bluuebunny/crossref_metadata_2025 huggingface dataset:
Ropivacaine Promotes Axon Regeneration by Regulating Nav1.8-mediated Macrophage Signaling after Sciatic Nerve Injury in Rats
Authors: Cui Yongchen , Wang Xiaofeng , Xu Yang , Cao Yue , Luo Gang , Zhao Zhe , Zhang Junfeng
Published: September 2023

Background

Continuous nerve block with ropivacaine is commonly performed after repair surgery for traumatic peripheral nerve injuries. After peripheral nerve injury, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated and contributes to macrophage inflammation. This study investigated whether ropivacaine promotes peripheral nerve regeneration through Nav1.8-mediated macrophage signaling.

Methods

A sciatic nerve transection-repair (SNT) model was established in adult Sprague–Dawley rats of both sexes. The rats received 0.2% ropivacaine or 10 μM Nav1.8-selective inhibitor A-803467 around the injured site or near the sacrum for 3 days. Nerve regeneration was evaluated using behavioral, electrophysiologic, and morphological examinations. Moreover, myelin debris removal, macrophage phenotype, Nav1.8 expression, and neuropeptide expression were assessed using immunostaining, enzyme-linked immunosorbent assay, and Western blotting.

Results

Compared to the SNT-plus-vehicle group, the sensory, motor, and sensory–motor coordination functions of the two ropivacaine groups were significantly improved. Electrophysiologic (mean ± SD: recovery index of amplitude, vehicle 0.43 ± 0.17 vs. ropivacaine 0.83 ± 0.25, n = 11, P < 0.001) and histological analysis collectively indicated that ropivacaine significantly promoted axonal regrowth (percentage of neurofilament 200 [NF-200]–positive area: vehicle 19.88 ± 2.81 vs. ropivacaine 31.07 ± 2.62, n = 6, P < 0.001). The authors also found that, compared to the SNT-plus-vehicle group, the SNT-plus-ropivacaine group showed faster clearance of myelin debris, accompanied by significantly increased macrophage infiltration and transition from the M1 to M2 phenotype. Moreover, ropivacaine significantly attenuated Nav1.8 upregulation at 9 days after sciatic nerve transection (vehicle 4.12 ± 0.30-fold vs. ropivacaine 2.75 ± 0.36-fold, n = 5, P < 0.001), which coincided with the increased expression of chemokine ligand 2 and substance P. Similar changes were observed when using the selective Nav1.8 channel inhibitor A-803467.

Conclusions

Continuous nerve block with ropivacaine promotes the structural and functional recovery of injured sciatic nerves, possibly by regulating Nav1.8-mediated macrophage signaling.

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Increased risk of osteomyelitis and septic arthritis in osteogenesis imperfecta
Authors: Bobak Lukas , Dorney Ian , Lavu Monish S. , Mistovich R. Justin , Kaelber David C.
Published: September 2023

We investigated the prevalence of osteomyelitis and septic arthritis in individuals with osteogenesis imperfecta (OI) as compared to the general population. We performed a retrospective cohort study utilizing the TriNetX Analytics platform, a federated, aggregated electronic health record (EHR) research network containing national, deidentified EHR data. We queried patients with OI, based on encounter diagnoses. Patients in this group with any occurrence of osteomyelitis or septic arthritis were recorded. A control cohort was established to compare the prevalence in patients without OI. Of 8444 individuals with OI, 433 (5.13%) had encounter diagnoses for osteomyelitis and 61 (0.72%) had encounter diagnoses for septic arthritis. In comparison, of 79 176 436 patients without OI, 352 009 (0.44%) had encounter diagnoses for osteomyelitis, while 106 647 (0.13%) had encounter diagnoses for septic arthritis. The relative risk for osteomyelitis in OI patients was 11.53 (95% CI: 10.52–12.64), while the relative risk for septic arthritis was 5.36 (95% CI: 4.18–6.89). The relative risk for osteomyelitis in pediatric OI patients was 30.55 (95% CI: 24.35–38.28). To our knowledge, this is the first study investigating musculoskeletal infections in patients with OI, as well as the first to report the overall prevalence in the general population. Clinicians may benefit from a high index of suspicion for musculoskeletal infections in OI patients with corresponding symptoms. Further study is warranted to investigate if modifications to conventional diagnostic pathways and criteria are valuable in this population. Level of evidence: Retrospective Cohort Study – Level II
Severity of hip dysplasia as the major factor affecting outcome of closed reduction in children with hip dysplasia
Authors: Cummings Jason L. , Oladeji Afolayan K. , Rosenfeld Scott , Johnson Megan , Goldstein Rachel , Georgopoulos Gaia , Stephenson Lindsay , White Nathan W. , Hosseinzadeh Pooya
Published: September 2023

