bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world Evidence for Impact of Opioid Agonist Therapy on Nonfatal Overdose in Patients with Opioid Use Disorder during the COVID-19 Pandemic
Authors: Lee Kenneth , Zhao Yue , Merali Tazmin , Fraser Christopher , Kozicky Jan-Marie , Mormont Marie-Christine , Conway Brian
Published: August 2023

Objectives

The primary objectives of this study were to describe the demographics and clinical characteristics of patients who were treated with buprenorphine extended-release versus buprenorphine-naloxone sublingual tablets versus methadone in a real-world setting and to evaluate the difference in nonfatal overdose events between treatment cohorts.

Methods

This study was a retrospective chart review of patients with opioid use disorder initiating opioid agonist therapy in Canada during the outset of the COVID-19 pandemic (March 11, 2020 to October 31, 2021). Three treatment cohorts were defined by the initial prescribed opioid agonist therapy regimen: buprenorphine extended-release, buprenorphine-naloxone sublingual tablets, and methadone. Baseline characteristics, as well as treatment status, overdose events, and substance use 6 months after treatment initiation were collected using a standardized form.

Results

Nine clinics provided data on 379 patient cases. The incidence rate (number of events per 100 person-years) for a self-reported nonfatal overdose was 46.8 (n = 18), 19.3 (n = 10), and 1.7 (n = 1) in the methadone, buprenorphine-naloxone sublingual tablets, and buprenorphine extended-release cohorts, respectively. The risk-adjusted difference for the proportion of patients with nonfatal overdose was 8.59% (95% confidence interval, 3.10–14.08%; P = 0.0022) for methadone versus buprenorphine extended-release and 6.51% (95% confidence interval, 1.46–11.56%; P = 0.0115) for buprenorphine-naloxone sublingual tablets versus buprenorphine extended-release.

Conclusions

Buprenorphine extended-release was associated with lower rates of nonfatal overdose events compared with daily opioid agonist therapy. Given the limitations of this naturalistic, retrospective design, further prospective studies are needed to validate these findings and demonstrate the potential for long-acting opioid agonist therapy in addressing the opioid crisis.
Early Women Pioneers and the Evolution of Women in Plastic Surgery
Authors: Koljonen Jessie L. , Petro Jane A. , Sommer Nicole Z.
Published: August 2023

The history of women in surgery has been documented since ancient times. Despite this, women physicians have historically encountered unique obstacles in achieving the same respect and privileges as their male counterparts. Early female physicians overcame many challenges to complete their training following graduation from medical school. The first woman in the field of plastic surgery in the United States was Dr. Alma Dea Morani, who became a member of the American Society of Plastic and Reconstructive Surgeons (ASPRS, now ASPS) in 1948. She applied for plastic surgery training six different times over 6 years, until she was accepted at a position where she had shadowing-only privileges. Yet, her steadfast determination and perseverance led her to build a successful career, becoming a role model and advocate for women in plastic surgery. The Women Plastic Surgeons Forum within ASPRS was officially established in 1992; however, informal events began as early as 1979. This group fostered mentorship among emerging female leaders, allowing women to take on leadership roles within national plastic surgery organizations. These women, in turn, have become role models for subsequent generations of women in this field. Plastic surgery has historically seen a higher percentage of female residents relative to other surgical specialties. Studies have shown that female role models are the most influential factor for female medical students interested in plastic surgery, a powerful fact considering women now comprise over 50% of graduating medical students. Female mentorship is essential in fostering the future generation of female plastic surgeons.
The Value of the Second QuantiFERON-TB Gold-Plus Antigen Tube at Diagnosis and at Treatment Completion in Spanish Children With Tuberculosis
Authors: Soler-Garcia Aleix , Gamell Anna , Monsonís Manuel , Korta-Murua José Javier , Espiau María , Rincón-López Elena , Rodríguez-Molino Paula , Pérez-Porcuna Tomàs , Bustillo-Alonso Matilde , Santiago Begoña , Tebruegge Marc , Noguera-Julian Antoni ,   on behalf of the QFT-Plus Study Group of the Spanish Pediatric TB Research Network
Published: August 2023

We studied 295 children (tuberculosis disease, n = 159; latent tuberculosis infection, n = 136) with positive QuantiFERON-TB Gold-Plus assay results. No significant differences between first and second antigen tube interferon-gamma responses were detected, irrespective of patient and disease characteristics at diagnosis. Of patients with a repeat assay after treatment completion (n = 65), only 16.9% converted to negative results.
Intraoperative endomanometric laparoscopic Nissen fundoplication improves postoperative outcomes in large sliding hiatus hernia with severe gastroesophageal reflux disease. A retrospective cohort study.
Authors: Habeeb Tamer.A.A.M. , Hussain Abdulzahra , Podda Mauro , Aiolfi Alberto , Kryvoruchko Igor A. , Kalmoush Abd-Elfattah , labib Mohamed fathy , Mustafa Fawzy M , Elbelkasi Hamdi , Hamdy Ahmed , Abo Alsaad Mohamed Ibrahim , Sallam Ahmed M. , Zaitoun Mohamed Abdallah , negm Mohamed , Mostafa Abdelshafy , Abdou Yassin Mahmoud , Elshahidy Tamer Mohamed , abdelmonem elsayed Ashraf , Mansour Mohamed Ibrahim , Elaidy Mostafa.M. , Moursi Adel Mahmoud , yehia Ahmed m , Ashour Hassan , Metwalli Abd-Elrahman M. , abdelhady Waleed A. , Abdelghani Amr , AbdAllah Ehab shehata , Ramadan Alaaedin , Rushdy Tamer
Published: August 2023

