA therapy, we developed a rodent model of human sleep-related upper airway muscle atonia. Using this model, we evaluated intralingual delivery of candidate optogenetic constructs, notably a muscle-targeted approach that will likely have a favorable safety profile.

Methods

rAAV serotype 9 viral vectors expressing a channelrhodopsin-2 variant, driven by a muscle-specific or nonspecific promoter were injected into rat tongues to compare strength and specificity of opsin expression. Light-evoked electromyographic responses were recorded in an acute, rodent model of OSA. Airway dilation was captured with ultrasound.

Results

The muscle-specific promoter produced sufficient opsin expression for light stimulation to restore and/or enhance electromyographic signals (linear mixed model, F = 140.0, p < 0.001) and induce visible tongue contraction and airway dilation. The muscle-specific promoter induced stronger (RM-ANOVA, F(1,8) = 10.0, p = 0.013) and more specific opsin expression than the nonspecific promoter in an otherwise equivalent construct. Viral DNA and RNA were robust in the tongue, but low or absent in all other tissues.

Conclusions

Significant functional responses to direct optogenetic muscle activation were achieved following muscle-specific promoter-driven rAAV-mediated transduction, providing proof-of-concept for an optogenetic therapy for patients with inadequate dilator muscle activity during sleep.
Catch-up vaccination and enhanced immunization against hepatitis B, hepatitis A, measles, mumps, rubella and varicella in children with idiopathic thrombocytopenic purpura
Authors: Taşar Serçin , Taşar Medine Ayşin , Saç Rukiye Ünsal , Alioğlu Bülent
Published: August 2023

Background

Limited data exist about the vaccination of children with idiopathic thrombocytopenic purpura (ITP) against vaccine preventable diseases. This study identified the vaccination status of children with ITP against hepatitis A, hepatitis B, measles, mumps, rubella and varicella, completed the immunization of children with inadequate immunization, re-evaluated post-vaccination antibody titers and identified probable vaccination-related complications.

Patients and methods

All of 46 children had chronic ITP were included. Seroconversion of hepatitis A, hepatitis B, varicella, measles, rubella and mumps vaccines was screened. All children with seronegative antibodies against vaccine preventable disease were given a vaccination appointment. Antibody levels were re-measured during a period ranging from 1 to 6 months. Potential complications were detected.

Results

There were 46 children with a mean age of 12.25 years. All children had chronic ITP and received intravenous immunoglobulin at least once previously. Considering the vaccination status, 50% (23 children) had vaccinations appropriate for their age, 47.8% (22 children) did not know their vaccination status and 2.2% (1 patient) did not have vaccinations. Seven children (15.2%) were seropositive for all antibody types and the remaining 39 children were scheduled for vaccination. Post-vaccination antibody titers confirmed that all children became seropositive for each disease. There was no complication in any patient.

Conclusion

Immunization against hepatitis B, hepatitis A, measles, mumps, rubella and varicella is insufficient in a considerable number of children with ITP, Hepatitis B Virus (HBV) and Hepatitis A Virus (HAV) immunization being the most frequently inadequate. After immunization, adequate seroconversion levels were achievable without complications.
Electromagnetic field and cardiovascular diseases: A state‐of‐the‐art review of diagnostic, therapeutic, and predictive values
Authors: Wang Yan , Zhao Zhen‐Gang , Chai Zheng , Fang Jian‐Cheng , Chen Mao
Published: August 2023

Despite encouraging advances in early diagnosis and treatment, cardiovascular diseases (CVDs) remained a leading cause of morbidity and mortality worldwide. Increasing evidence has shown that the electromagnetic field (EMF) influences many biological processes, which has attracted much attention for its potential therapeutic and diagnostic modalities in multiple diseases, such as musculoskeletal disorders and neurodegenerative diseases. Nonionizing EMF has been studied as a therapeutic or diagnostic tool in CVDs. In this review, we summarize the current literature ranging from in vitro to clinical studies focusing on the therapeutic potential (external EMF) and diagnostic potential (internal EMF generated from the heart) of EMF in CVDs. First, we provided an overview of the therapeutic potential of EMF and associated mechanisms in the context of CVDs, including cardiac arrhythmia, myocardial ischemia, atherosclerosis, and hypertension. Furthermore, we investigated the diagnostic and predictive value of magnetocardiography in CVDs. Finally, we discussed the critical steps necessary to translate this promising approach into clinical practice.
Pan‐cancer analysis: SPAG5 is an immunological and prognostic biomarker for multiple cancers
Authors: Gao Xiaofeng , Bu Huitong , Gao Xuzheng , Wang Ying , Wang Long , Zhang Zhenwang
Published: August 2023