The objective of this study was to analyze a multicenter cohort of children with developmental dysplasia of the hip (DDH) who underwent treatment with closed reduction. We sought to report the effects that severity of hip dysplasia and age have on the development of femoral head avascular necrosis (AVN) and the need for additional procedures. All patients with DDH and minimum 2 years of follow-up who underwent closed reduction were identified. The following variables were recorded: sex, laterality of hip involvement, age, acetabular index (AI), and International Hip Dysplasia Institute (IHDI) grade. The effects of patient age and pre-procedure IHDI grade on the rate of AVN and need for additional procedures after the closed reduction were analyzed using an alpha of 0.05. Seventy-eight total hips were included in the final analysis. The average patient age was 12 months. AVN of the femoral head was reported in 24 hips (30.8%) and 32 hips (41.0%) required additional surgery. Higher pre-op IHDI grade was associated with higher risk of developing Bucholz-Ogden grades II-IV AVN of the femoral head (P = 0.025) and requiring additional surgery (P= 0.033) regardless of patient age. There were no statistically significant differences for the effect of age on the measured outcomes (P > 0.05). These findings suggest that severity of dislocation (IHDI grade) is a significant risk factor for the development of AVN and need for additional procedure.
Functional gastrointestinal disorders, mental health, genetic susceptibility, and incident chronic kidney disease
Authors: Liu Mengyi , He Panpan , Ye Ziliang , Yang Sisi , Zhang Yanjun , Wu Qimeng , Zhou Chun , Zhang Yuanyuan , Hou Fan Fan , Qin Xianhui
Published: September 2023

Background:

Whether functional gastrointestinal disorders (FGIDs) are associated with the long-term risk of chronic kidney disease (CKD) remains unclear. We aimed to investigate the prospective association of FGIDs with CKD and examine whether mental health mediated the association.

Methods:

About 416,258 participants without a prior CKD diagnosis enrolled in the UK Biobank between 2006 and 2010 were included. Participants with FGIDs (including irritable bowel syndrome [IBS], dyspepsia, and other functional intestinal disorders [FIDs; mainly composed of constipation]) were the exposure group, and non-FGID participants were the non-exposure group. The primary outcome was incident CKD, ascertained from hospital admission and death registry records. A Cox proportional hazard regression model was used to investigate the association between FGIDs and CKD, and the mediation analysis was performed to investigate the mediation proportions of mental health.

Results:

At baseline, 33,156 (8.0%) participants were diagnosed with FGIDs, including 21,060 (5.1%), 8262 (2.0%), and 6437 (1.6%) cases of IBS, dyspepsia, and other FIDs, respectively. During a mean follow-up period of 12.1 years, 11,001 (2.6%) participants developed CKD. FGIDs were significantly associated with a higher risk of incident CKD compared to the absence of FGIDs (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.28–1.44). Similar results were observed for IBS (HR, 1.27; 95% CI, 1.17–1.38), dyspepsia (HR, 1.30; 95% CI, 1.17–1.44), and other FIDs (HR, 1.60; 95% CI, 1.43–1.79). Mediation analyses suggested that the mental health score significantly mediated 9.05% of the association of FGIDs with incident CKD and 5.63–13.97% of the associations of FGID subtypes with CKD. Specifically, the positive associations of FGIDs and FGID subtypes with CKD were more pronounced in participants with a high genetic risk of CKD.