Background:

Laparoscopic Nissen Fundoplication (LNF) is the gold standard surgical intervention for gastroesophageal reflux disease (GERD). LNF can be followed by recurrent symptoms or complications affecting patient satisfaction. The aim of this study is to assess the value of the intraoperative endomanometric evaluation of esophagogastric competence and pressure combined with LNF in patients with large sliding hiatus hernia (> 5 cm) with severe GERD (DeMeester score >100).

Materials and Methods:

This is a retrospective, multicenter cohort study. Baseline characteristics, postoperative dysphagia and gas bloat syndrome, recurrent symptoms, and satisfaction were collected from a prospectively maintained database. Outcomes analyzed included recurrent reflux symptoms, postoperative side effects, and satisfaction with surgery.

Results:

360 patients were stratified into endomanometric LNF (180 patients, LNF+) and LNF alone (180 patients, LNF). Recurrent heartburn (3.9% vs. 8.3%) and recurrent regurgitation (2.2% vs. 5%) showed a lower incidence in the LNF+ group (P=0.012). Postoperative score III recurrent heartburn and score III regurgitations occurred in 0% vs. 3.3% and 0% vs. 2.8% cases in the LNF+ and LNF groups, respectively (P=0.005). Postoperative persistent dysphagia and gas bloat syndrome occurred in 1.75% vs. 5.6% and 0% vs. 3.9% of patients (P=0.001). Score III postoperative persistent dysphagia was 0% vs. 2.8% in the two groups (P=0.007). There was no redo surgery for dysphagia after LNF+. Patient satisfaction at the end of the study was 93.3% vs. 86.7% in both cohorts, respectively (P=0.05).

Conclusions:

Intraoperative high-resolution manometry (HRM) and endoscopic were feasible in all patients, and the outcomes were favorable from an effectiveness and safety standpoint.
Effect of Anesthesia Induction on Cardiac Hemodynamics in Patients Undergoing Durable Left Ventricular Assist Device Implantation: The EACH-LVAD Study
Authors: Schurr James W. , Sigal Ian , Usman Asad , Patel Prakash , Lefebvre Benedicte , Kurcik Kristy , Atluri Pavan , Acker Michael , Bermudez Christian , Rame J. Eduardo , Hanff Thomas , Cevasco Marisa , Wald Joyce
Published: August 2023

Right ventricular (RV) dysfunction is common after left ventricular assist device (LVAD) implantation leading to clinical right heart failure (RHF) associated with worsened survival and quality of life. It is likely that intraoperative events such as anesthesia induction play a role in the development or unmasking of RV dysfunction in addition to known effects from hemodynamic changes that occur after LVAD implantation. The EACH-LVAD Study is a prospective, single-center, single-arm, observational cohort study of adult patients with advanced heart failure undergoing durable LVAD implantation with standard anesthesia induction. Intraoperative RV hemodynamics via central venous pressure, mean pulmonary artery pressure, pulmonary artery pulsatility index, and vasoactive-inotropic score (a simple weighted summation of standardized drug doses) and echocardiographic parameters (RV fractional area change, RV area in diastole, RV basal diameter, septum position, RV function, tricuspid regurgitation) were measured and compared at prespecified timepoints, including postinduction. Postoperative clinical RHF was determined based on published definitions. Forty-two patients receiving a first-time LVAD were included between September 2017 and March 2019. Propofol-based induction was used in 31 patients and etomidate-based induction in eight patients. A significant increase in central venous pressure (CVP; p < 0.001), mean pulmonary artery pressure (mPAP; p < 0.001), and vasoactive inotropic score (VIS; p < 0.001) with associated decrease in pulmonary artery pulsatility index (PAPi; p < 0.001) was observed. Right ventricular function worsened throughout. Right heart failure occurred in 70% of patients. Propofol-based induction was not associated with a higher risk of RHF (relative risk [RR], 1.01 [95% confidence interval {CI}, 0.64–1.61]). The EACH-LVAD study demonstrates an effect of anesthesia induction on worsened RV hemodynamics and echocardiographic changes which may have an effect on the development of RHF.
Buddi-Chiari syndrome associated with hypereosinophilic syndrome: A case report
Authors: Li Zhaoxia , Li Nan , Ji Zhuhui , Shi Jiahe , Xin Guijie
Published: August 2023

Rationale:

Budd-Chiari Syndrome (BCS) is a relatively rare clinical disorder with a wide range of symptoms, caused by the obstruction of the hepatic venous outflow. The etiology and pathogenesis of BCS vary in different countries and regions. In Western countries, hepatic venous obstruction is the most common type, and its main cause is closely related to the hypercoagulable state of the body. Inferior vena cava obstruction is common in Asia, and its etiology progresses slowly due to the lack of epidemiological data. [3] Here, we report a rare case of BCS associated with the hypereosinophilic syndrome and discuss the possible causal relationship between the two.

