bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Clinical Characteristics and Outcomes of Idiopathic Acute Pancreatitis
Authors: Anderson Kelsey L. , Shah Ishani , Tintara Supisara , Ahmed Awais , Freedman Steven D. , Kothari Darshan J. , Sheth Sunil G.
Published: April 2023

Objective

Up to 30% of acute pancreatitis (AP) cases do not have an established etiology (idiopathic AP [IAP]). We evaluated the characteristics and outcomes of hospitalized IAP patients compared with those with established AP cause (non-IAP).

Methods

A retrospective study of AP patients admitted to a single center from 2008 to 2018 was performed. Patients were divided into IAP and non-IAP groups. Outcomes included mortality, 30-day and 1-year readmission, length of stay (LOS), intensive care unit admissions, and complications.

Results

Of 878 AP patients, 338 had IAP and 540 non-IAP (234 gallstone, 178 alcohol). Groups had similar demographics, Charlson Comorbidity Index, and pancreatitis severity. The IAP patients had more 1-year readmissions (0.64 vs 0.55, P = 0.006) but similar 30-day readmissions and mortality. Patients with IAP had shorter LOS (4.98 vs 5.99 days, P = 0.01), and fewer intensive care unit admissions (3.25% vs 6.85%, P = 0.03) and extrapancreatic complications (15.4% vs 25.2%, P = 0.001). There was no difference in pain level between groups.

Conclusions

The IAP patients tend to have more readmissions in 1 year, but less severe presentations, shorter LOS, and fewer complications. Readmission rates may be related to lack of defined etiology and treatment to prevent recurrence.
Cytokine-Induced Killer Cell Immunotherapy Combined With Gemcitabine Reduces Systemic Metastasis in Pancreatic Cancer
Authors: Choi Jin Ho , Nam Gun He , Hong Jun-man , Cho In Rae , Paik Woo Hyun , Ryu Ji Kon , Kim Yong-Tae , Lee Sang Hyub
Published: April 2023

Objectives

To evaluate the efficacy and safety of cytokine-induced killer (CIK) cell therapy in pancreatic cancer.

Methods

An orthotopic murine model of pancreatic cancer and adjuvant therapy-mimicking xenograft murine model that underwent splenectomy was created. Eighty mice were randomized into four groups: the control, gemcitabine alone, CIK alone, and CIK with gemcitabine groups. The tumor growth was monitored using bioluminescence imaging once weekly.

Results

In the orthotopic murine model, the treatment groups showed a significantly longer survival than the control group (median: not reached vs 125.0 days; 95% confidence interval, 119.87–130.13; P = 0.04); however, the overall survival did not differ significantly among the treatment groups (P = 0.779). The metastatic recurrence rate and overall survival were also not significantly different among the groups in the adjuvant therapy-mimicking xenograft murine model (P = 0.497). However, the CIK and gemcitabine combination suppressed the metastatic recurrence effectively, with recurrence-free survival being significantly longer in the CIK with gemcitabine group than in the control group (median, 54 days; 95% confidence interval, 25.00–102.00; P = 0.013).

Conclusions

The combination of CIK and gemcitabine suppressed systemic metastatic recurrence, with promising efficacy and good tolerability in an adjuvant setting of pancreatic cancer.
Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis
Authors: Neubauer Claudia , Ewers Maren , Schulz Hans-Ulrich , Weiß Frank Ulrich , Lämmerhirt Felix , Lerch Markus M. , Bugert Peter , Landt Olfert , Algül Hana , Rosendahl Jonas , Witt Heiko
Published: April 2023

Objectives

Human and animal studies suggest an important role of autophagy in the pathogenesis of pancreatitis. ATG16L1 (autophagy-related 16 like 1) is part of a protein complex that is involved in the formation of autophagosomes. The c.898A > G (p.T300A) variant of ATG16L1 is associated with Crohn disease. In this study, we analyzed ATG16L1 c.898A > G (p.T300A) for an association with pancreatitis.

Methods

We genotyped 777 patients and 551 control subjects of German origin by melting curve analysis using fluorescence resonance energy transfer probes. The patient group included 429 patients with nonalcoholic chronic pancreatitis (CP), 141 patients with alcoholic CP, and 207 patients with acute pancreatitis (AP). We classified AP by severity according to the Atlanta symposium 1992.

Results

Allele and genotype frequencies of ATG16L1 c.898A > G (p.T300A) did not differ significantly between patients and controls (G allele frequencies: nonalcoholic CP, 49.9%; alcoholic CP, 48.2%; AP, 49.5%; controls, 52.7%). We found no significant association with the severity of AP either.

Conclusions

Our data do not support a role of ATG16L1 c.898A > G (p.T300A) in the pathogenesis of AP or CP or an influence on the severity of AP.
The Association Between COVID-19 and Febrile Seizure
Authors: Hanlon Sean M. , Sim Don , Schneider Jack G. , Yang Ziyi , Thompson Sean M.
Published: April 2023

Background/Objective

Throughout the pandemic, febrile seizures have resulted from infection secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The objective of this study is to determine if there is an increased association between COVID-19 and febrile seizures as compared with other causes of febrile seizures.