Conclusion:

Participants with FGIDs had a higher risk of incident CKD, which was partly explained by mental health scores and was more pronounced in those with high genetic susceptibility to CKD.
Effects of acute and chronic nicotine administration on probability discounting
Authors: Nolder Katya A. , Anderson Karen G.
Published: September 2023

Nicotine use is a continuing public health concern. Smokers are more likely to make risky or maladaptive decisions compared to nonsmokers, so the relation between nicotine and risky choice warrants further investigation. Risky choice can be operationally defined as the choice for a larger, uncertain reinforcer over a smaller, certain reinforcer and can be assessed through a probability-discounting procedure. Acute nicotine administration has been shown to alter risky choice, but because the everyday smoker uses nicotine repeatedly, more research on chronic administration is needed and would allow for assessment of tolerance or sensitization of any effects. The present study examined effects of acute and repeated nicotine administration on probability discounting. Sprague–Dawley rats were used as subjects and the probability-discounting task involved discrete-trial choices between a small, certain reinforcer and a larger, uncertain reinforcer. The probability of larger-reinforcer delivery decreased across blocks within each session. Acute nicotine (0.1–1.0 mg/kg) administration dose-dependently increased risky choice, increased lose-stay ratios (a measure of response perseveration), and decreased reinforcement frequency. Tolerance to nicotine’s effects on larger-reinforcer choice was observed after repeated 1.0 mg/kg nicotine administration. The results of the present study add to the existing literature that acute nicotine administration increases risky choice and demonstrates that tolerance to this effect develops after chronic exposure to the drug. Possible behavioral mechanisms behind this effect are discussed, as are suggestions for future research on nicotine and risky choice.
LIM domain only 7 negatively controls nonalcoholic steatohepatitis in the setting of hyperlipidemia
Authors: Wu Tiangen , Chen Xi , Xu Kequan , Dai Caixia , Li Xiaomian , Zhang Yang-Wen-Qing , Li Jinghua , Gao Meng , Liu Yingyi , Liu Fusheng , Zhang Xutao , Wang Bicheng , Xia Peng , Li Zhen , Ma Weijie , Yuan Yufeng
Published: September 2023

Background and Aims:

Hyperlipidemia has been extensively recognized as a high-risk factor for NASH; however, clinical susceptibility to NASH is highly heterogeneous. The key controller(s) of NASH susceptibility in patients with hyperlipidemia has not yet been elucidated. Here, we aimed to reveal the key regulators of NASH in patients with hyperlipidemia and to explore its role and underlying mechanisms.

Approach and Results:

To identify the predominant suppressors of NASH in the setting of hyperlipidemia, we collected liver biopsy samples from patients with hyperlipidemia, with or without NASH, and performed RNA-sequencing analysis. Notably, decreased Lineage specific Interacting Motif domain only 7 (LMO7) expression robustly correlated with the occurrence and severity of NASH. Although overexpression of LMO7 effectively blocked hepatic lipid accumulation and inflammation, LMO7 deficiency in hepatocytes greatly exacerbated diet–induced NASH progression. Mechanistically, lysine 48 (K48)-linked ubiquitin-mediated proteasomal degradation of tripartite motif-containing 47 (TRIM47) and subsequent inactivation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) cascade are required for the protective function of LMO7 in NASH.