Patient concerns:

The patient was a 33-year-old female with intermittent epistaxis, gum bleeding, and excessive menstrual flow for the past 6 months. The routine blood tests showed elevated levels of eosinophils, and the liver function test showed mildly elevated levels of γ-glutamyl transpeptidase and alkaline phosphatase, and abdominal ultrasound showed hepatosplenomegaly and suspicion of intrahepatic arteriovenous or arteriovenous-portal fistula.

Diagnoses:

Finally, through the improvement of bone marrow aspiration, digital subtraction angiography and gene detection, the diagnosis of BCS combined with hypereosinophilic syndrome was confirmed, and JAK2V617F mutation was highly associated with it.

Interventions:

The patient received endovascular stent implantation and regular oral rivaroxaban anticoagulation therapy after operation.

Outcomes:

Seven months later, enhanced computed tomography (CT) of the hepatobiliary showed that the hepatic bruise-like changes were significantly reduced compared with before, and the right hepatic vein and the right perihepatic vein stent were left in place with a good filling of contrast in the stent.

Lessons:

The patient, in this case, was finally diagnosed with BCS combined with hypereosinophilic syndrome, and to our knowledge, such case reports are rare. Our case report suggest an association between BCS and hypereosinophilic syndrome, but relevant studies are minimal, we hope to conduct larger and higher quality studies on these patients in the future, to provide new directions and basis for the etiology and pathogenesis of these diseases, as well as provide new targets and ideas for clinical treatment.
ChatGPT performance in the medical specialty exam: An observational study
Authors: Oztermeli Ayse Dilara , Oztermeli Ahmet
Published: August 2023

In our study, we aimed to evaluate the success of ChatGPT by determining its performance in the last 5 medical specialty exams (MSE) conducted and its ranking among the candidates of that year, and to determine its potential use in healthcare services. Publicly available MSE questions and answer keys from the last 5 years were scanned, a total of 1177 questions were included in the study, all questions were asked to the ChatGPT (OpenAI; San Francisco, CA) GPT-3.5 series, which is the March 23, 2023 version. The average score and rank that ChatGPT would receive if it had entered the exam that year were determined. Questions were categorized as short question group, long question group, single select multiple-choice questions, and multi-select multiple-choice questions. The lowest success proportion was determined as 54.3%, and the highest success proportion was 70.9% correct answer percentage. It achieved a sufficient result as 1787th out of 22,214 people in its most successful exam, and 4428th out of 21,476 participants in its least successful one. No statistically significant difference was found between the correct answers it gave to clinical and basic science questions (P: .66). ChatGPT statistically significantly answered a higher proportion of questions correctly in the short questions group compared to the long questions group (P = .03), and in the single select multiple choice questions group compared to the multi-select multiple choice questions group (P < .001). ChatGPT has been successful in the MSE, a challenging exam for doctors in our country. However, it is a fact that ChatGPT is still behind the expert in the field for now, and what will happen with program developments in the future is a matter of curiosity for all of us.
Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis
Authors: Yang Linfu , Zhao Wenzheng , Gong Xueyang , Yue Dan , Liu Yiqiu , Tian Yakai , Dong Kun
Published: August 2023

Background:

Rheumatoid arthritis (RA) is a type of difficult-to-cure arthralgia with a worldwide prevalence. It severely affects people’s living standards. For a long time, bee venom has been used to treat RA and has shown good results. Melittin is the main active component of bee venom used for RA treatment, but the molecular mechanism of melittin in RA treatments remains unclear.

Methods:

Potential melittin and RA targets were obtained from relevant databases, and common targets of melittin and RA were screened. The STRING database was used to build the PPI network and screen the core targets after visualization. The core targets were enriched by Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway. Finally, the binding of melittin to target proteins was evaluated through simulated molecular docking, which verified the reliability of the prediction results of network pharmacology.

Results:

In total, 138 melittin targets and 5795 RA targets were obtained from relevant databases, and 90 common targets were obtained through intersection. Eighteen core targets, such as STAT3, AKT1, tumor necrosis factor, and JUN, were screened out. Enrichment analysis results suggested that melittin plays an anti-RA role mainly through tumor necrosis factor, interleukin-17, toll-like receptors, and advanced glycation end products–RAGE signaling pathways, and pathogenic bacterial infection. Molecular docking results suggested that melittin has good docking activity with core target proteins.