Methods

This was a retrospective case control study. Data were collected from the National Institute of Health (NIH) supported National COVID Cohort Collaborative (N3C). Patients from 6 to 60 months who were tested for COVID-19 were included; cases were defined as COVID-19–positive patients whereas controls were defined as COVID-19–negative patients. Febrile seizures diagnosed within 48 hours of the COVID-19 test were considered to be associated with the test result. Patients were subjected to a stratified gender and date matching design followed by a logistic regression controlling for age and race.

Results

During the study period, 27,692 patients were included. Of those, 6923 patients were COVID-19–positive, among which 189 had febrile seizures (2.7%). After logistic regression, the likelihood of having febrile seizures concurrently with COVID-19 as compared with other causes was 0.96 (P = 0.949; confidence interval, 0.81, 1.14).

Conclusions

There were 2.7% of the patients with COVID-19 that were diagnosed with a febrile seizure. However, when subjected to a matched case control design with logistic regression controlling for confounding variables, there does not appear to be an increased risk of febrile seizures secondary to COVID-19 as compared with other causes.
Self-Efficacy in the Cannulation Technique for Intraosseous Access in Pediatric Cardiac Arrest
Authors: Márquez-Hernández Verónica V. , Gutiérrez-Puertas Lorena , García-Viola Alba , Garrido-Molina José Miguel , Gutiérrez-Puertas Vanesa , Aguilera-Manrique Gabriel , Rodríguez-García Ma. Carmen
Published: April 2023

Objectives

The use of intraosseous (IO) access is recommended in cardiac arrest when peripheral venous access is not accessible. Various methodologies exist that are used for teaching and learning about cannulation of the IO route both in education and in research. The purpose of the present study was to compare self-efficacy in the cannulation technique for IO access through different techniques.

Methods

A randomized comparative study was conducted. A total of 118 nursing students participated. The participants were randomly distributed into 2 intervention groups: chicken bone and egg. A checklist was used for data collection to evaluate the IO cannulation technique in nursing students and another to analyze self-efficacy.

Results

The average total score of self-efficacy for all participants was 8.84 (standard deviation (SD) = 0.98). No statistically significant differences were found when comparing the total self-efficacy score and the intervention group (U = 1604.500; z = −0.733; P = 0.463). No statistically significant differences were found between both groups for the average total score of the procedure (U = 6916.500; z = −0.939; P = 0.348). The egg group carried out the IO cannulation procedure in a significantly less amount of time (M = 126.88, SD = 82.18) than the chicken bone group (M = 183.77, SD = 108.28), finding statistically significant differences (U = 4983.500; z = −5.326; P < 0.001).

Conclusions

Using an egg to teach and learn about IO access could be considered a methodology that is equally effective as using a chicken bone, with the advantage of achieving IO access in a lesser amount of time.
Diagnostic Yield of Abdominal Radiographs in the Pediatric Emergency Department
Authors: Kubiszewski Kacper , Patterson Suzannah , Chalise Sweta , Rivera-Sepulveda Andrea
Published: April 2023

Background and objectives

Abdominal radiographs (ARs) are commonly used in the pediatric emergency department (PED). Their low diagnostic accuracy leads to overuse, excess radiation exposure, and increased resource usage. This study aims to assess the diagnostic yield of ARs in the evaluation of intraabdominal pathology in the PED.

Methods

Retrospective, cross-sectional study of patients aged 0 to 18 years with an AR who visited the PED between 2017 and 2019. Diagnostic yield was analyzed with sensitivity, specificity, positive predictive value, negative predictive value (NPV), and likelihood ratio.

Results

A total of 4288 ARs were identified, with a rate of 6%. The overall abnormal AR rate was 31%. The incidences of an abnormal AR in abdominal pain, vomiting, and constipation were 26%, 37%, and 50%, respectively. There was a 13% rate of clinically significant diagnoses. The AR diagnostic yield showed 44% sensitivity, 70% specificity, 17% positive predictive value, and 90% NPV (P< 0.05). Unadjusted odds ratio analysis of positive AR and abdominal pain, vomiting, and constipation revealed an odds ratio of 0.68 (95% confidence interval [CI], 0.63–0.75), 1.22 (95% CI, 1.06–1.39), and 1.72 (95% CI, 1.54–1.91), respectively.

Conclusions

There is a low rate of intraabdominal pathologic processes that an AR can identify. A normal AR does not change patient management, nor does it reduce the need for further radiologic imaging. Despite a good NPV, the AR is not a useful diagnostic tool in the PED because of its limited ability to rule in or rule out clinically significant diagnoses.
Occupational Characteristics Associated With Professional Fulfillment and Burnout Among US Physiatrists
Authors: Makowski Maryam S. , Trockel Mickey , Paganoni Sabrina , Weinstein Stuart , Verduzco-Gutierrez Monica , Kinney Carolyn , Kennedy David J. , Sliwa James , Wang Hanhan , Knowlton Tiffany , Stautzenbach Tom , Shanafelt Tait D.
Published: April 2023

Introduction

Multiple national studies suggest that among physicians, physiatrists are at increased risk for occupational burnout.