Sperm‐associated antigen 5 (SPAG5) is a mitotic spindle protein that regulates the separation of sister chromatids into daughter cells. Recent studies have discovered its overexpression in various cancers, suggesting its oncogenic characteristics and functions. However, a comprehensive analysis of SPAG5 regarding its diagnostic, prognostic, and immune‐related effects across different cancer types is lacking. In this study, we employed bioinformatics methods and integrated multiple public databases to explore the potential oncogenic role of SPAG5. We analyzed its expression, prognosis, related chemicals, enriched pathways, immune infiltration, and its impact on different tumor genetic alterations. The results revealed that SPAG5 is highly expressed in most cancers and significantly correlates with poor patient prognosis. Additionally, SPAG5 expression showed potential for early cancer diagnosis in 15 different cancer types. In terms of tumor immunity, high expression of SPAG5 was associated with an immunosuppressive tumor microenvironment and immune therapy efficacy indicators. SPAG5 expression exhibited a negative correlation with most immune cell infiltrates but demonstrated a significant positive correlation with Th2 cells and MDSC cells. Multicolor fluorescence immunohistochemistry demonstrated that SPAG5 activates immune cell populations within tumors, indicating its significant role in the tumor microenvironment. Enrichment analysis indicated that SPAG5‐related genes are mainly involved in cell cycle, cellular senescence, P53 signaling pathway, and FoxO signaling pathway. Furthermore, we confirmed the high expression of SPAG5 in cancer cells and observed that its knockdown upregulated the expression of the p53 protein. In conclusion, SPAG5 holds value as a diagnostic, prognostic, and immune biomarker in various cancers and may provide a novel target for tumor immunotherapy.
Evidence-based Perioperative Practice Utilization among Various Racial Populations—A Retrospective Cohort Trending Analysis of Lower Extremity Total Joint Arthroplasty Patients
Authors: Liu Jiabin , Zhong Haoyan , Reynolds Michael , Illescas Alex , Cozowicz Crispiana , Wu Christopher L. , Poeran Jashvant , Memtsoudis Stavros
Published: August 2023

Background

Various studies have demonstrated racial disparities in perioperative care and outcomes. The authors hypothesize that among lower extremity total joint arthroplasty patients, evidence-based perioperative practice utilization increased over time among all racial groups, and that standardized evidence-based perioperative practice care protocols resulted in reduction of racial disparities and improved outcomes.

Methods

The study analyzed 3,356,805 lower extremity total joint arthroplasty patients from the Premier Healthcare database (Premier Healthcare Solutions, Inc., USA). The exposure of interest was race (White, Black, Asian, other). Outcomes were evidence-based perioperative practice adherence (eight individual care components; more than 80% of these implemented was defined as “high evidence-based perioperative practice”), any major complication (including acute renal failure, delirium, myocardial infarction, pulmonary embolism, respiratory failure, stroke, or in-hospital mortality), in-hospital mortality, and prolonged length of stay.

Results

Evidence-based perioperative practice adherence rate has increased over time and was associated with reduced complications across all racial groups. However, utilization among Black patients was below that for White patients between 2006 and 2021 (odds ratio, 0.94 [95% CI, 0.93 to 0.95]; 45.50% vs. 47.90% on average). Independent of whether evidence-based perioperative practice components were applied, Black patients exhibited higher odds of major complications (1.61 [95% CI, 1.55 to 1.67] with high evidence-based perioperative practice; 1.43 [95% CI, 1.39 to 1.48] without high evidence-based perioperative practice), mortality (1.70 [95% CI, 1.29 to 2.25] with high evidence-based perioperative practice; 1.29 [95% CI, 1.10 to 1.51] without high evidence-based perioperative practice), and prolonged length of stay (1.45 [95% CI, 1.42 to 1.48] with high evidence-based perioperative practice; 1.38 [95% CI, 1.37 to 1.40] without high evidence-based perioperative practice) compared to White patients.