Conclusion:

RA treatment with melittin is the result of a multi-target and multi-pathway interaction. This study offers a theoretical basis and scientific evidence for further exploring melittin in RA therapy.
Analysis of risk factors of pituitary neoplasms invading the sphenoidal sinus
Authors: Luo Bin , Ren Hecheng , Wang Yubo , Ma Lin , Yu MingSheng , Ma YuXiang , Yin Long , Huang Ying
Published: August 2023

High-resolution computed tomography (HR-CT) can more effectively discern the relationship between pituitary neoplasms (PNs) and neighboring anatomical structures. Moreover, pathological features can facilitate a more accurate determination of the growth pattern of PNs. Consequently, integrating imaging and pathological data might enhance our predictive capability regarding the growth patterns of PNs and aid in the formulation of surgical plans. We compared HR-CT images of 54 patients and 52 volunteers. Using ITK-SNAP software, we segmented and reconstructed the anatomical features of the sphenoidal sinus (SS) and calculated its volume. A comparative analysis of the invasive attributes of the 54 PNs was carried out based on clinical features and pathological data. The average volume of the SS in the volunteer group was 11.05 (8.10) mL, significantly larger than that of the PNs group at 7.45 (4.88) mL (P = .005). The postsellar type was the most common pneumatization type, and a significantly higher proportion in the PNs group exhibited a depressed saddle base (83.3%). A notable male predominance was observed for SS invasion in the PNs group (72.7%), with the Ki-67 antigen and maximum diameter significantly higher (P < .05), showing a positive correlation. The optimal cutoff points for Ki-67 antigen and the maximum diameter of PNs were 3.25% (AUC = 0.754, Sensitivity 54.5%, Specificity 90.6%) and 24.5 mm (AUC = 0.854, Sensitivity 86.4%, Specificity 78.1%), respectively. The type of pneumatization and the morphology of the sellar-floor serve as anatomical foundations for SS invasion. Factors such as the Ki-67 antigen, the maximum diameter of PNs, and high-risk sub-types constitute risk factors for PNs invasion into the SS. These insights are of significant utility for clinicians in crafting treatment strategies for PNs.
Using emergency department triage for machine learning-based admission and mortality prediction
Authors: Tschoellitsch Thomas , Seidl Philipp , Böck Carl , Maletzky Alexander , Moser Philipp , Thumfart Stefan , Giretzlehner Michael , Hochreiter Sepp , Meier Jens
Published: August 2023

Aims

Patient admission is a decision relying on sparsely available data. This study aims to provide prediction models for discharge versus admission for ward observation or intensive care, and 30 day-mortality for patients triaged with the Manchester Triage System.

Methods

This is a single-centre, observational, retrospective cohort study from data within ten minutes of patient presentation at the interdisciplinary emergency department of the Kepler University Hospital, Linz, Austria. We trained machine learning models including Random Forests and Neural Networks individually to predict discharge versus ward observation or intensive care admission, and 30 day-mortality. For analysis of the features’ relevance, we used permutation feature importance.

Results

A total of 58323 adult patients between 1 December 2015 and 31 August 2020 were included. Neural Networks and Random Forests predicted admission to ward observation with an AUC-ROC of 0.842 ± 0.00 with the most important features being age and chief complaint. For admission to intensive care, the models had an AUC-ROC of 0.819 ± 0.002 with the most important features being the Manchester Triage category and heart rate, and for the outcome 30 day-mortality an AUC-ROC of 0.925 ± 0.001. The most important features for the prediction of 30 day-mortality were age and general ward admission.

Conclusion

Machine learning can provide prediction on discharge versus admission to general wards and intensive care and inform about risk on 30 day-mortality for patients in the emergency department.
Male infertility with muscle weakness: a point of view
Authors: Khalayli Naram , Achmeh Bassel , Ali Khalil , Aziz Aghiad , Kudsi Maysoun
Published: August 2023

Introduction and importance:

The most common causes of infertility are idiopathic spermatogenetic disorders, occurring in multiple reproductive or systemic diseases. The underlying genetic disorders influence the treatment and transmission of the disease to the offspring.

Case presentation:

A 32-year-old Syrian male, married for 6 years, presented with primary infertility. The patient had a history of muscle dystrophy for 12 years. He had no previous medical or drug addiction or family history. He had gynecomastia. Semen analysis revealed oligospermia in the patient. Follicle-stimulating hormone was elevated. Gene analysis could not be done due to funding issues. The percutaneous testicular biopsy revealed hypospermatogenesis, atrophy, and marked hyalinization of the seminiferous tubules. Electromyography of the upper extremities demonstrated myotonic discharges, with a waxing–waning frequency, amplitude, and a characteristic ‘engine revving’ sound.

Clinical discussion:

Myotonic dystrophy (MD) is an autosomal dominant inheritance disease with adult onset. Muscle weakness is the predominant presenting feature, with early involvement of the distal limbs and neck muscles and a characteristic facial appearance.

Systemic clinical manifestations may include cardiac conduction defects, cataracts, insulin resistance and diabetes, testicular atrophy with impaired spermatogenesis, and others. Testicular biopsy findings are specific. To our knowledge, this is the first case of male infertility associated with MD in Syria. However, there are no data on the prevalence of myotonic dystrophy type 1 (MD1) in Syria.