Objective

The aim of the study is to identify characteristics of the work environment associated with professional fulfillment and burnout among US physiatrists.

Design

Between May and December 2021, a mixed qualitative and quantitative approach was used to identify factors contributing to professional fulfillment and burnout in physiatrists.

Setting

Online interviews, focus groups, and survey were conducted.

Participants

The participants are physiatrists in the American Academy of Physical Medicine and Rehabilitation Membership Masterfile.

Main Outcome Measures

Burnout and professional fulfillment were assessed using the Stanford Professional Fulfillment Index.

Results

Individual interviews with 21 physiatrists were conducted to identify domains that contributed to professional fulfillment followed by focus groups for further definition. Based on themes identified, scales were identified or developed to evaluate: control over schedule (6 items, Cronbach α = 0.86); integration of physiatry into patient care (3 items, Cronbach α = 0.71); personal-organizational values alignment (3 items, Cronbach α = 0.90); meaningfulness of physiatrist clinical work (6 items, Cronbach α = 0.90); teamwork and collaboration (3 items, Cronbach α = 0.89). Of 5760 physiatrists contacted in the subsequent national survey, 882 (15.4%) returned surveys (median age, 52 yrs; 46.1% women). Overall, 42.6% (336 of 788) experienced burnout and 30.6% (244 of 798) had high levels of professional fulfillment. In multivariable analysis, each one-point improvement in control over schedule (odds ratio = 1.96; 95% confidence interval = 1.45–2.69), integration of physiatry into patient care (odds ratio = 1.77; 95% confidence interval = 1.32–2.38), personal-organizational values alignment (odds ratio = 1.92; 95% confidence interval = 1.48–2.52), meaningfulness of physiatrist clinical work (odds ratio = 2.79; 95% confidence interval = 1.71–4.71), and teamwork and collaboration score (odds ratio = 2.11; 95% confidence interval = 1.48–3.03) was independently associated with higher likelihood of professional fulfillment.

Conclusions

Control over schedule, optimal integration of physiatry into clinical care, personal-organizational values alignment, teamwork, and meaningfulness of physiatrist clinical work are strong and independent drivers of occupational well-being in US physiatrists. Variation in these domains by practice setting and subspecialty suggests that tailored approaches are needed to promote professional fulfillment and reduce burnout among US physiatrists.
PROTECTIVE EFFECTS OF HUMANIN-G IN HEMORRHAGIC SHOCK IN FEMALE MICE VIA AMPKα1-INDEPENDENT MECHANISMS
Authors: Wagner Monica L. , Ammann Allison , Piraino Giovanna , Wolfe Vivian , O'Connor Michael , Lahni Patrick , Ziady Assem , Zingarelli Basilia
Published: April 2023

Introduction: Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. We previously showed that the α1 subunit of AMP-activated protein kinase (AMPK), a crucial regulator of mitochondrial function, exerts a protective role in hemorrhagic shock. Humanin is a mitochondrial peptide with cytoprotective properties against cellular stress. Here, we investigated whether AMPKα1 influences systemic levels of endogenous humanin in hemorrhagic shock and whether treatment with the synthetic analog humanin-G affords beneficial effects. Methods: AMPKα1 wild-type (WT) and knockout (KO) female mice were subjected to hemorrhagic shock followed by resuscitation with blood and lactated Ringer's solution. In short-term studies, mice were treated with humanin-G or vehicle and sacrificed at 3 h after resuscitation; in survival studies, mice were treated with PEGylated humanin-G and monitored for 7 days. Results: Compared with the vehicle WT group, KO mice exhibited severe hypotension, cardiac mitochondrial damage, and higher plasma levels of Th17 cytokines but had similar lung injury and similar plasma elevation of endogenous humanin. Treatment with humanin-G improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice, without affecting systemic cytokine or humanin levels. Humanin-G also ameliorated cardiac mitochondrial damage and increased adenosine triphosphate levels in KO mice. Beneficial effects of humanin-G were associated with lung cytoplasmic and nuclear activation of the signal transducer and activator of transcription-3 (STAT3) in AMPKα1-independent manner with marginal or no effects on mitochondrial STAT3 and complex I subunit GRIM-19. Conclusions: Our data indicate that circulating levels of humanin increase during hemorrhagic shock in AMPKα1-independent fashion as a defense mechanism to counteract metabolic derangement and that administration of humanin-G affords beneficial effects through STAT3 activation even in the absence of a functional AMPKα1.
Is severe traumatic brain injury no longer a contraindication for surgical stabilization of rib fractures in patients with multiple rib fractures? A propensity-matched analysis
Authors: Lagazzi Emanuele , de Roulet Amory , Proaño-Zamudio Jefferson A. , Argandykov Dias , Romijn Anne-Sophie , Abiad May , Rafaqat Wardah , Hwabejire John O. , Velmahos George C. , Paranjape Charudutt
Published: April 2023

BACKGROUND

Traumatic brain injury (TBI) is often considered a contraindication to surgical stabilization of rib fractures (SSRF). In this study, we hypothesized that, compared with nonoperative management, SSRF is associated with improved outcomes in TBI patients.