Conclusions

Evidence-based perioperative practice utilization in lower extremity joint arthroplasty has been increasing during the last decade. However, racial disparities still exist with Black patients consistently having lower odds of evidence-based perioperative practice adherence. Black patients (compared to the White patients) exhibited higher odds of composite major complications, mortality, and prolonged length of stay, independent of evidence-based perioperative practice use, suggesting that evidence-based perioperative practice did not impact racial disparities regarding particularly the Black patients in this surgical cohort.

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What We Already Know about This Topic

What This Article Tells Us That Is New
Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches
Authors: Lescoat Alain , Kato Hiroshi , Varga John
Published: August 2023

Purpose of review

Although two targeted therapies have received recent approval for systemic sclerosis (SSc)-associated interstitial lung disease, they do not show major disease-modifying activity, highlighting the need for novel therapies and innovative paradigms. To that end, cellular therapies may represent a new opportunity for the treatment of SSc. The purpose of this review is to provide an up-to-date overview of emerging cell-based disease-modifying therapies in SSc.

Recent findings

Initial small studies in patients with severe refractory systemic lupus erythematosus (SLE) using engineered regulatory cells show promising results. CD19-directed CAR-T have shown promising results in one case report of refractory diffuse cutaneous SSc patients. T cells engineered to express a chimeric autoantibody receptor (CAAR-T cells) may be even more relevant via the specific elimination of auto-reactive B cells. Targeting pro-fibrotic or senescence-related pathways may also constitute promising approaches in SSc.

Building on the classification of the clinical phenotype and prediction of clinical trajectory based on individual patients’ autoantigen and/or autoantibody profile, cellular therapies targeting the same autoantigen or related autoreactive cells may represent an unprecedented opportunity to implement personalized medicine in SSc.
Operative Management Improves Near-term Survival of Patients With Odontoid Type II Fractures
Authors: Foote Christopher W. , Salottolo Kristin , Doan Xuan-Lan , Vanier Cheryl , Betancourt Alejandro J. , Bar-Or David , Palacio Carlos H.
Published: August 2023

Study design:

National Trauma Data Bank (NTDB) review and propensity-matched analysis.

Objective:

To evaluate differences in clinical outcomes by operative management.

Summary of background data:

Odontoid type II fractures are the most prevalent cervical fracture. Operative intervention on these fractures is frequently debated; surgical risks are compounded by clinical severity, patient age, and comorbidities.

Methods:

This registry review included index admissions for odontoid type II fractures [International Classification of Diseases (ICD)-10 codes beginning with S12.11] from 1/1/2017 to 1/1/2020; patients who died in the emergency department (ED) were excluded. Propensity score techniques were used to match patients 1:1 by surgical management, using a caliper distance of 0.05, after matching on the following covariates that differed significantly between surgical and nonsurgical patients: age, sex, race, cause of injury, transfer status, injury severity score, ED Glasgow coma score, ED systolic blood pressure, presence of transverse ligamentous injury, cervical dislocation, and 8 comorbidities. The following outcomes were analyzed with McNemar tests and Wilcoxon signed-rank tests: near-term survival (discharged from the hospital to locations other than morgue or hospice), intensive care unit (ICU) admission, hospital complications, median hospital length of stay (LOS), and median ICU LOS.

Results:

There were 16,607 patients, 2916 (17.6%) were operatively managed and 13,691 were nonoperatively managed. Before matching, survival was greater for patients managed operatively compared with nonoperatively (95.0% vs. 88.2%). The matched population consisted of 5334 patients: 2667 patients in the operative group (91.5% of this population) and 2667 well-matched patients in the nonoperative group. After matching, there was a survival benefit for patients who were operatively managed compared with nonoperative management (94.8% vs. 91.4% P<0.001). However, operative management was associated with greater development of complications, ICU admission, and longer hospital and ICU LOS.

Conclusion:

Compared with nonoperative management, operative management demonstrated a significant near-term survival benefit for patients with odontoid type II fractures in select patients.

