bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiomics for predicting MGMT status in cerebral glioblastoma: comparison of different MRI sequences
Authors: Zheng Fei , Zhang Lingling , Chen Hongyan , Zang Yuying , Chen Xuzhu , Li Yiming
Published: April 2024

Using radiomics to predict O6-methylguanine-DNA methyltransferase promoter methylation status in patients with newly diagnosed glioblastoma and compare the performances of different MRI sequences. Preoperative MRI scans from 215 patients were included in this retrospective study. After image preprocessing and feature extraction, two kinds of machine-learning models were established and compared for their performances. One kind was established using all MRI sequences (T1-weighted image, T2-weighted image, contrast enhancement, fluid-attenuated inversion recovery, DWI_b_high, DWI_b_low and apparent diffusion coefficient), and the other kind was based on single MRI sequence as listed above. For the machine-learning model based on all sequences, a total of seven radiomic features were selected with the Maximum Relevance and Minimum Redundancy algorithm. The predictive accuracy was 0.993 and 0.750 in the training and validation sets, respectively, and the area under curves were 1.000 and 0.754 in the two sets, respectively. For the machine-learning model based on single sequence, the numbers of selected features were 8, 10, 10, 13, 9, 7 and 6 for T1-weighted image, T2-weighted image, contrast enhancement, fluid-attenuated inversion recovery, DWI_b_high, DWI_b_low and apparent diffusion coefficient, respectively, with predictive accuracies of 0.797–1.000 and 0.583–0.694 in the training and validation sets, respectively, and the area under curves of 0.874–1.000 and 0.538–0.697 in the two sets, respectively. Specifically, T1-weighted image-based model performed best, while contrast enhancement-based model performed worst in the independent validation set. The machine-learning models based on seven different single MRI sequences performed differently in predicting O6-methylguanine-DNA methyltransferase status in glioblastoma, while the machine-learning model based on the combination of all sequences performed best.
Realism at the end of the rainbow? An argument towards diversifying hydrogen in EU regulation
Authors: Talus Kim , Pinto Jaqueline , Gallegos Francisca
Published: April 2024

The European Union’s (EU) decarbonization strategy involves hydrogen as an integral pillar. Since hydrogen is a secondary energy carrier, meaning it must be manufactured, not all hydrogen is made equal. Renewable hydrogen or RFNBOs (Renewable Fuel of Non-Biological Origins) have been given high priority by the EU in their strategy to establish a market for hydrogen. The EU’s creation of RFNBO usage objectives is a step towards establishing a demand-side market. One such goal is to bring into the EU up to 10 million tonnes of renewable hydrogen. However, it is doubtful that this large amount can be reached given the strict criteria for what qualifies as renewable hydrogen and, thus, as RFNBO. This article analyses key provisions of the EU framework that affect the EU’s aim to produce and import up to 20 million tonnes of hydrogen overall. It concludes the EU’s emphasis on RFNBOs rather than a broader range of hydrogen pathways undermines the goal of rapidly developing a hydrogen market. Using turquoise hydrogen as a case study, the article shows how the EU’s decarbonization efforts would be aided, trade would be enabled, and fragmentation would be decreased if targets were expanded to encompass additional forms of hydrogen.
Non-canonical bases differentially represented in the sex chromosomes of the dioecious plant Silene latifolia
Authors: Hubinský Marcel , Hobza Roman , Starczak Marta , Gackowski Daniel , Kubát Zdeněk , Janíček Tomáš , Horáková Lucie , Rodriguez Lorenzo Jose Luis
Published: April 2024

The oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), known as oxi-mCs, garners significant interest in plants as potential epigenetic marks. While research in mammals has established a role in cell reprogramming, carcinogenesis, and gene regulation, their functions in plants remain unclear. In rice, 5hmC has been associated with transposable elements (TEs) and heterochromatin. This study utilizes Silene latifolia, a dioecious plant with heteromorphic sex chromosomes and a genome with a large proportion of TEs, which provides a favourable environment for the study of oxi-mCs in individual sexes. Notably, we detected surprisingly high levels of oxi-mCs in S. latifolia comparable with mammals. Nuclei showed enrichment in heterochromatic regions, except for 5hmC whose signal was homogeneously distributed. Intriguingly, the same X chromosome in females displayed overall enrichment of 5hmC and 5fC compared with its counterpart. This fact is shared with 5mC, resembling dosage compensation. Co-localization showed higher correlation between 5mC and 5fC than with 5hmC, indicating no potential relationship between 5hmC and 5fC. Additionally, the promoter of several sex-linked genes and sex-biased TEs clustered in a clear sex-dependent way. Together, these findings unveil a hypothetical role for oxi-mCs in S. latifolia sex chromosome development, warranting further exploration.
Analyzing and Assessing the Current Status of Heat-Related Illnesses in the South Korean Military
Authors: Jung Jae-Hyeop , Lim Hunjong , Hwang Sung Il , Yu Jeong-A
Published: April 2024