METHODS

Using the American College of Surgeons Trauma Quality Improvement Program 2016–2019, we performed a retrospective analysis of patients with concurrent TBI and multiple rib fractures. Following propensity score matching, we compared patients who underwent SSRF with those who were managed nonoperatively. Our primary outcome was mortality. Secondary outcomes included ventilator-associated pneumonia, hospital and intensive care unit (ICU) length of stay (LOS), ventilator days, tracheostomy rate, and hospital discharge disposition. In a subgroup analysis, we stratified patients into mild and moderate TBI (GCS score >8) and severe TBI (GCS score ≤8).

RESULTS

Of 36,088 patients included in this study, 879 (2.4%) underwent SSRF. After propensity-score matching, compared with nonoperative management, SSRF was associated with decreased mortality (5.4% vs. 14.5%,p < 0.001), increased hospital LOS (15 days vs. 9 days, p < 0.001), increased ICU LOS (12 days vs. 8 days, p < 0.001), and increased ventilator days (7 days vs. 4 days, p < 0.001). In the subgroup analyses, in mild and moderate TBI, SSRF was associated with decreased in-hospital mortality (5.0% vs. 9.9%, p = 0.006), increased hospital LOS (13 days vs. 9 days, p < 0.001), ICU LOS (10 days vs. 7 days, p < 0.001), and ventilator days (5 days vs. 2 days, p < 0.001). In patients with severe TBI, SSRF was associated with decreased mortality (6.2% vs. 18%, p < 0.001), increased hospital LOS (20 days vs. 14 days, p = 0.001), and increased ICU LOS (16 days vs. 13 days, p = 0.004).

CONCLUSION

In patients with TBI and multiple rib fractures, SSRF is associated with a significant decrease in in-hospital mortality and with longer hospital and ICU LOSs. These findings suggest that SSRF should be considered in patients with TBI and multiple rib fractures.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Long COVID and especially headache syndromes
Authors: Tana Claudio , Giamberardino Maria Adele , Martelletti Paolo
Published: April 2023

Purpose of review

This is an expert overview on recent literature about the complex relationship between coronavirus disease 2019 (COVID-19) and headache.

Recent findings

Long COVID is a clinical syndrome characterized by the presence of persistent symptoms following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Headache is one of the most common symptoms and is described most often as throbbing pain, associated with photo and phonofobia and worsening with physical exercise. In acute COVID-19, headache is usually described as moderate or severe, diffuse and oppressive although sometimes it has been described with a migraine-like phenotype, especially in patients with a previous history of migraine. Headache intensity during acute phase seems to be the most important predictor of duration of headache over time. Some COVID-19 cases can be associated with cerebrovascular complications, and red flags of secondary headaches (e.g. new worsening or unresponsive headache, or new onset of neurological focal signs) should be urgently investigated with imaging. Treatment goals are the reduction of number and intensity of headache crises, and the prevention of chronic forms.

This review can help clinicians to approach patients with headache and infection from SARS-CoV-2, with particular attention to persistent headache in long COVID.
Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series
Authors: Cohen Devon A. , Tajfirouz Deena , Vodopivec Ivana , Kyle Kevin , Bouffard Marc A. , Bhattacharyya Shamik , Douglas Vanja C. , Rasool Nailyn , Bhatti M. Tariq , McKeon Andrew , Pittock Sean , Flanagan Eoin P. , Prasad Sashank , Nagagopal Venna , Egan Robert A. , Chen John J. , Chwalisz Bart K.
Published: April 2023

Background:

Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA.

Methods:

This multicenter, retrospective case series was institutional review board–approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse.

Results:

Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21–63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%).

Conclusions:

New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.
Dyadobacter pollutisoli sp. nov., isolated from plastic waste landfill soil
Authors: Kim Kyeong Ryeol , Kim Jeong Min , Lee Jae Kyeong , Han Dong Min , Hao Lujiang , Jeon Che Ok
Published: April 2023

A Gram-stain-negative, yellow-pigmented and facultatively aerobic bacterium, designated strain U1T, was isolated from plastic dumped soil sampled in the Republic of Korea. Cell of strain U1T were non-motile rods showing catalase-negative and oxidase-positive activities. Strain U1T was shown to grow at 10–37 °C (optimum, 25–30 °C) and pH 6.0–9.0 (optimum, pH 8.0), and in the presence of 0–0.5 % (w/v) NaCl (optimum, 0 %). Strain U1T contained iso-C15 : 0, C16 : 0, C16 : 1 ω5c and summed feature 3 (comprising C16 : 1
 ω6c and/or C16 : 1 ω7c) as the major cellular fatty acids (>5 %) and menaquinone-7 as the sole respiratory quinone. Phosphatidylethanolamine, two unidentified aminolipids and three unidentified lipids were identified as the major polar lipids. The DNA G+C content of strain U1T calculated from the whole-genome sequence was 45.5 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain U1T formed a distinct phylogenetic lineage within the genus