Conclusions:

These findings provide proof-of-concept evidence supporting LMO7 as a robust suppressor of NASH in the context of hyperlipidemia, indicating that targeting the LMO7-TRIM47 axis is a promising therapeutic strategy for NASH.
Open-Source Automated Segmentation of Neuronal Structures in Corneal Confocal Microscopy Images of the Subbasal Nerve Plexus With Accuracy on Par With Human Segmentation
Authors: Zemborain Zane Zenon , Soifer Matias , Azar Nadim S. , Murillo Sofia , Mousa Hazem M. , Perez Victor L. , Farsiu Sina
Published: September 2023

Purpose:

The aim of this study was to perform automated segmentation of corneal nerves and other structures in corneal confocal microscopy (CCM) images of the subbasal nerve plexus (SNP) in eyes with ocular surface diseases (OSDs).

Methods:

A deep learning–based 2-stage algorithm was designed to perform segmentation of SNP features. In the first stage, to address applanation artifacts, a generative adversarial network–enabled deep network was constructed to identify 3 neighboring corneal layers on each CCM image: epithelium, SNP, and stroma. This network was trained/validated on 470 images of each layer from 73 individuals. The segmented SNP regions were further classified in the second stage by another deep network as follows: background, nerve, neuroma, and immune cells. Twenty-one-fold cross-validation was used to assess the performance of the overall algorithm on a separate data set of 207 manually segmented SNP images from 43 patients with OSD.

Results:

For the background, nerve, neuroma, and immune cell classes, the Dice similarity coefficients of the proposed automatic method were 0.992, 0.814, 0.748, and 0.736, respectively. The performance metrics for automatic segmentations were statistically better or equal as compared to human segmentation. In addition, the resulting clinical metrics had good to excellent intraclass correlation coefficients between automatic and human segmentations.

Conclusions:

The proposed automatic method can reliably segment potential CCM biomarkers of OSD onset and progression with accuracy on par with human gradings in real clinical data, which frequently exhibited image acquisition artifacts. To facilitate future studies on OSD, we made our data set and algorithms freely available online as an open-source software package.
Relationship Between Intraocular Pressure and Age: A Population-Based Study in Nepal
Authors: Bhandari Gopal , Bhandari Sadhan , Byanju Raghunandan , Pradhan Sangita , Sah Ranjeet Kumar , Kandel Ram Prasad , Thompson Isabel J. , Rotchford Alan P. , West Sheila K. , Muñoz Beatriz , Stevens Valerie M. , Oatts Julius T. , Ou Yvonne , Lietman Thomas M. , O’Brien Kieran S. , Keenan Jeremy D.
Published: September 2023

Précis:

Intraocular pressure (IOP) decreased with age in a population-based study in Nepal, from a mean of 14.1 mm Hg among those 60–64 years old to 13.0 mm Hg among those 80 years old or older.

Purpose:

Few studies have assessed the distribution of IOP from the Indian subcontinent, despite its large population and high burden of glaucoma. The objective of this study was to assess the distribution of IOP measurements from adults living in a lowland region of Nepal.

Methods:

In a population-based cross-sectional study, all individuals aged 60 years and older from an area of lowland Nepal were invited for an IOP assessment with a rebound tonometer.

Results:

Of 160 communities (28,672 people aged ≥60 y) enrolled, 79 (13,808 people aged ≥60 y) were randomly selected for IOP testing. Of those eligible, 10,017 (72.5%) individuals underwent tonometry. Mean IOP decreased monotonically over 5-year age groups, from 14.1 mm Hg (SD: 3.6) among those aged 60–64 years to 13.0 mm Hg (SD: 4.2) among those 80 years or older. The 97.5th percentile IOP measurement was 21.0 mm Hg for all age groups. In adjusted analyses, younger age, self-reported diabetes, and higher population density were each associated with higher IOP, and self-reported cataract surgery was associated with lower IOP.