Level of evidence:

III
The Effect of Hyperlipidemia as a Risk Factor on Postoperative Complications in Patients Undergoing Anterior Cervical Discectomy and Fusion
Authors: Son Seung Min , Okada Rintaro , Fresquez Zoe , Formanek Blake , Mertz Kevin , Wang Jeffrey C. , Buser Zorica
Published: August 2023

Study Design:

Retrospective cohort study.

Objective:

To analyze the effect of hyperlipidemia (HLD) on postoperative complications in patients who underwent anterior cervical discectomy and fusion (ACDF).

Summary of Background Data:

ACDF represents the standard procedure performed for focal anterior nerve root or spinal cord compression with low complication rates. HLD is well known as a risk factor for major complications after vascular and transplant surgery, and orthopedic surgery. To date, there have been no studies on HLD as a risk factor for cervical spine surgery.

Patients and Methods:

Patients who underwent ACDF from 2010 through quarter 3 of 2020 were enrolled using the MSpine subset of the PearlDiver Patient Record Database. The patients were divided into single-level ACDF and multilevel ACDF groups. In addition, each group was divided into subgroups according to the presence or absence of HLD. The incidence of surgical and medical complications was queried using relevant International Classification of Disease and Current Procedural Terminology codes. Charlson Comorbidity Index was used as a broad measure of comorbidity. χ2 analysis, with populations matched for age, sex, and Charlson Comorbidity Index, was performed.

Results:

A total of 24,936 patients who underwent single-level ACDF and 26,921 patients who underwent multilevel ACDF were included. In the multilevel ACDF group, wound complications were significantly higher in the patients with HLD. Among medical complications, myocardial infarction, renal failure, and urinary tract infection/urinary incontinence were significantly higher in the patients with HLD in both groups. Revision surgery and readmission were significantly higher in the patients with HLD who underwent multilevel ACDF.

Conclusions:

In patients who underwent ACDF, several surgical and medical complications were found to be higher in patients with HLD than in patients without HLD. Preoperative serum lipid concentration levels and management of HLD should be considered during preoperative planning to prevent postoperative complications in patients undergoing ACDF.
Genome-wide methylation profiling identified methylated KCNA3 and OTOP2 as promising diagnostic markers for esophageal squamous cell carcinoma
Authors: Bian Yan , Gao Ye , Lu Chaojing , Tian Bo , Xin Lei , Lin Han , Zhang Yanhui , Zhang Xun , Zhou Siwei , Wan Kangkang , Zhou Jun , Li Zhaoshen , Chen Hezhong , Wang Luowei
Published: August 2023

Background:

Early detection of esophageal squamous cell carcinoma (ESCC) can considerably improve the prognosis of patients. Aberrant cell-free DNA (cfDNA) methylation signatures are a promising tool for detecting ESCC. However, available markers based on cell-free DNA methylation are still inadequate. This study aimed to identify ESCC-specific cfDNA methylation markers and evaluate the diagnostic performance in the early detection of ESCC.

Methods:

We performed whole-genome bisulfite sequencing (WGBS) for 24 ESCC tissues and their normal adjacent tissues. Based on the WGBS data, we identified 21,469,837 eligible CpG sites (CpGs). By integrating several methylation datasets, we identified several promising ESCC-specific cell-free DNA methylation markers. Finally, we developed a dual-marker panel based on methylated KCNA3 and OTOP2, and then, we evaluated its performance in our training and validation cohorts.

Results:

The ESCC diagnostic model constructed based on KCNA3 and OTOP2 had an AUC of 0.91 [95% CI: 0.85–0.95], and an optimal sensitivity and specificity of 84.91% and 94.32%, respectively, in the training cohort. In the independent validation cohort, the AUC was 0.88 [95% CI: 0.83–0.92], along with an optimal sensitivity of 81.5% and specificity of 92.9%. The model sensitivity for stage I–II ESCC was 78.4%, which was slightly lower than the sensitivity of the model (85.7%) for stage III–IV ESCC.