Conclusion:

The practicing physician should keep in mind the frequent association between MD and infertility.
Dexmedetomidine as a myocardial protector in pediatric heart surgery using cardiopulmonary bypass: a systematic review
Authors: Kesumarini Dian , Widyastuti Yunita , Boom Cindy E. , Dinarti Lucia K.
Published: August 2023

Background:

In recent years, dexmedetomidine has been studied as a cardioprotective agent. However, studies on its application in pediatric heart surgery using cardiopulmonary bypass (CPB) remain limited. This systematic review aimed to provide information on the cardioprotective effect of dexmedetomidine in children undergoing heart surgery using CPB.

Methods:

The authors searched several databases (MEDLINE, Embase, Cochrane Library, etc.) to identify all trials comparing the levels of myocardial injury via biomarkers, including pediatric patients undergoing heart surgery using CPB who received dexmedetomidine versus placebo or other anesthetic agents. Literatures from non-primary studies were excluded. Two reviewers independently screened studies for eligibility and extracted data. The Cochrane Risk-of-Bias tool was implemented to evaluate any potential biases. Information from eligible studies was summarized and correspondingly reviewed based on any quantitative outcomes.

Results:

We identified six trials composed of 419 participants, three of which (n=241) showed significantly reduced interleukin-6 (IL-6) levels in the dexmedetomidine group, while one study (n=40) showed no IL-6 difference between groups. Cardiac troponin I (cTnI) and creatinine kinase-myocardial band (CK-MB), as myocardial injury biomarkers, were found to be lower in two trials (n=180). Despite several limitations hindering this review from pooling the data objectively, the majority of published studies indicated that dexmedetomidine is a seemingly efficacious agent protecting against cardiac injury during bypass.

Conclusions:

These studies suggest that dexmedetomidine has cardioprotective effects through the lowering of cardiac injury biomarkers while improving its clinical outcomes after heart surgery using bypass.
The Role of Level of Play in Concussions in High School Athletes
Authors: Waltzman Dana , DePadilla Lara , Breiding Matthew , Pierpoint Lauren , Collins Christy
Published: August 2023

Objectives:

To examine level of play (LOP) as a risk factor for concussion severity and recovery-related outcomes among high school athletes, stratified by sex, and among boys, by sport (football, non-football male sports).

Design/Setting:

Secondary analysis of data collected through the High School Reporting Information Online surveillance system for academic years 2007-2008 through 2018-2019.

Participants:

A total of 9916 concussions were reported between the academic years 2007-2008 and 2018-2019 from 9 sports (5189 from football; 2096 from non-football male sports; 2631 from female sports).

Main Outcome Measure:

Examined the association between LOP (Freshman, Junior Varsity [JV], and Varsity teams) and concussion outcomes (number of concussion symptoms, symptom resolution time [SRT], and time to return to play [RTP]).

Results:

Compared with Varsity football athletes, concussed JV football athletes had on average 0.19 fewer concussion symptoms, longer SRT (>1 week vs <1 week: odds ratio [OR] = 1.3; 95% confidence interval [CI], 1.1-1.5), and longer RTP (1-3 weeks vs <1 week: OR = 1.5; 95% CI, 1.2-1.9; >3 weeks vs <1 week: OR = 1.6; 95% CI, 1.1-2.3). Compared with Varsity football athletes, Freshman football athletes had on average 0.48 fewer concussion symptoms, longer SRT (OR = 1.3; 95% CI, 1.1-1.5), and longer RTP (1-3 weeks vs <1 week: OR = 1.5; 95% CI, 1.1-2.0; >3 weeks vs <1 week: OR = 2.0; 95% CI, 1.3-3.0). Similarly, compared with female athletes on Varsity teams, concussed JV female athletes had longer RTP (1-3 weeks vs <1 week: OR = 1.8; 95% CI, 1.2-2.7). Trend analyses revealed an increase in the number of concussion symptoms between 2015-2016 and 2018-2019, a decrease between 2009-2010 and 2018-2019 for SRT of less than 1 week, and an increase between 2014-2015 and 2018-2019 for RTP of less than 1 week among Varsity football athletes. Among Varsity female athletes, there was a linear decrease during the study period for RTP of less than 1 week.

Conclusions:

Despite a higher number of symptoms overall and in recent years, Varsity football players had shorter RTP than Freshman and JV athletes.
Technical Note: Assessment of Pulse Pileup on Single-Energy and Multienergy Images From a Clinical Photon-Counting Detector Computed Tomography
Authors: Chen Joshua Ray , Winfree Timothy N. , Bruesewitz Michael R. , Swicklik Joseph R. , Thorne Jamison E. , Leng Shuai , McCollough Cynthia H.
Published: August 2023

Objective

Pulse pileup effects occur when pulses occur so close together that they fall on top of one another, resulting in count loss and errors in energy thresholding. To date, there has been little work systematically detailing the quantitative effects of pulse pileup on material decomposition accuracy for photon-counting detector (PCD) computed tomography (CT). Our aim in this work was to quantify the effects of pulse pileup on single-energy and multienergy CT images, including low-energy bin (BL), high-energy bin (BH), iodine map, and virtual noncontrast images from a commercial PCD-CT.