Conclusions:

Mean IOP was lower among older individuals in Nepal, consistent with many studies from East Asia and in contrast to many studies from western populations. These results suggest that ethnic background might be a consideration when diagnosing ocular hypertension.
Glaucoma Surgery Shifts Among Medicare Beneficiaries After 2022 Reimbursement Changes in the United States
Authors: Williams Parker J. , Hussain Zain , Paauw Mark , Kim Chaesik , Juzych Mark S. , Hughes Bret A. , Ridha Faisal
Published: September 2023

Précis:

This study revealed the best-estimated surgical procedural counts for 2021 and 2022 and suggests a direct influence of coding and reimbursement changes on surgical device selection.

Purpose:

To analyze utilization rates of glaucoma surgeries and minimally invasive (microinvasive) glaucoma surgery among US Medicare beneficiaries between 2021 and 2022.

Design:

Retrospective comparative analysis of 68,118 unique patients.

Methods:

National claims data from a 5% sample of all Medicare beneficiaries were utilized to compare glaucoma procedure counts between the first quarter of 2021 and the first quarter of 2022. Duplicate claims were excluded, and 50 modifiers were counted as 2 distinct procedures. A multiplier was applied to estimate annual utilization for the entire Medicare population. χ2 analysis was employed to compare categorical data from the 2 time periods.

Results:

Current Procedural Terminology codes for angle-based stenting decreased by an estimated 20,960 procedures between 2021 and 2022 (28.60%). Goniotomy increased by an estimated 11,680 procedures (66.97%) and canaloplasty increased by an estimated 6640 procedures (47.43%). Glaucoma surgeries decreased by an estimated 5760 procedures (4.25%) despite an increase of cataract surgery by 234,960 procedures (15.63%), an increase in YAG capsulotomy by 19,280 procedures (3.31%), and an increase in intravitreal injections by 146,320 procedures (3.86%).

Conclusion:

Despite overall surgical volume increases among the ophthalmology procedures, angle-based stenting utilization decreased significantly with an accompanying trend change following the coding and reimbursement changes implemented in January 2022. Of the minimally invasive (microinvasive) glaucoma surgery procedures, goniotomy and canaloplasty counts increased the most between these periods. Trabeculectomy and glaucoma drainage device procedures continued to decrease, following well-established trends. Future studies are warranted to examine how these shifts in utilization may impact patient care outcomes.
Incidence of and Risk Factors for Fellow-Eye Involvement in Sturge-Weber Syndrome Children With Unilateral Glaucoma
Authors: Shin Young In , Ha Ahnul , Jeong Yoon , Huh Min Gu , Jeoung Jin Wook , Park Ki Ho , Kim Young Kook
Published: September 2023

Précis:

Among children with unilateral glaucoma associated with Sturge-Weber syndrome (SWS), 7 of 47 demonstrated involvement in the fellow eye, and that group had had earlier first-eye surgery relative to the noninvolvement group.

Purpose:

The aim of this study was to determine the incidence of and risk factors for fellow-eye involvement in children with unilateral SWS-associated glaucoma.

Materials and Methods:

Children diagnosed with a unilateral facial port-wine stain and ipsilateral glaucoma before the age of 5 and followed up for at least 5 years were enrolled. The incidence rates of fellow-eye glaucoma involvement were estimated per 100 person-years, and factors associated with a higher incidence of fellow-eye involvement were investigated.

Results:

A total of 47 children [24 (51.1%) girls] with unilateral SWS-associated glaucoma were included. All of them had facial port-wine stain involving ophthalmic division of the trigeminal nerve, and 18 (38.3%) had neurological comorbidities. The mean age at glaucoma diagnosis was 0.8±1.2 years [range, 0.08 (1 mo)–4.0 y]. Over a median follow-up of 8.4 years, glaucoma was diagnosed in the fellow eye of 7 of the children (14.9%; incidence rate of 1.8 per 100 person-years), 6 of whom were girls (P=0.097) and 5 of whom were diagnosed before the age of 4 years (P=0.508). The fellow-eye–involvement group showed significantly higher mean follow-up intraocular pressure in the fellow eye, older age at first-eye surgery (both P<0.005), and higher frequency of choroidal hemangioma both at first onset and in fellow eyes (P=0.026 and 0.019, respectively).