Introduction

The population of the Republic of Korea often experiences heat-related illnesses during summer that are exacerbated by significant variations. With rising temperatures attributed to global warming and other environmental changes within the military, combined with the military medical services’ mission to uphold combat capabilities and promote health, it has become crucial to accurately understand the status of heat-related illnesses and integrate more comprehensive and systematic preventive measures. This study aimed to analyze data on heat-related illnesses between 2018 and 2022 to assess and reflect on the said diseases in the South Korean Military.

Materials and Methods

We performed a secondary analysis using data provided by the Defense Medical Statistic Information System. This single-institution retrospective, cross-sectional study was approved by the Institutional Review Board of the Armed Forces Medical Command (approval number: AFMC-2023-11-001).

Results

Over the past 5 years, the annual number of soldiers treated for heat-related illnesses, whether as outpatients or inpatients, at division medical facilities and military hospitals ranged from 846 to 1,250 cases per year. The proportion of severe cases fluctuates annually between 1.1% and 1.8%. Notably, 94 to 96% of all heat-related illnesses were recorded between May and September, with peak rates in July and August.

Conclusion

The army reported the highest number of heat-related illnesses among military branches, with soldiers comprising the majority of cases. This highlights the urgent need for enhanced heat illness prevention measures within army ranks. Notably, the incidence of these illnesses peaked during July and August, underlining the critical periods for intensified preventive efforts.
Iron biology
Authors: Del Vecchio Lucia , Girelli Domenico , Vinchi Francesca , Cozzolino Mario , Elliott Steve , Mark Patrick B , Valenti Luca , Qian Christopher , Guo Qian , Qian Zhong-Ming , Ciceri Paola , Locatelli Francesco
Published: April 2024

Iron is a fundamental element for biological life, from bacteria to humans. Iron is essential for cell function and survival, energy production and metabolism, whereas increased levels cause oxidative stress. It is also a constituent of haemoglobin and thus it is necessary for oxygen transportation through the body. Given these multiple functions, the regulation of iron metabolism is complex and tight coupled with oxygen homeostasis at tissue and cellular levels, thanks to the interaction with the hypoxia inducible factor system. In patients with chronic kidney disease (CKD), iron deficiency significantly contributes to anaemia development. This frequently overlaps with chronic inflammation, causing iron- restricted erythropoiesis. To add further complexity, metabolic hyperferritinemia may, on one hand, increase the risk for CKD and, on the other, overlaps with functional iron deficiency. Excessive intracellular iron in certain cell types during CKD can also mediate cellular death (called ferroptosis), and contribute to the pathogenesis of kidney damage, atherosclerosis and vascular calcifications. This review is aimed at broadening the perspective of iron metabolism in the setting of CKD not just as a contributor to anaemia in CKD patients, but also as an important player with an impact on cell metabolism, renal fibrosis and the cardiovascular system.
Deciphering the Efficacy of β-Lactams in the Face of Metallo-β-Lactamase-Derived Resistance in Enterobacterales: Supraphysiologic Zinc in the Broth Is the Culprit
Authors: Abdelraouf Kamilia , Gill Christian M , Gethers Matthew , Tiseo Giusy , Barnini Simona , Falcone Marco , Menichetti Francesco , Nicolau David P
Published: April 2024

Background

In vitro–in vivo discordance in β-lactams’ activities against metallo-ß-lactamase (MBL)-producing Enterobacterales has been described. We aimed to assess whether this discordance is attributed to the supra-physiologic zinc concentration in in vitro testing media.

Methods

A clinical and microbiological observational study of patients with bloodstream infections due to New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae was performed. Outcomes of patients treated empirically with non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam + aztreonam) were documented. The patients’ isolates were used to induce septicemia in mice, and survival upon meropenem treatment was recorded. Meropenem minimum inhibitory concentrations (MICs) were determined in standard media and in the presence of physiological zinc concentrations.