Conclusion:

The dual-target panel based on cfDNA showed excellent performance for detecting ESCC and might be an alternative strategy for screening ESCC.
Cost-effectiveness analysis of an orphan drug-tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing
Authors: Luo Shaohong , Xie Chen , Lin Ningning , Lin Dong , Gu Dian , Lin Shen , Huang Xiaoting , Xu Xiongwei , Weng Xiuhua
Published: August 2023

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator’s choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.
Deficiency in the Midst of Abundance: Xerophthalmia Case Series and Vitamin A Levels in a New England Hospital
Authors: Li Xiao Y. , Maja Ayodele K. , Sanchez George , Srinivas Sowmya , Zegans Michael E.
Published: August 2023

Purpose:

To describe 3 adult cases of keratitis secondary to vitamin A deficiency (VAD) in relation to vitamin A levels Dartmouth-Hitchcock Medical Center (DHMC) population and published literature.

Methods:

Records of 3 patients with xerophthalmia were reviewed. All serum vitamin A levels obtained at DHMC during the same time period of our 3 cases (2019–2020) were analyzed. Outcomes were examined by age and range of deficiency.

Results:

Three patients, with short gut syndrome, chronic esophagitis, and alcohol use disorder, presented with xerophthalmia over 1 year. Serum vitamin A levels were 6.4 μg/dL, 16.1 μg/dL, and undetectable (<5.0 μg/dL), respectively (normal: 32.5–78.0 μg/dL). Findings ranged from conjunctival keratinization to corneal perforation. Corneal cultures in patient 3 grew methicillin-sensitive Staphylococcus aureus. The ocular surface improved significantly in 2 patients following vitamin A supplementation. Two patients died during treatment. Analysis of 1596 vitamin A levels at DHMC revealed 431 patients with VAD, including 158 levels at or below those of our presented symptomatic cases.

Conclusions:

Vitamin A deficiency can occur in adults in high resource settings and lead to severe ocular morbidities, and is commonly associated with comorbidities such as alcohol use disorder and gastrointestinal disease. Vitamin A supplementation improved ocular findings in 2 of our patients. VAD was identified in 431 patients at DHMC over one year, indicating a surprisingly large population of patients at risk for xerophthalmia.
Management of Abnormal Cervical Cancer Screening Test: A Risk-based Approach
Authors: Guido Richard , Perkins Rebecca B.
Published: August 2023

Cervical cancer screening plays a major role in preventing cervical cancer. The field is based on understanding the natural history of human papillomavirus and its role in cervical cancer. Screening has evolved to assessing the risk for cervical intraepithelial neoplasia grade 3, a true cancer precursor, and performing diagnostic tests based on those risks. This article summarizes the present state of management of abnormal cervical cancer screening tests in the United States, based on the most recent 2019 American Society of Colposcopy and Cervical Pathology guidelines.
Cell-free DNA Screening for Aneuploidy
Authors: Norton Mary E.
Published: August 2023

Cell-free DNA (cfDNA) screening has high detection for the common fetal autosomal aneuploidies, but is not diagnostic. The positive predictive value should be utilized in counseling after a positive cell-free DNA screen, and diagnostic testing should be offered for confirmation. cfDNA screening does not report a result in ~3% of cases; nonreportable results indicate an increased risk for aneuploidy and some adverse perinatal outcomes. False-positive cfDNA screening occurs due to confined placental mosaicism, maternal copy number variants, mosaicism, and cancer. Pretest education and counseling should be provided with emphasis on the potential benefits, risks, and limitations before cfDNA screening.
Cell-based Noninvasive Prenatal Testing (cbNIPT)—A Review on the Current Developments and Future Prospects
Authors: Maktabi Mohamad Ali , Vossaert Liesbeth , Van den Veyver Ignatia B.
Published: August 2023

Considering the diagnostic limitations of cfDNA-based noninvasive prenatal testing (NIPT), scientists have long been interested in isolating and analyzing rare intact fetal and trophoblast cells from maternal blood or endocervical samples to diagnose fetal genetic conditions. These cells may be scarce and difficult to isolate, but they are a direct source of pure fetal genetic material. In this review, we summarize the history of cell-based NIPT, present an updated review on its current developments, evaluate its genetic diagnostic potential, and discuss its future prospects for clinical use.
Unique Challenges of NIPT for Sex Chromosome Aneuploidy
Authors: WILKINS-HAUG LOUISE , REIMERS REBECCA
Published: August 2023