Dyadobacter

. Strain U1T has the highest 16S rRNA sequence similarity to

Dyadobacter bucti

QTA69T (97.9 %). Average nucleotide identity and digital DNA–DNA hybridization values between strain U1T and

D. bucti

QTA69T were 74.6 % and 18.9 %, respectively. Based on phenotypic, chemotaxonomic and molecular features, strain U1T represents a novel species of the genus

Dyadobacter

, for which the name Dyadobacter pollutisoli sp. nov. is proposed. The type strain is U1T (= KACC 22210T=JCM 34491T).
Aeoliella straminimaris sp. nov., a novel member of the phylum Planctomycetota with an unusual filamentous structure
Authors: Vitorino Inês Rosado , Lobo-da-Cunha Alexandre , Vasconcelos Vítor , Lage Olga Maria
Published: April 2023

Organisms with distinctive biological features and cellular organization constitute the bacterial phylum

Planctomycetota

. In this study, we formally describe a novel isolate, strain ICT_H6.2T, isolated from sediment samples collected in the brackish environment of the Tagus River estuary (Portugal) using an iChip-based culturing technique. The 16S rRNA gene analysis placed this strain into the phylum

Planctomycetota

and family

Lacipirellulaceae

, with a similarity value of 98.0 % to its closest relative

Aeoliella mucimassa

Pan181T, the currently only known member of the genus. Strain ICT_H6.2T has a genome size of 7.8 Mbp and a DNA G+C content of 59.6 mol %. Strain ICT_H6.2T is heterotrophic, aerobic and capable of microaerobic growth. This strain grows from 10 to 37 °C and from pH 6.5 to 10.0, requires salt to grow, and can tolerate up to 4 % (w/v) NaCl. Diverse nitrogen and carbon sources are utilized for growth. Morphologically, strain ICT_H6.2T is white to beige pigmented, spherical to ovoid in shape and around 1.4×1.1 µm in size. The strain clusters mainly in aggregates and younger cells show motility. Ultrastructural studies showed a cell plan with cytoplasmatic membrane invaginations and unusual filamentous structures with hexagonal organization in transversal section. Morphological, physiological and genomic comparison between strain ICT_H6.2T and its closest relatives strongly suggests it represents a novel species within the genus

Aeoliella

, for which we propose the name Aeoliella straminimaris sp. nov., represented by strain ICT_H6.2T as the type strain (=CECT 30574T=DSM 114064T).
Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea
Authors: Kim Jonguk , Kim Jun Yup , Kang Jihoon , Kim Beom Joon , Han Moon-Ku , Lee Jeong-Yoon , Park Tai Hwan , Lee Ji Sung , Lee Keon-Joo , Kim Joon-Tae , Choi Kang-Ho , Park Jong-Moo , Kang Kyusik , Lee Soo Joo , Kim Jae Guk , Cha Jae-Kwan , Kim Dae-Hyun , Lee Kyungbok , Lee Jun , Hong Keun-Sik , Cho Yong-Jin , Park Hong-Kyun , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi-Sun , Kim Dong-Eog , Ryu Wi-Sun , Choi Jay Chol , Kwon Jee-Hyun , Kim Wook-Joo , Shin Dong-Ick , Yum Kyu Sun , Sohn Sung Il , Hong Jeong-ho , Lee Sang-Hwa , Lee Juneyoung , Gorelick Philip B. , Bae Hee-Joon
Published: April 2023

Background

There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke (AIS). This study investigated whether advances in these treatments improved outcomes in this population.

Methods

Using a prospective multicenter stroke registry in Korea, young adults (aged 18–50 years) with AIS hospitalized between 2008 and 2019 were identified. The observation period was divided into four epochs: 2008–2010, 2011–2013, 2014–2016, and 2017–2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed.

Results

A total of 7,050 eligible patients (mean age 43.1; men 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008–2010 to 2017–2019 (9.5% to 13.8% and 3.2% to 9.2%, respectively; Ptrend’s<0.01). Door-to-needle time improved (Ptrend<.001), but onset-to-door and door-to-puncture time remained constant. Secondary prevention including the administration of dual antiplatelets for noncardioembolic minor stroke (26.7% to 47.0%), direct oral anticoagulants for atrial fibrillation (0.0% to 56.2%), and statins for large artery atherosclerosis (76.1% to 95.3%) increased (Ptrend’s<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011–2013 and 2.3% in 2017–2019) and 3-month modified Rankin scale scores 0–1 (68.3% to 69.1%) and 0–2 (87.6% to 86.2%) remained unchanged. The one-year stroke recurrence rate increased (4.1% to 5.5%, Ptrend=0.04), altough the differnce was not significant after adjusting for sex and age.