Results

Twenty-nine patients receiving empiric non-MBL-active β-lactams (median duration, 4 days) were compared with 29 receiving MBL-active β-lactams. The 14-day mortality rates were 21% and 14%, respectively. In the murine septicemia model, meropenem treatment resulted in protection from mortality (P < .0001). Meropenem MICs in the physiologic zinc concentration broth were 1- to >16-fold lower vs MICs in zinc-unadjusted broth (≥64 mg/L).

Conclusions

Our data provide foundational support to establish pharmacokinetic/pharmacodynamic relationships using MICs derived in physiologic zinc concentration, which may better predict β-lactam therapy outcome.
Brentuximab vedotin for skin involvement in refractory diffuse cutaneous systemic sclerosis, an open-label trial
Authors: Fernández-Codina Andreu , Nevskaya Tatiana , Baron Murray , Appleton C Thomas , Cecchini Matthew J , Philip Amanda , El-Shimy Maha , Vanderhoek Louise , Pinal-Fernández Iago , Pope Janet E
Published: April 2024

Objective

We explored the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous systemic sclerosis (dcSSc).

Methods

This phase II proof-of-concept, single centre, open-label, single arm, investigator-initiated trial included patients ≥18 years, with dcSSc, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud’s symptom and/or skin worsening despite immunosuppression who were treated with intravenous brentuximab vedotin 0.6 mg/kg q3 weeks for 45 weeks. The primary end point was a decrease in mRSS of ≥8 points at 48 weeks.

Results

Eleven patients were treated with brentuximab vedotin, with nine completing the study. The mean mRSS reduction at week 48 was 11.3 (95% CI 6.9, 15.8; P = 0.001), meeting the primary end point in the intention to treat analysis (7/11 had a decrease in mRSS ≥8). The % forced vital capacity increased by 7.8% (12.5). The Composite Response Index in dcSSc (CRISS) suggested a beneficial treatment effect (86% ≥0.6). Most adverse events were mild. No SAEs were attributed to brentuximab vedotin.

Conclusion

In dcSSc, brentuximab vedotin improved skin and FVC without safety concerns. A placebo-controlled trial is warranted to corroborate these initial findings.

Trial registration

ClinicalTrials.gov, http://clinicaltrials.gov, NCT03198689.
Association of the multi-biomarker disease activity score with arterial 18-fluorodeoxyglucose uptake in rheumatoid arthritis
Authors: Giles Jon T , Solomon Daniel H , Liao Katherine P , Rist Pamela M , Fayad Zahi A , Tawakol Ahmed , Bathon Joan M
Published: April 2024

Objectives

Rheumatoid arthritis (RA) and atherosclerosis share many common inflammatory pathways. We studied whether a multi-biomarker panel for RA disease activity (MBDA) would associate with changes in arterial inflammation in an interventional trial.

Methods

In the TARGET Trial, RA patients with active disease despite methotrexate were randomly assigned to the addition of either a TNF inhibitor or sulfasalazine+hydroxychloroquine (triple therapy). Baseline and 24-week follow-up [18F]fluorodeoxyglucose–PET/CT scans were assessed for change in arterial inflammation measured as the maximal arterial target-to-blood background ratio of FDG uptake in the most diseased segment of the carotid arteries or aorta (MDS-TBRmax). The MBDA test, measured at baseline and weeks 6, 18 and 24, was assessed for its association with the change in MDS-TBRmax.

Results

Interpretable scans were available at baseline and week 24 for 112 patients. The MBDA score at week 24 was significantly correlated with the change in MDS-TBRmax (Spearman’s rho = 0.239; P = 0.011) and remained significantly associated after adjustment for relevant confounders. Those with low MBDA at week 24 had a statistically significant adjusted reduction in arterial inflammation of 0.35 units vs no significant reduction in those who did not achieve low MBDA. Neither DAS28-CRP nor CRP predicted change in arterial inflammation. The MBDA component with the strongest association with change in arterial inflammation was serum amyloid A.