Methods

Scans of a 20-cm diameter multienergy CT phantom with 10 solid inserts were acquired at a fixed tube potential as the tube current was varied across the available range. Four types of images (BL, BH, iodine map, and virtual noncontrast) were reconstructed using an iterative reconstruction algorithm at strength 2, a quantitative reconstruction kernel (Qr40), 2-/1-mm slice thickness/increment, and a 210-mm field-of-view. The mean and standard deviation of CT numbers were recorded and the ratios of CT number between BL and BH images were calculated and plotted, along with noise versus tube current and noise ×

versus tube current.

Results

As tube current was increased, the range of variations in CT numbers was less than 13.4 HU for all inserts and image types evaluated. Noise ×

versus tube current showed a small positive slope equal to a noise increase from 100 mA of 10% at 500 mA and 15% at 900 mA compared with what would be expected if the slope was zero.

Conclusions

Minimal impact on single-energy and multienergy CT numbers and noise performance was observed for the evaluated clinical PCD-CT system.
Asthma as an Inflammatory Reason of Tracheobronchial PSMA Uptake
Authors: Bronte Viedma Ángela , Bastidas Tamayo Juan Fernando , Rosales Castillo Juan José , Campo Ezquibela Arantza , Rodriguez-Fraile Macarena
Published: August 2023

A 53-year-old man with persisting increased serum prostate-specific antigen level (9.53 ng/mL) and repeated negative prostate biopsies was referred for a PET/CT with 68Ga-PSMA-11. The PET/CT revealed focal uptake in the prostate suggestive of localized prostate cancer. Incidentally, it also showed a diffuse uptake in the tracheobronchial tree suspicious for a benign etiology. Because of the clinical history of asthma exacerbation in the previous week, further supplementary studies were performed showing a pathological fractional exhaled nitric oxide level (92 ppb; reference values, <25 ppb) and mild airway obstruction in the spirometry. These findings confirmed asthma as an inflammatory etiology of the tracheobronchial PSMA uptake.
Mediastinal Hemangioma Masquerading as a Simple Cyst
Authors: D'Souza Romina , Pal Prodipto , Chacko Binita , Kha Lan-Chau , Oikonomou Anastasia , Houbois Christian
Published: August 2023

This report presents imaging from a mediastinal mass in a patient with colon cancer. At baseline and surveillance chest computed tomography examinations, it was characterized as a pericardial cyst. However, during chemotherapy, complications arose and this mass was further characterized with a chest MRI. It was then decided to be removed, and histopathology confirmed the diagnosis of a hemangioma.
Inhibition of the Complement Pathway Induces Cellular Proliferation and Migration in Pancreatic Ductal Adenocarcinoma
Authors: Nsingwane Zanele , Naicker Previn , Omoshoro-Jones Jones , Devar John , Smith Martin , Candy Geoffrey , Augustine Tanya Nadine , Nweke Ekene Emmanuel
Published: August 2023

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and may elevate pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. In this study, 30 tissues and 34 plasma samples were obtained from a cohort of PDAC patients including controls. Targeted pathway-specific PCR analysis was conducted to determine the gene expression profiles of immune-response-related genes. The circulating levels of complement proteins C3 and C5 were further investigated. Pharmacological inhibition of the complement pathway in MIA PaCa-2 pancreatic cancer cell lines was performed and the effect on cells was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, SWATH-mass spectrometry was performed to identify potential molecular mechanisms during inhibition. The results identified C3 and C5 to be overly expressed in early PDAC compared to later stages. Pharmacological inhibition of the complement pathway led to increased cell growth, proliferation and migrationin vitro. Proteomic analysis implicated several proteins such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype. This study helps to further delineate the role of the complement pathway in PDAC progression suggesting a context-dependent function.
Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study
Authors: Hietikko Ronja , Mirtti Tuomas , Kilpeläinen Tuomas P. , Tolonen Teemu , Räisänen-Sokolowski Anne , Nordling Stig , Hannus Jill , Laurila Marita , Taari Kimmo , Tammela Teuvo LJ , Autio Reija , Natunen Kari , Auvinen Anssi , Rannikko Antti
Published: August 2023

Background

Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI).

Objective

To assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen).

Design, setting, and participants

From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate.

Intervention

Six pathologists individually reviewed the pathology slides of the prostate biopsies.

Outcome measurements and statistical analysis

The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss’ weighted kappa (κ) and Model based kappa for associations were computed to estimate the combined agreement between individual pathologists.

Results and limitations

GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG 1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss’ kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG 2-5 vs. GG 0 vs GG1) it was good (Model-based kappa 0.70, Fleiss’ kappa κ 0.67).

Conclusions

Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.