Conclusions:

In this cohort of SWS children diagnosed with unilateral glaucoma, the risk of fellow-eye involvement was higher in girls, within the first 4 years, and in cases with choroidal hemangioma. The fellow-eye–involved children underwent surgery on the first eye earlier than those without fellow-eye involvement.
Assessment of the iCare HOME2, a New Intraocular Pressure Self-Measurement Tonometer
Authors: Kratz Assaf , Zbidat Rabia , Kishner Rina , Cohen Michal , Shalata Walid , Goldberg Ivan
Published: September 2023

Précis:

The iCare HOME2 tonometer generally can be considered reliable for most eyes and clinical settings, although it may produce slightly overestimated or underestimated intraocular pressure (IOP) readings in thicker and thinner corneas, respectively.

Purpose:

To evaluate the accuracy, correlation, and analysis of differences in IOP measurements between the gold standard Goldmann applanation tonometer (GAT) and the new, self-measurement iCare HOME2 tonometer (icare).

Patients and Methods:

In this retrospective study, patients were randomly selected from those who attended a routine examination in our clinic. After a complete ocular examination, each patient’s IOP was measured and recorded with GAT and iCare HOME2. Central corneal thickness was measured. Eyes with any corneal morbidity were excluded. Pearson correlation coefficient was used to determine the correlation between paired IOP measurements. Bland-Altman plots were graphed for the analysis of differences in IOP between the instruments.

Results:

One hundred thirty-five eyes of 70 patients were included in the study. The mean IOP measured with GAT was 16.3 ± 6.5 mm Hg (range: 3–56). The mean IOP measured with iCare HOME2 was 16.5 ± 7.3 mm Hg (range: 3–55), (P = 0.47). A strong, significant positive correlation was found for paired IOP measurements by the 2 instruments (r = 0.94; P < 0.0001). A small systematic proportional bias was seen for the paired IOP measurements, meaning that with higher IOPs the iCare HOME2 yielded higher IOP readings than GAT, but this difference was clinically insignificant. The instrument underestimated IOPs with corneas thinner than 522 µm, whereas it overestimated IOPs when corneas were thicker than this.

Conclusion:

The iCare HOME2 could be a reliable tonometer for most eyes and clinical settings. Central corneal thickness measurement is recommended in patients who use the instrument.
An Integrated Process for Co-Developing and Implementing Written and Computable Clinical Practice Guidelines
Authors: Matson-Koffman Dyann M. , Robinson Susan J. , Jakhmola Priya , Fochtmann Laura J. , Willett DuWayne , Lubin Ira M. , Burton Matthew M. , Tailor Amrita , Pitts Dana L. , Casey Donald E. , Opelka Frank G. , Mullins Ryan , Elder Randy , Michaels Maria
Published: September 2023

The goal of this article is to describe an integrated parallel process for the co-development of written and computable clinical practice guidelines (CPGs) to accelerate adoption and increase the impact of guideline recommendations in clinical practice. From February 2018 through December 2021, interdisciplinary work groups were formed after an initial Kaizen event and using expert consensus and available literature, produced a 12-phase integrated process (IP). The IP includes activities, resources, and iterative feedback loops for developing, implementing, disseminating, communicating, and evaluating CPGs. The IP incorporates guideline standards and informatics practices and clarifies how informaticians, implementers, health communicators, evaluators, and clinicians can help guideline developers throughout the development and implementation cycle to effectively co-develop written and computable guidelines. More efficient processes are essential to create actionable CPGs, disseminate and communicate recommendations to clinical end users, and evaluate CPG performance. Pilot testing is underway to determine how this IP expedites the implementation of CPGs into clinical practice and improves guideline uptake and health outcomes.
Cow’s Milk-Related Symptom Score (CoMiSS): From Bristol to Brussels Stool Scale
Authors: Bajerova Katerina , Salvatore Silvia , Dupont Christophe , Kuitunen Mikael , Meyer Rosan , Ribes-Koninckx Carmen , Shamir Raanan , Szajewska Hania , Staiano Annamaria , Vandenplas Yvan
Published: September 2023