Conclusion

Among treated RA patients, achieved MBDA predicts changes in arterial inflammation. Achieving low MBDA at 24 weeks was associated with clinically meaningful reductions in arterial inflammation, regardless of treatment.
Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis
Authors: Yin Nuoming , Xu Binqiang , Huang Zehua , Fu Yang , Huang Huizheng , Fan Junjie , Huang Chunlan , Mei Qixiang , Zeng Yue
Published: April 2024

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L‐arginine‐induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up‐regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D‐lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C‐reactive protein. Inhibition of Pck1 by 3‐Mercaptopicolinic acid hydrochloride (3‐MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3‐MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D‐lactate, endotoxin, and FITC‐Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3‐MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3‐MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.
Preventing Iatrogenic Injury to the Vertebral Artery in Cervical Spine Surgery
Authors: Garg Sahil , Maniakhina Lana , Muir Sean M. , Gill Arianna K. , Gill Sonny S.
Published: April 2024

Summary of Background Data:

Iatrogenic injury of the vertebral artery (VA) in the context of surgical approaches to the cervical spine has been cited as a relatively rare complication with varying degrees of severity ranging from minimal injury to acute stroke and can result in death. It is estimated that ~50% of cases of iatrogenic VA injury are preventable after postoperatively examining a patient’s preoperative imaging. Despite the low incidence (<2%) of this complication, the potential associated morbidity demonstrates the importance of meticulous preoperative vascular consideration.

Objective:

This study aims to emphasize the importance of preoperative vascular screening during anterior cervical access planning visualized through a rare case of a VA aberration in a 47-year-old patient.

Study Design:

This study is designed as a retrospective case report.

Methods:

A thorough chart review was performed for this subject including all prior medical records, imaging studies, imaging reports, operative notes, and communication records.

Results:

The subject was found to have a history of patent foramen ovale (PFO) repair with a rare vertebral artery malformation described as a medial transposition of the vertebral artery out of the vertebral artery foramen between C3 and C4.

Conclusions:

Consideration of cervical anatomy, particularly the VA, is key to minimizing the risk of adverse surgical outcomes in both anterior and posterior approaches to the cervical spine. During the workup process, the patient’s primary care providers, radiologists, and surgeons should be aware of the potential variations of the VA with particular attention given to the course of the VA on MR imaging.

Level of Evidence:

Level IV.
Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials
Authors: Kagan Risa , Simon James A. , Goldstein Steven R. , Komm Barry S. , Jenkins Simon N. , Portman David J.
Published: April 2024

Objective

The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause.

Methods

Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test.

Results

The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo (P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: −0.4 and −0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (−0.65, −0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (−39.9%, −34.9%) cells; study 2: most bothersome symptom (−0.4, −0.5), vaginal pH (−0.57, −0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (−34.1%, −33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%–23% vs 9%–11%). Serious adverse events were infrequent and no deaths occurred.

Conclusions

In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.
The Posthyaluronidase Syndrome: Dosing Strategies for Hyaluronidase in the Dissolving of Facial Filler and Independent Predictors of Poor Outcomes
Authors: Wilde Caroline L. , Jiang Kailun , Lee Sieun , Ezra Daniel G.
Published: April 2024

Background:

Hyaluronic acid dermal fillers are used extensively in periocular aesthetic medicine, and the incidence of filler-related complications is increasing. This study aimed to investigate the optimal dosing strategy for hyaluronidase and to identify predictors of poor outcomes.

Methods:

We performed a retrospective review of 157 orbits of 90 patients treated with hyaluronidase over a 4-year period. Demographic data, indication, and details of hyaluronidase treatment and outcomes were recorded.

Results:

The primary indication for dissolving filler was swelling in 52%, lumpiness in 20%, and before surgical blepharoplasty in 17%. The most frequently used hyaluronidase concentration was 150 U per mL in 66%, followed by 75 U per mL in 31%, 37.5 U per mL in 3%, and 100 U per mL in 1%. Outcomes were characterized as follows: 59% with a satisfactory result; 24% as insufficient treatment requiring further hyaluronidase; and 18% complaining of facial changes such as hollowing, indicating a post hyaluronidase syndrome. There was no statistical difference in outcomes between the 75 and 150 U per mL dosage groups (P = 0.625). A significant correlation was identified between posthyaluronidase syndrome and duration of filler in situ (P = 0.00019) and volume of filler (P = 0.000017).