Conclusion

Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with AIS over the past decade, indicating a need for further progress.
Ki-67 is necessary during DNA replication for forks protection and genome stability
Authors: Stamatiou Konstantinos , Huguet Florentin , Spanos Christos , Rappsilber Juri , Vagnarelli Paola
Published: April 2023

Background

The proliferation antigen Ki-67 has been widely used in clinical settings for cancer staging for many years but investigations on its biological functions have lagged. Recently, Ki-67 was shown to regulate both the composition of the chromosome periphery and chromosome behaviour in mitosis as well as to play a role in heterochromatin organisation and gene transcription. However, a role for Ki-67 in regulating cell cycle progression has never been reported. The progress towards understanding Ki-67 function have been limited by the tools available to deplete the protein coupled to its abundance and fluctuation during the cell cycle.

Results

Here we have used an auxin-inducible degron tag (AID) to achieve a rapid and homogeneous degradation of Ki-67 in HCT116 cells. This system, coupled with APEX2 proteomics and phospho-proteomics approaches, allowed us to show for the first time that Ki-67 plays a role during DNA replication. In its absence, DNA replication is severely delayed, the replication machinery is unloaded, causing DNA damage that is not sensed by the canonical pathways and dependant on HUWE1 ligase. This leads to replication and sister chromatids cohesion defects, but it also triggers an interferon response mediated by the cGAS/STING pathway in all the cell lines tested.

Conclusions

We have unveiled a new function of Ki-67 in DNA replication and genome maintenance that is independent of its previously known role in mitosis and gene regulation.
Spatial-extent inference for testing variance components in reliability and heritability studies
Authors: Pan Ruyi , Dickie Erin W. , Hawco Colin , Reid Nancy , Voineskos Aristotle N. , Park Jun Young
Published: April 2023

Clusterwise inference is a popular approach in neuroimaging to increase sensitivity, but most existing methods are currently restricted to the General Linear Model (GLM) for testing mean parameters. Statistical methods for testingvariance components, which are critical in neuroimaging studies that involve estimation of narrow-sense heritability or test-retest reliability, are underdeveloped due to methodological and computational challenges, which would potentially lead to low power. We propose a fast and powerful test for variance components called CLEAN-V (CLEANfor testingVariance components). CLEAN-V models the global spatial dependence structure of imaging data and computes a locally powerful variance component test statistic by data-adaptively pooling neighborhood information. Correction for multiple comparisons is achieved by permutations to control family-wise error rate (FWER). Through analysis of task-fMRI data from the Human Connectome Project across five tasks and comprehensive data-driven simulations, we show that CLEAN-V outperforms existing methods in detecting test-retest reliability and narrow-sense heritability with significantly improved power, with the detected areas aligning with activation maps. The computational efficiency of CLEAN-V also speaks of its practical utility, and it is available as an R package.
Contigs directed gene annotation (ConDiGA) for accurate protein sequence database construction in metaproteomics
Authors: Wu Enhui , Mallawaarachchi Vijini , Zhao Jinzhi , Yang Yi , Liu Hebin , Wang Xiaoqing , Shen Chengpin , Lin Yu , Qiao Liang
Published: April 2023

Microbiota are closely associated to human health and disease. Metaproteomics can provide a direct means to identify microbial proteins in microbiota for compositional and functional characterization. However, in-depth and accurate metaproteomics is still limited due to the extreme complexity and high diversity of microbiota samples. One of the main challenges is constructing a protein sequence database that best fits the microbiota sample. Herein, we proposed an accurate taxonomic annotation pipeline from metagenomic data for deep metaproteomic coverage, namely contigs directed gene annotation (ConDiGA). We mixed 12 known bacterial species to derive a synthetic microbial community to benchmark metagenomic and metaproteomic pipelines. With the optimized taxonomic annotation strategy by ConDiGA, we built a protein sequence database from the metagenomic data for metaproteomic analysis and identified about 12,000 protein groups, which was very close to the result obtained with the reference proteome protein sequence database of the 12 species. We also demonstrated the practicability of the method in real fecal samples, achieved deep proteome coverage of human gut microbiome, and compared the function and taxonomy of gut microbiota at metagenomic level and metaproteomic level. Our study can tackle the current taxonomic annotation reliability problem in metagenomics-derived protein sequence database for metaproteomics. The unique dataset of metagenomic and the metaproteomic data of the 12 bacterial species is publicly available as a standard benchmarking sample for evaluating various analysis pipelines. The code of ConDiGA is open access at GitHub for the analysis of real microbiota samples.
VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy
Authors: Herrera Alfa , Packer Megan M. , Rosas-Lemus Monica , Minasov George , Brummel John H. , Satchell Karla J. F.
Published: April 2023

Vibrio vulnificuscauses life threatening infections dependent upon the effectors released from the Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The Makes Caterpillars Floppy-like (MCF) cysteine protease effector is activated by host ADP ribosylation factors (ARFs), although the targets of processing activity were unknown. In this study we show MCF bindsRas-related proteins inbrain (Rab) GTPases at the same interface occupied by ARFs and then cleaves and/or degrades 24 distinct members of the Rab GTPases family. The cleavage occurs in the C-terminal tails of Rabs. We determine the crystal structure of MCF as a swapped dimer revealing the open, activated state of MCF and then use structure prediction algorithms to show that structural composition, rather than sequence or localization, determine Rabs selected as MCF proteolytic targets. Once cleaved, Rabs become dispersed in cells to drive organelle damage and cell death to promote pathogenesis of these rapidly fatal infections.
Upregulated NF-κB pathway proteins may underlieAPOE44associated astrocyte phenotypes in sporadic Alzheimer’s disease
Authors: Roberts Adele Pryce , Dec Karolina , McAllister Branduff , Tyrrell Victoria , O’Donnell Valerie B , Harwood Adrian , Williams Julie
Published: April 2023