Noninvasive prenatal testing (NIPT) for the sex chromosome aneuploidies (45,X, 47,XXY, 47,XXX, and 47,XYY) differs significantly from that for the autosomal aneuploidies (trisomy 13, 18, and 21). As a group, sex chromosome aneuploidies occur more commonly (1/400) than any one isolated autosomal aneuploidy, the phenotypic variation is greater, the role of mosaicism more challenging, and the positive predictive value of a high-risk NIPT result is substantially lower. These considerations should be identified during pretest counseling, the inclusion of sex chromosome testing offered separately, and the differences from autosomal aneuploidy NIPT clearly delineated.
Safety and Immunogenicity of SARS-CoV-2 Vaccines in People Living With HIV (PLWH): A Systematic Review and Meta-analysis of Real-World Studies
Authors: Fan Xueying , Zhao Yangguo , Wu Fan , Yuan Yue , Lang Bing , Yin Di , Xu Zhongliang , Jiang Shiqiang , Zou Huachun , Yuan Jianhui , Sun Caijun
Published: August 2023

The safety and immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in people living with HIV (PLWH) in real world studies remain controversial. Thus, we conducted a comprehensive systematic review and meta-analysis to address this issue. Data search were conducted from PubMed, Web of science, and Embase. Adverse events following vaccination, the risk ratio (RR) of SARS-CoV-2-specific IgG seroconversion, and the level of anti-SARS-CoV-2 neutralizing antibodies were compared between the PLWH group and a healthy control group. A total of 10,582 PLWH from 22 studies were included. In our analysis, the incidence of local or systemic adverse events after the first SARS-CoV-2 vaccine dose was not statistically different between PLWH and healthy controls. However, there was a statistical difference after the second dose (RR = 0.83, 95% CI: 0.71 – 0.98). The seroconversion rate of SARS-CoV-2 IgG antibodies in PLWH was significantly lower than that in the healthy control group (RR = 0.94, 95% CI: 0.89-0.98; I2
= 80%, P < 0.01). The anti-SARS-CoV-2 neutralizing antibody titers in PLWH after full immunization were also significantly lower than that in the healthy control group (RR = 0.91, 95% CI: 0.85-0.98; I2
= 81%, P < 0.01). The safety and tolerance of COVID-19 vaccines in PLWH are acceptable. However, their immunogenicity may be impaired to a certain extent, characterized by a lower IgG seroconversion rate and neutralizing antibody titers compared with healthy individuals. These findings should provide guidance for optimizing future COVID-19 vaccination strategies among PLWH.
Making space and taking space: Promoting inclusion and belonging, a crucial imperative for nurse practitioner organizations
Authors: McCamey Danielle
Published: August 2023

In the ever-evolving landscape of health care, professional nursing organizations (PNOs) play a vital role in establishing a supportive and inclusive environment for nurses to thrive. These organizations are built on creating a community based on shared mission, vision, and goals. Professional nursing organizations are critical for fostering innovation, advancement of the ethics and values of the profession that advocates for the needs of nurses, social justice, and the trust of society. However, historically and present day, PNOs still have an underrepresentation of communities that have been historically racialized and marginalized, largely because PNOs reflect the landscape of nursing being a predominately White female profession. Because of this fact, it is a crucial imperative for PNOs to be deliberate and intentional in creating structural changes that establish a culture and commitment to inclusion and belonging. In doing so, this makes space for the nurses who represent historically racialized and marginalized communities in order for them to take up their space in these professional arenas. The significance of inclusion and belonging in PNOs can enhance member experience for everyone and can improve overall organizational success, which will ultimately affect nursing practice. Advanced practice nursing uniquely positions nurse practitioners to be the catalyst that sparks progressive and transformative changes toward advancing inclusion and belonging.
Evidence-based nutritional approaches to enhance exercise adaptations
Authors: Roberts Michael D. , Moulding Blake , Forbes Scott C. , Candow Darren G.
Published: August 2023

Purpose of review

The purpose of this opinion paper is to provide current-day and evidence-based information regarding dietary supplements that support resistance training adaptations or acutely enhance strength-power or endurance performance.