Conclusions:

The posthyaluronidase syndrome may be related to previous filler volume and duration, rather than the concentration or dose of hyaluronidase used. All patients should be informed about the risks of adverse effects after hyaluronidase treatment; patients with longer histories of filler use and higher total volumes should be advised of the increased risk.
PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic dysfunction-associated steatotic liver disease
Authors: Chalasani Naga , Vilar-Gomez Eduardo , Loomba Rohit , Yates Katherine P. , Diehl Anna Mae , Neuschwander-Tetri Brent A. , Dasarathy Srinivasan , Kowdley Kris V. , Terrault Norah , Wilson Laura A. , Tonascia James , Sanyal Arun J.
Published: April 2024

Background and Aims:

The patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship.

Approach and Results:

A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07–1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4–13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3–6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8–4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p=0.03, and p-value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5–2.8), women (sHR: 1.4, 95% CI: 1.1–1.9), and those with AF (sHR: 1.9, 95% CI: 1.5–2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5–2.8) as compared with their counterparts, p-value for interaction between PNPLA3 and each factor<0.01.

Conclusions:

The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex.
The Value of Warning Signs From the WHO 2009 Dengue Classification in Detecting Severe Dengue in Children
Authors: Karyanti Mulya Rahma , Uiterwaal Cuno S. P. M. , Hadinegoro Sri Rezeki , Widyahening Indah Suci , Saldi Siti Rizny F. , Heesterbeek J. A. P. Hans , Hoes Arno W. , Bruijning-Verhagen Patricia
Published: April 2024

Background:

World Health Organization proposed 7 warning signs to identify the risk of severe dengue in 2009. This study aimed to evaluate the value of these warning signs in detecting severe dengue in children.

Material and Methods:

A cross-sectional study was conducted utilizing data of children with clinical dengue infection obtained from medical records between January 2009 and December 2018 in Jakarta. Children with confirmed dengue were analyzed and stratified into 3 age groups: infants less than 1 year old, children 1–14 years and adolescents 15–18 years of age. Positive predictive value, negative predictive value (NPV), sensitivity and specificity of each warning sign present or absent on admission in detecting severe dengue were computed.

Results:

Six hundred ninety-nine children with clinical dengue infection were enrolled, among whom 614 (87.8%) had confirmed dengue infection, either by antigen or antibody serological tests. Severe dengue occurred in 211/614 (34.4%) cases. In infants, important warning signs on admission to detect or exclude severe dengue were liver enlargement (NPV 80.8%) and clinical fluid accumulation (NPV 75%). In children and adolescents, warning sign with highest NPV (in children 76.6% and in adolescents 91.9%) was increase in hematocrit concurrent with a rapid decrease in platelet count. Other warning signs with high NPV values in children were abdominal pain (72%), vomiting (70%), clinical fluid accumulation (69.3%), and in adolescents’ abdominal pain (80.7%), vomiting (75.7%), clinical fluid accumulation (82.7%). NPVs increase with more than 1 warning sign in all age groups.

Conclusion:

In infants, liver enlargement or clinical fluid accumulation are important warning signs for severe dengue, when both are absent, severe dengue is unlikely. In older children and adolescents, an increase in hematocrit with the concurrent rapid decrease in platelet count is most discriminative; followed by the absence of abdominal pain, vomiting or fluid accumulation are unlikely severe dengue.
Flange depth for scleral pocket vs no pocket techniques for intrascleral intraocular lens fixation
Authors: Amado Sebastian F. , Amado Norberto M. , Hermosa Luciano
Published: April 2024

Purpose:

To compare flange depth for a modified scleral pocket (SP) vs no scleral pocket (NSP) technique (Yamane technique) for intrascleral intraocular lens (IOL) fixation.

Setting:

Instituto de Oftalmología Santa Fe, Santa Fe, Argentina.

Design:

Prospective, randomized, single-surgeon, observational study.

Methods:

Eyes with aphakia and no capsular support were included. They were divided into 2 groups: one was programmed for a double-needle flanged intrascleral IOL fixation as originally described by Shin Yamane with NSP and the second group had a modified SP technique. Flange depth was measured with anterior-segment optical coherence tomography (AS-OCT) at 1 month, 3 months, 6 months, and 12 months postoperatively, and the results were compared.

Results:

Each group comprised 18 eyes of 18 patients, giving a total of 36 flanges per group. The groups were comparable preoperatively. At 12 months, uncorrected distance visual acuity and corrected distance visual acuity (CDVA) were not statistically different for both groups (P = .333; P = .448). Spherical equivalent (SEQ) was not significantly different between groups at 12 months postoperatively (P = .078). AS-OCT revealed a significantly deeper flange position for the SP group at 1 month, 3 months, 6 months, and 12 months postoperatively (P < .05).