Patient summary

It is currently unknown to what extent pathologists differ in their evaluation of histopathology in MRI-targeted prostate biopsies. We show that the agreement is good to excellent. We expect individual pathologist to have a minimal impact on MRI-based prostate cancer screening including the ProScreen trial.
Study Protocol for the Intraoperative Complications Assessment and Reporting with Universal Standards (ICARUS) Global Cross-Specialty Surveys Among Surgeons, Anesthesiologists, Nurses, Interventional Cardiologists, and Interventional Radiologists
Authors: Cacciamani Giovanni E. , Sholklapper Tamir , Eppler Michael B. , Sayegh Aref , Stornino Ramacciotti Lorenzo , Abreu Andre L. , Sotelo Rene , Desai Mihir M. , Gill Inderbir S.
Published: August 2023

Every year, approximately 200 million surgeries are performed worldwide, and intraoperative adverse events (iAEs) have a significant impact on patients and surgeons. Despite their importance, the true scale of iAEs remains underestimated due to inadequate methods for assessment, collection, grading, and reporting. Various grading systems have been introduced over the past decade, but their adoption has been limited, leading to inconsistencies in reporting. Furthermore, a lack of standardized frameworks for defining, assessing, and collecting iAEs, coupled with litigation concerns, contributes to underreporting. Only half of surgery and anesthesiology journals provide guidance on reporting perioperative adverse events, and recommendations for reporting iAEs are notably lacking in surgical literature. To address these issues, the Intraoperative Complications Assessment and Reporting with Universal Standard (ICARUS) Global Surgical Collaboration was established in 2022. The initiative involves conducting global surveys and a Delphi consensus to understand the barriers for poor reporting of iAEs, validate shared criteria for reporting, define iAEs according to surgical procedures, evaluate the existing grading systems’ reliability, and identify strategies for enhancing the collection, reporting, and management of iAEs. A sample size of 2,398 respondents was calculated for the study, with invitations extended to 86,574 healthcare providers. This effort represents an essential step towards improved patient safety and the well-being of healthcare professionals in the surgical field.
Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine
Authors: Sun Yang , Rodríguez-Rangel Sofia , Zhang Lauren L. , Sánchez-Rodríguez Jorge E. , Brugarolas Pedro
Published: August 2023

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+channels in demyelinated axons, reducing the leakage of intracellular K+and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). Here, we describe 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP), a novel K+channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP is more lipophilic (logD = 0.664 ± 0.005vs.0.414 ± 0.002) and slightly more basic (pKa= 7.46 ± 0.01vs. 7.37 ± 0.07). In addition, 5Me3F4AP appears to be more permeable to an artificial brain membrane and more stable towards oxidation by the cytochrome P450 enzyme family 2 subfamily E member 1 (CYP2E1), responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties for PET imaging warranting additional investigation.

Significance Statement

The PET tracer [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) binds to K+channels in demyelinated axons and has shown promise for imaging demyelinated lesions in animal models. However, its use in humans may be compromised due to rapid metabolism. Thus, a novel 3F4AP derivative amenable to labeling with fluorine-18 was designed and evaluatedin vitro. The results indicate that 5-methyl-3F4AP exhibits high binding affinity, good physicochemical properties and slower oxidation by CYP2E1 than 3F4AP, making it a promising candidate for further PET studies.
Genetic variation at transcription factor binding sites largely explains phenotypic heritability in maize
Authors: Engelhorn Julia , Snodgrass Samantha J. , Kok Amelie , Seetharam Arun S. , Schneider Michael , Kiwit Tatjana , Singh Ayush , Banf Michael , Khaipho-Burch Merritt , Runcie Daniel E. , Sanchez-Camargo Victor A. , Torres-Rodriguez J. Vladimir , Sun Guangchao , Stam Maike , Fiorani Fabio , Beier Sebastian , Schnable James C. , Bass Hank W. , Hufford Matthew B. , Stich Benjamin , Frommer Wolf B. , Ross-Ibarra Jeffrey , Hartwig Thomas
Published: August 2023

Comprehensive maps of functional variation at transcription factor (TF) binding sites (cis-elements) are crucial for elucidating how genotype shapes phenotype. Here we report the construction of a pan-cistrome of the maize leaf under well-watered and drought conditions. We quantified haplotype-specific TF footprints across a pan-genome of 25 maize hybrids and mapped over two-hundred thousand genetic variants (termed binding-QTL) linked tocis-element occupancy. Three lines of evidence support the functional significance of binding-QTL: i) they coincide with numerous known causative loci that regulate traits, includingVGT1,Trehalase1, and the MITE transposon nearZmNAC111under drought; ii) their footprint bias is mirrored between inbred parents and by ChIP-seq; iii) partitioning genetic variation across genomic regions demonstrates that binding-QTL capture the majority of heritable trait variation across ∼70% of 143 phenotypes. Our study provides a promising approach to make previously hiddencis-variation more accessible for genetic studies and multi-target engineering of complex traits.
ERK signaling drives evolutionary expansion of the mammalian cerebral cortex
Authors: Sun Mengge , Gao Yanjing , Li Zhenmeiyu , Yang Lin , Liu Guoping , Xu Zhejun , Guo Rongliang , You Yan , Yang Zhengang
Published: August 2023

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we found that FGF-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells.