Recent findings

Several independent lines of evidence support that higher protein diets, which can be readily achieved through animal-based protein supplements, optimize muscle mass during periods of resistance training, and this likely facilitates strength increases. Creatine monohydrate supplementation and peri-exercise caffeine consumption also enhance strength and power through distinct mechanisms. Supplements that favorably affect aspects of endurance performance include peri-exercise caffeine, nitrate-containing supplements (e.g., beet root juice), and sodium bicarbonate consumption. Further, beta-alanine supplementation can enhance high-intensity endurance exercise efforts.

Select dietary supplements can enhance strength and endurance outcomes, and take-home recommendations will be provided for athletes and practitioners aiming to adopt these strategies.
Characteristics of Pediatric Emergency Department Presentations of Anaphylaxis in Spain
Authors: Olabarri Mikel , Sanz Nuria , Gonzalez-Peris Sebastià , Vazquez Paula , Gonzalez-Posada Aranzazu , Diez Nuria , Vinuesa Ana , Benito Javier , Mintegi Santiago
Published: August 2023

Objective

This study aimed to identify the triggers of pediatric anaphylaxis in Spain and to analyze the circumstances of the episode.

Methods

Planned secondary analysis of a prospective observational multicenter study endorsed by the Spanish Society of Pediatric Emergencies including children aged younger than 18 years diagnosed with anaphylaxis in 7 Spanish pediatric emergency departments (EDs) between 2016 and 2018. We analyzed factors related to the anaphylaxis episode and its management.

Results

Four hundred fifty-three cases were registered, happening mainly at home (295 [65.1%]), school (65 [14.3%]), and street (61 [13.5%]). The median age was 5 years, 143 (31.6%) had previous episodes, and 165 (36.4%) had previously been prescribed an epinephrine autoinjector, used in 40 (24.2% of those prescribed). Two thirds were well-appearing when arriving to the pediatric ED. Food was the trigger in 396 (87.4%). In 349 with a single food involved, the most frequent were milk (108 [30.4%]), nuts (103 [29.0%]), hen's egg (40 [11.3%]), and fish (31 [8.7%]), with variations related to the age of the child.

Conclusions

Food, especially milk and nuts, are responsible for most anaphylaxis diagnosed in Spanish pediatric EDs. Consideration should be given to improving health education due to the low use of epinephrine autoinjectors.
Trends of nonoccupational postexposure prophylaxis in the United States
Authors: McCormick Carter D. , Sullivan Patrick S. , Qato Dima M. , Crawford Stephanie Y. , Schumock Glen T. , Lee Todd A.
Published: August 2023

Objective:

To describe national annual rates of nonoccupational postexposure prophylaxis (nPEP) in the United States.

Design:

Retrospective cohort study of commercially insured individuals in the Merative MarketScan Database from January 1, 2010 to December 31, 2019.

Methods:

Patients at least 13 years old prescribed nPEP per recommended Centers for Disease Control and Prevention guidelines were identified using pharmacy claims. Rates of use were described overall and stratified by sex, age group, and region. These rates were qualitatively compared to the diagnosis rates of human immunodeficiency virus (HIV) observed in the data. Joinpoint analysis identified inflection points of nPEP use.

Results:

Eleven thousand, three hundred and ninety-seven nPEP users were identified, with a mean age of 33.7 years. Most were males (64.6%) and lived in the south (33.2%) and northeast (32.4%). The rate of nPEP use increased 515%, from 1.42 nPEP users per 100 000 enrollees in 2010 to 8.71 nPEP users per 10 000 enrollees in 2019. The comparative nPEP use rates among subgroups largely mirrored their HIV diagnosis rates, that is, subgroups with a higher HIV rate had higher nPEP use. In the Joinpoint analysis significant growth was observed from 2012 to 2015 [estimated annual percentage change (EAPC): 45.8%; 95% confidence interval (CI): 29.4 – 64.3] followed by a more moderate increase from 2015 to 2019 (EAPC 16.0%; 95% CI: 12.6–19.6).

Conclusions:

nPEP use increased from 2010 to 2019, but not equally across all risk groups. Further policy interventions should be developed to reduce barriers and ensure adequate access to this important HIV prevention tool.