Conclusions:

When performing a double-needle intrascleral IOL fixation in aphakic eyes with no capsular support, a modified scleral pocket technique provides a significantly deeper flange position with no difference in CDVA or SEQ 12 months postoperatively.
Severely subluxated cataract
Authors: Chee Soon-Phaik , McKee Yuri , Snyder Michael E. , Lockington David , Vasavada Abhay , Vasavada Vaishali , Daoud Yassine J. , Rodgers Emily Grace , Al-Mohtaseb Zaina
Published: April 2024

A 56-year-old man with a history of myopic LASIK presented with left eye gradual blurring of vision over 3 months. There was no history of trauma. His uncorrected visual acuities were 20/25 in the right eye and 20/400 in the left eye. The right eye was normal except for an early cataract. The left eye had a moderate cataract that was phacodonetic. Vitreous was present in the shallow anterior chamber (AC) (Figure 1

JOURNAL/jcrs/04.03/02158034-202405000-00018/figure1/v/2024-04-22T135154Z/r/image-tiff

). The fundus was normal. The intraocular pressures (IOPs) were 14 mm Hg in the right eye and 20 mm Hg in the left eye.

Ultrasound biomicroscopy of the anterior segment in the left eye revealed near total zonular loss with few intact zonular strands at the 6 and 10 o'clock regions (Figure 2

JOURNAL/jcrs/04.03/02158034-202405000-00018/figure2/v/2024-04-22T135154Z/r/image-tiff

). Vitreous was observed in the AC, herniating mostly from the 3 o'clock region. The endothelial cell density and optical coherence tomography (OCT) of the macular and disc in both eyes were normal. Central corneal thickness was 527 µm in the right eye and 520 µm in the left eye.

Describe how you would manage this case surgically. Optical biometry had been obtained, and the axial length in both eyes was similar. Discuss how you would select the monofocal intraocular lens (IOL) diopter (D) targeted for −1.50 D if the AC depth in the left eye was 2.48 mm and in the right eye was 3.25 mm.
Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial
Authors: Zhang Rong-xin , Wu Xiao-jun , Wan De-sen , Lin Jun-zhong , Ding Pei-rong , Liao Le-en , Lei Jian , Lu Zhen-hai , Li Li-ren , Chen Gong , Kong Ling-heng , Wang Fu-long , Zhang Jian , Fan Wen-hua , Jiang Wu , Zhou Wen-hao , Li Cong , Li Yuan , Li Xue-ying , Peng Jian-hong , Pan Zhi-zhong
Published: April 2024

Background:

The authors aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients.

Methods:

The authors performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival after long-term follow-up was performed in patients analyzed on an intention-to-treat basis.

Results:

From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients [3-year disease-free survival (DFS): 91.1 vs. 90.0%, P=0.328; 3-year OS: 94.4 vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148–0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353–0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment carcinoembryonic antigen (CEA) levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233–0.921, P=0.029 and OS: HR=0.476, 95% CI: 0.223–1.017, P=0.049).

Conclusions:

Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.
Surgical Management of Airway Obstruction following Posterior Pharyngeal Flap
Authors: Li Yanan , Yin Xing , Shi Bing , Li Jingtao
Published: April 2024

Background:

The posterior pharyngeal flap (PPF) is effective in managing velopharyngeal insufficiency but is associated with airway obstruction risk. This study compared the effectiveness and complications of 2 PPF revision procedures and screened potential prognostic factors to postoperative hypernasality and persistent obstruction.

Methods:

Patients who received flap division (FD) or port enlargement (PE) for airway obstruction following PPF were reviewed. Ventilation status was assessed using the Nasal Obstruction Symptom Evaluation scale, and velopharyngeal closure was assessed using subjective speech evaluation and nasopharyngoscopy. The effectiveness of ventilation relief and complication rate (hypernasality and persistent obstruction) of the 2 techniques were compared. A comprehensive panel of factors—including age, velopharyngeal mobility, obstruction laterality, body mass index, jaw relationship, and adenoid hypertrophy—was evaluated for correlation with complications.