Furthermore, FGF-ERK signaling inducesBmp7expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and SHH signaling mutually inhibit each other in cortical RG cells. We also provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We conclude that the evolutionary expansion of the mammalian cortex, notably in human, is driven by ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the molecular basis for cortical evolutionary dwarfism, exemplified by the lissencephalic mouse which originated from a larger and gyrencephalic ancestor, is due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.
Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina
Authors: Lyu Pin , Iribarne Maria , Serjanov Dmitri , Zhai Yijie , Hoang Thanh , Campbell Leah J. , Boyd Patrick , Palazzo Isabella , Nagashima Mikiko , Silva Nicholas J. , HItchcock Peter F. , Qian Jiang , Hyde David R. , Blackshaw Seth
Published: August 2023

Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes. This regeneration requires Müller glia (MG) to reprogram and divide asymmetrically to produce a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, does loss of different retinal cell subtypes induce unique MG regeneration responses? Second, do MG reprogram to a developmental retinal progenitor cell state? And finally, to what extent does regeneration recapitulate retinal development? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. While MG reprogram to a state similar to late-stage retinal progenitors in developing retinas, there are transcriptional differences between reprogrammed MG/MGPCs and late progenitors, as well as reprogrammed MG in outer and inner retinal damage models. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes. This work identifies major differences between gene regulatory networks activated following the selective loss of different subtypes of retina neurons, as well as between retinal regeneration and development.
Heterogeneity of synaptic NMDA receptor responses within individual lamina I pain processing neurons across sex in rats and humans
Authors: Dedek Annemarie , Topcu Emine , Dedek Christopher , McDermott Jeff S. , Krajewski Jeffrey L. , Tsai Eve C. , Hildebrand Michael E.
Published: August 2023

Excitatory glutamatergic NMDA receptors (NMDARs) are key regulators of spinal pain processing, and yet the biophysical properties of NMDARs in dorsal horn nociceptive neurons remain poorly understood. Despite the clinical implications, it is unknown whether the molecular and functional properties of NMDAR synaptic responses are conserved between males and females as well as from rodents to humans. To address these translational gaps, we systematically compared individual and averaged excitatory synaptic responses from lamina I pain-processing neurons of adult Sprague Dawley rats and human organ donors, including both sexes. By combining patch-clamp recordings of outward miniature excitatory postsynaptic currents with non-biased data analyses, we uncovered a wide range of decay constants of excitatory synaptic events within individual lamina I neurons. Decay constants of quantal synaptic responses were distributed in a continuum from 1-20 ms to greater than 1000 ms, suggesting that individual lamina I neurons contain AMPA receptor (AMPAR)-only as well as GluN2A-, GluN2B-, and GluN2D-NMDAR-dominated synaptic events. This intraneuronal heterogeneity in AMPAR– and NMDAR-mediated decay kinetics was observed across sex and species. However, we discovered a decreased relative contribution of GluN2B-dominated NMDAR responses as well as larger amplitude GluN2D-like events at human lamina I synapses compared to rodent synapses, suggesting species differences relevant to NMDAR subunit-targeting therapeutic approaches. The conserved heterogeneity in decay rates of excitatory synaptic events within individual lamina I pain-processing neurons may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks.
Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer
Authors: Brás Ana Rita , Lopes Ana , Mendes Nuno , Costa Paulo J. , Ferreira Anabela , Granja Sara , Silva Ana Paula , Tortosa Francisco , Baltazar Fátima , Gärtner Fátima , Sousa Maria João , Valente Andreia , Preto Ana
Published: August 2023

KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a new ruthenium compound, PMC79, that inhibits specifically mutated KRAS and the downstream signaling ERK and AKT proteins both “in vitro” and “in vivo”. We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. “In vivo” PMC79 “proof of concept” showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new “magic bullet” for CRCs harboring mutated KRAS.
Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases
Authors: Betancurt-Anzola Leonardo , Martinez-Carranza Markel , Delarue Marc , Zatopek Kelly M. , Gardner Andrew F. , Sauguet Ludovic
Published: August 2023

Replicative DNA polymerases duplicate entire genomes at high fidelity. This feature is shared among the three domains of life and is facilitated by their dual polymerase and exonuclease activities. Family D replicative DNA polymerases (PolD), found exclusively in Archaea, contain an unusual RNA polymerase-like catalytic core, and a unique Mre11-like proofreading active site. Here, we present cryo-EM structures of PolD trapped in a proofreading mode, revealing an unanticipated correction mechanism that extends the repertoire of protein domains known to be involved in DNA proofreading. Based on our experimental structures, mutants of PolD were designed and their contribution to mismatch bypass and exonuclease kinetics was determined. This study sheds light on the convergent evolution of structurally distinct families of DNA polymerases, and the domain acquisition and exchange mechanism that occurred during the evolution of the replisome in the three domains of life.