The Apolipoprotein-E4 allele (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s disease but its role in disease pathogenesis is incompletely understood. TheAPOEgene encodes Apolipoprotein E (ApoE). Astrocytes are the main source of ApoE in the central nervous system (CNS) and are essential for homeostasis in health and disease. In response to CNS insult, a coordinated multicellular inflammatory response is triggered causing reactive astrogliosis with changes in astrocytic gene expression, cellular structure and function.

Human embryonic stem-cells with the ‘neutral’APOE33genotype were edited using CRISPR Cas-9 gene-editing to create isogenicAPOElines with an APOE44 genotype. Quiescent astrocytes were differentiated then stimulated with TNF-α, IL1α and C1q inducing an astrogliotic A1 phenotype. Several potentially pathologicalAPOE44-related phenotypes were identified in both quiescent cells and reactive A1 astrocytes including significantly decreased phagocytosis, impaired glutamate and a defective immunomodulatory response.

In quiescentAPOE44astrocytes there was significantly decreased secretion of IL6, IL8 and several oxylipins. In A1 astrocytes there was a pro-inflammatory phenotype in APOE44 astrocytes with increases in GRO, ENA78, IL6 and IL8, a decrease in IL10 as well as significant differences in oxylipin expression. As TNF-α induced signaling in astrocytes is driven by Nuclear factor kappa B (NF-κB) proteins of this pathway were measured. Significantly higher levels of the p50, p65 and IκBα sub-units were found in both quiescent and A1APOE44astrocytes. This suggests that perturbation of NF-κB signaling may contribute to the damagingAPOE44cell phenotypes observed providing a new direction for targeted disease therapeutics.
Wnt5a-Ror2 signaling activates p62-Nrf2 axis in reactive astrocytes after brain injury
Authors: Endo Mitsuharu , Tanaka Yuki , Fukuoka Mayo , Suzuki Hayata , Minami Yasuhiro
Published: April 2023

In the brains under pathological conditions, astrocytes become reactive astrocytes that exhibit various context-dependent functions through the regulation of specific signaling pathways and transcriptional mechanisms in response to environmental changes. Reactive astrocytes induced in injured brains begin proliferating and play a role in promoting protection and repair of damaged tissues, but the relationship between the proliferative characteristics and tissue-protective and repair functions of reactive astrocytes remains unclear. Here, we show that growth factor signaling elicited by bFGF and HB-EGF, whose expression is up-regulated in the injured brains, acts synergistically with inflammatory cytokine signaling in astrocytes, thereby markedly up-regulating gene expression of the Ror-family protein Ror2, a receptor for Wnt5a. Activation of Wnt5a-Ror2 signaling in astrocytes results in intracellular accumulation of phosphorylated p62, thereby activating antioxidative transcription factor Nrf2. Finally, we provide evidence demonstrating that forced activation of Wnt5a-Ror2-p62-Nrf2 signaling axis in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
A Comprehensive Benchmark Study on Biomedical Text Generation and Mining with ChatGPT
Authors: Chen Qijie , Sun Haotong , Liu Haoyang , Jiang Yinghui , Ran Ting , Jin Xurui , Xiao Xianglu , Lin Zhimin , Niu Zhangming , Chen Hongming
Published: April 2023

In recent years, the development of natural language process (NLP) technologies and deep learning hardware has led to significant improvement in large language models(LLMs). The ChatGPT, the state-of-the-art LLM built on GPT-3.5, shows excellent capabilities in general language understanding and reasoning. Researchers also tested the GPTs on a variety of NLP related tasks and benchmarks and got excellent results. To evaluate the performance of ChatGPT on biomedical related tasks, this paper presents a comprehensive benchmark study on the use of ChatGPT for biomedical corpus, including article abstracts, clinical trials description, biomedical questions and so on. Through a series of experiments, we demonstrated the effectiveness and versatility of Chat-GPT in biomedical text understanding, reasoning and generation.
Neural Extracellular Matrix Remodeling Signatures in Genetic and Acquired Mouse Models of Epilepsy
Authors: Blondiaux Armand , Jia Shaobo , Annamneedi Anil , Çalışkan Gürsel , Schulze Jana , Montenegro-Venegas Carolina , Wykes Robert C. , Fejtova Anna , Walker Matthew C. , Stork Oliver , Gundelfinger Eckart D. , Dityatev Alexander , Seidenbecher Constanze I.
Published: April 2023

Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g., caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brain’s excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutiveBsnmutants and GABAergic neuron-specific knockouts (BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null andBsnDlx5/6cKOmutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link protein Hapln1 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype.
Instant Effects of Semantic Information on Visual Perception
Authors: Enge Alexander , Süß Franziska , Rahman Rasha Abdel
Published: April 2023

Does our perception of an object change once we discover what function it serves? We showed human participants (n= 48, 31 female, 17 male) pictures of unfamiliar objects either together with keywords matching their function, leading to semantically informed perception, or together with non-matching keywords, resulting in uninformed perception. We measured event-related potentials (ERPs) to investigate at which stages in the visual processing hierarchy these two types of object perception differed from one another. We found that semantically informed as compared to uninformed perception was associated with larger amplitudes in the N170 component (150–200 ms), reduced amplitudes in the N400 component (400–700 ms), and a late decrease in alpha/beta band power. When the same objects were presented once more without any information, the N400 and event-related power effects persisted, and we also observed enlarged amplitudes in the P1 component (100–150 ms) in response to objects for which semantically informed perception had taken place. Consistent with previous work, this suggests that obtaining semantic information about previously unfamiliar objects alters aspects of their lower-level visual perception (P1 component), higher-level visual perception (N170 component), and semantic processing (N400 component, event-related power). Our study is the first to show that such effects occur instantly after semantic information has been provided for the first time, without requiring extensive learning.

Significance Statement

There has been a long-standing debate about whether or not higher-level cognitive capacities such as semantic knowledge can influence lower-level perceptual processing in a top-down fashion. Here we could show for the first time that information about the function of previously unfamiliar objects immediately influences cortical processing within less than 200 ms. Of note, this influence does not require training or experience with the objects and related semantic information. Therefore, our study is the first to show effects of cognition on perception while ruling out the possibility that prior knowledge merely acts by pre-activating or altering stored visual representations. Instead, this knowledge seems to alter perception online, thus providing a compelling case against the impenetrability of perception by cognition.
Design principles of Cdr2 node patterns in fission yeast cells
Authors: Opalko Hannah , Geng Shuhan , Hall Aaron R. , Vavylonis Dimitrios , Moseley James B.
Published: April 2023

Pattern forming networks have diverse roles in cell biology. Rod-shaped fission yeast cells use pattern formation to control the localization of mitotic signaling proteins and the cytokinetic ring. During interphase, the kinase Cdr2 forms membrane-bound multiprotein complexes termed nodes, which are positioned in the cell middle due in part to the node inhibitor Pom1 enriched at cell tips. Node positioning is important for timely cell cycle progression and positioning of the cytokinetic ring. Here, we combined experimental and modeling approaches to investigate pattern formation by the Pom1-Cdr2 system. We found that Cdr2 nodes accumulate near the nucleus, and Cdr2 undergoes nucleocytoplasmic shuttling when cortical anchoring is reduced. We generated particle-based simulations based on tip inhibition, nuclear positioning, and cortical anchoring. We tested model predictions by investigating Pom1-Cdr2 localization patterns after perturbing each positioning mechanism, including in both anucleate and multinucleated cells. Experiments show that tip inhibition and cortical anchoring alone are sufficient for the assembly and positioning of nodes in the absence of the nucleus, but that the nucleus and Pom1 facilitate the formation of unexpected node patterns in multinucleated cells. These findings have implications for spatial control of cytokinesis by nodes and for spatial patterning in other biological systems.
Impaired AMPK activity contributes to the inflammatory phenotype and the reduced phagocytosis capacity of VASP-deficient macrophages
Authors: Laban Hebatullah , Frömel Timo , Fleming Ingrid , Benz Peter M.
Published: April 2023

Macrophage polarization plays an important role in tissue regeneration. Numerous factors and signaling molecules affect polarization processes. Here we investigated the consequences of the genetic deletion of vasodilator-stimulated phosphoprotein (VASP), which increases macrophage M1 polarization through augmented signal transducer and activator of transcription 1 (STAT1) signaling, and AMP-activated protein kinase (AMPK), which attenuates inflammation by inhibiting STAT1 expression and signaling. While a basal activity of AMPK (phosphorylation on Thr172) was detected in macrophages from wild-type mice, AMPK phosphorylation was significantly reduced in VASP-deficient M1 macrophagesin vitroand the expression of the pro-inflammatory cytokines TNFα and IL-1β was increased in these cells. Consistent with the role of AMPK in macrophage phagocytosis, VASP-/-macrophage phagocytosis was also significantly impaired. Interestingly, impaired phagocytosis could be rescued by exogenous activation of AMPK. Mechanistically, we found that VASP binds directly to protein phosphatase 1 regulatory subunit 6 (PP1-R6) and we hypothesize that VASP-binding to PP1- R6/PP1 limits the PP1-dependent de-phosphorylation of AMPK in wild-type cells. Conversely, AMPK dephosphorylation by the PP1-R6/PP1 complex is enhanced in the absence of VASP. In summary, we have identified a link between VASP and AMP-activated protein kinase (AMPK) activity, which may contribute to the pro-inflammatory phenotype of VASP-deficient macrophages.