Results:

A total of 79 patients were enrolled, with 51 undergoing FD and 28 undergoing PE. Both techniques significantly improved ventilation dysfunction and hyponasality. Mild hypernasality occurred in 10 cases in the FD group and 3 in the PE group. Age at surgery was significantly associated with persistent obstruction after PPF revision. The occurrence of persistent obstruction was significantly higher among patients younger than 12 years than those older than 12 years. Obstruction laterality was suggested in significant correlation with hypernasality after PPF revision. Among patients with unilateral port obstruction, the occurrence of hypernasality after FD was significantly higher than after PE.

Conclusions:

Both flap division and port enlargement are effective revision procedures to relieve airway obstruction after PPF. Patients younger than 12 years are more likely to experience persistent ventilation problems after PPF revision.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Histopathological Evaluation of Bipolar and Microneedle Radiofrequency Energy on the Skin and Fat of the Abdominal Region of the Rat
Authors: Gelbal Caner , Tatar Burak Ergün , Yilmaz Bengi , Uyanikgil Yiğit , Tomruk Canberk , Bozkurt Mehmet
Published: April 2024

Background:

Radiofrequency-based devices are used frequently in plastic surgery procedures. In the current literature, no comparative experimental study has demonstrated the histologic and immunologic effects of these devices, which are used frequently in the facial area. In this study, the authors investigated the histologic and immunologic effects of bipolar radiofrequency (BodyTite) and microneedle radiofrequency (Morpheus 8) devices in the rat abdominal region.

Methods:

A total of 24 rats were used in this study. The rats were divided into 4 groups: controls (group 1), BodyTite applied to the abdominal region (group 2), Morpheus 8 applied to the abdominal region (group 3), and both Morpheus 8 and BodyTite applied to the abdominal region (group 4). The histologic and immunologic features of the tissues, collagen formation, and desmosome structures were examined using light microscopy.

Results:

Collagens in group 2 were thinner than those in the other groups. In addition, there were fewer vessels in group 3. The collagen scores were as follows: group 2, 1.5; group 3, 2; and group 4, 3. Vascular endothelial growth factor scores were 2.5 in group 2, 2 in group 3, and 3 in group 4. The collagen score in group 2 and vascular endothelial growth factor score in group 3 were significantly lower than in the other groups. In addition, the bonds between desmosomes in group 3 were found to be looser using electron microscopy. Collagen morphology in groups 3 and 4 was found to be similar to that in group 1.

Conclusion:

Radiofrequency-based devices increased tissue regeneration and healing.

Clinical Relevance Statement:

The use of radiofrequency devices has increased in plastic surgery practice over the past 2 decades, particularly emerging as a unique alternative for nonsurgical candidates. There is a lack of experimental studies concerning these devices, which are commonly used in clinical practice.
Reducing False-Positives Due to Urinary Stagnation in the Prostatic Urethra on 18F-DCFPyL PSMA PET/CT With MRI
Authors: Gelikman David G. , Mena Esther , Lindenberg Liza , Azar William S. , Rathi Nityam , Yilmaz Enis C. , Harmon Stephanie A. , Schuppe Kyle C. , Hsueh Jessica Y. , Huth Hannah , Wood Bradford J. , Gurram Sandeep , Choyke Peter L. , Pinto Peter A. , Turkbey Baris
Published: April 2024

Purpose

Prostate-specific membrane antigen (PSMA)–targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra.

Patients and Methods

Eighty-five patients who underwent both 18F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored.

Results

Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively (P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls.

Conclusions

Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer.
Activity-driven trafficking of endogenous synaptic proteins through proximity labeling
Authors: Pascual-Caro Carlos , de Juan-Sanz Jaime
Published: April 2024

To enable transmission of information in the brain, synaptic vesicles fuse to presynaptic membranes, liberating their content and exposing transiently a myriad of vesicular transmembrane proteins. However, versatile methods for quantifying the synaptic translocation of endogenous proteins during neuronal activity remain unavailable, as the fast dynamics of synaptic vesicle cycling difficult specific isolation trafficking proteins during such a transient surface exposure. Here we developed a novel approach using synaptic cleft proximity labeling to capture and quantify activity-driven trafficking of endogenous synaptic proteins at the synapse. We show that accelerating cleft biotinylation times to match the fast dynamics of vesicle exocytosis allows capturing endogenous proteins transiently exposed at the synaptic surface during neural activity, enabling for the first time the study of the translocation of nearly every endogenous synaptic protein. As proof-of-concept, we further applied this technology to obtain direct evidence of the surface translocation of non-canonical trafficking proteins, such as ATG9A and NPTX1, which had been proposed to traffic during activity but for which direct proof had not yet been shown. The technological advancement presented here will facilitate future studies dissecting the molecular identity of proteins exocytosed at the synapse during activity, helping to define the molecular machinery that sustains neurotransmission in the mammalian brain.

Significance statement

Synaptic trafficking is critical for neurons to communicate and sustain brain function. Pascual-Caro and de Juan-Sanz develop a pioneering method to enable the study of the activity-driven translocation of any endogenous synaptic protein. Coordinating neuronal activity and proximity labeling at synaptic clefts during just a few seconds, the authors visualize the trafficking of endogenous synaptic vesicle proteins and non-canonical trafficking proteins at the synapse. This work provides a technological framework to uncover the complex molecular choreography of translocation events occurring within firing synapses, enabling a deeper study of the molecular control of neuronal communication and circuit physiology in the brain.
LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment
Authors: Reina Jeffrey , Vallmajo-Martin Queralt , Ning Jia , Michi Aubrey N. , Yeung Kay , Wahl Geoffrey M. , Hunter Tony
Published: April 2024

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP’s role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.
No evidence that visual impulses enhance the readout of retrieved long-term memory contents from EEG activity
Authors: van Bree Sander , Mackenzie Abbie Sarah , Wimber Maria
Published: April 2024

The application of multivariate pattern analysis (MVPA) to electroencephalography (EEG) data allows neuroscientists to track neural representations at temporally fine-grained scales. This approach has been leveraged to study the locus and evolution of long-term memory contents in the brain, but a limiting factor is that decoding performance remains low. A key reason for this is that processes like encoding and retrieval are intrinsically dynamic across trials and participants, and this runs in tension with MVPA and other techniques that rely on consistently unfolding neural codes to generate predictions about memory contents. The presentation of visually perturbing stimuli may experimentally regularize brain dynamics, making neural codes more stable across measurements to enhance representational readouts. Such enhancements, which have repeatedly been demonstrated in working memory contexts, remain to our knowledge unexplored in long-term memory tasks. In this study, we evaluated whether visual perturbations—orpings—improve our ability to predict the category of retrieved images from EEG activity during cued recall. Overall, our findings suggest that while pings evoked a prominent neural response, they did not reliably produce improvements in MVPA-based classification across several analyses. We discuss possibilities that could explain these results, including the role of experimental and analysis parameter choices and mechanistic differences between working and long-term memory.
Structural visualisation of the dynamics of DNA unwinding by a replicative helicase
Authors: Shahid Taha , Tehseen Muhammad , Alhudhali Lubna , Clark Alice , Savva Christos G. , Hamdan Samir M. , De Biasio Alfredo
Published: April 2024

Ring-shaped hexameric helicases are nucleotide hydrolases that unwind double-stranded DNA into single strands, a necessary step in DNA replication. Two main questions are critical to understanding their function: the location of DNA strand separation within the helicase, and the precise dynamic linkage between nucleotide hydrolysis and DNA translocation. We explore these questions by employing cryo-EM to visualize the translocation mechanics of a AAA+ helicase, the SV40 Large Tumor Antigen (LTag), on forked DNA. We find the DNA fork nexus is positioned deep within the core helicase domain, with each DNA-binding loop from the six subunits securing the tracking strand by forming a paired staircase spiral that substitutes the passive strand. This structure forges an internal separation wedge, channeling the passive strand through a gap in the subunit C-tiers at the back of the helicase. Via cryo-EM continuous heterogeneity analysis we capture, and exhaustively model, a seamless spectrum of conformations of translocating LTag at high resolution. ATP hydrolysis at the tightest inter-subunit interface operates like an ‘entropy switch’, triggering coordinated rigid-body rotations of the subunit C-tiers and DNA-binding loops, resulting in directional escorting of the tracking strand through the central channel, concomitantly setting preparatory steps for cycle restart. Overall, we demonstrate a dynamic model for hydrolysis-coupled translocation and DNA unwinding by a model helicase active in replication, with implications for origin unwinding. High structural conservation of core helicase regions suggests this mechanism is applicable to hexameric helicases across domains.