Objectives:

The Cow’s Milk-related Symptom Score (CoMISS) is an awareness tool for evaluating cow’s milk-related symptoms in otherwise healthy infants <1 year of age. This study assessed whether replacing the Bristol Stool Form Scale (BSFS) with the Brussels Infants and Toddlers Stool Scale (BITSS) in non-toilet-trained infants would modify the overall CoMiSS and change the clinical approach regarding potential cow’s milk allergy.

Methods:

Non-toilet-trained infants aged <13 months were assessed by CoMiSS using the 7 images from the BSFS (CoMiSS-BSFS) compared to the 4 images of stools from BITSS (CoMiSS-BITSS). The Wilcoxon signed-rank test and Pearson correlation coefficient were calculated. A post hoc analysis using identical tests was performed in subsets of CoMiSS-BSFS scores ≥10, ≥12, ≤5, and ≥6.

Results:

Eight hundred forty-four pairwise scores were collected. Applying the Wilcoxon test over the complete dataset, the difference between CoMiSS-BSFS and CoMiSS-BITSS was statistically significant (P < 0.001). However, there was no significant difference in the subsets with CoMiSS-BSFS ≥10, ≥12, and ≥6 (P = 0.84, P = 0.48, and P = 0.81, respectively). The significant difference remained restricted to the group with CoMiSS-BSFS ≤5, considered at low risk for CM-related symptoms (P < 0.001).

Conclusion:

Replacing BSFS with BITSS does not change the cutoff for awareness of possible CM-related symptoms and will not impact the use of CoMiSS in clinical practice. Changes in CoMiSS remained limited to the subgroup with a low risk for CM-related symptoms.
Hypoxia-inducible Factor-1α and mTOR as a Potential Therapeutic Target in Endometriosis: An Immunohistochemical Study
Authors: Badary Dalia M. , Abou-Taleb Hisham A. , Ibrahim Maha
Published: September 2023

Background and Study Aim:

We aim to study the immunohistochemical expression of both hypoxia-inducible factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR) in endometriosis to provide new evidence for a targeted endometriosis therapy.

Patients and Methods:

This study comprised 106 endometriotic cases diagnosed clinically and histopathologically. The immunohistochemical method was done to determine the expression of HIF-1α and mTOR

Results:

Endometriotic glands showed significant cytoplasmic expression of both markers in patients with poor ovulation, severe endometriosis, and infertile for >2 years (P<0.001). Also, patients with intense and worst pain show significant immunohistochemical expression of both markers (P<0.001). There is a significant correlation between mTOR and HIF-1α expression in endometriotic tissue samples as P<0.001.

Conclusions:

Our data suggest that both mTOR and its downstream target HIF-1α transcription factor are both disrupted in patients with endometriosis, which is consistent with aberrant activation of these pathways and their possible contribution to the pathogenesis of endometriosis. These results could offer a promising novel opportunity to be blocked therapeutically. As new management options need to be refined in particular in severe cases and infertile patients with endometriosis, therefore future studies are warranted to investigate treating endometriosis with mTOR inhibitors; the latter are already in clinical trials in phase III and IV, treating solid tumors as well as non-neoplastic disorders.
Extraovarian Dysgerminoma Involving the Uterine Cervix: A Rare Case Report With Literature Review
Authors: Yoshino Yasunori , Yanai Shiori , Sawada Mari , Sakate Shintaro , Kanno Kiyoshi , Hada Tomonori , Ueda Toshihiro , Tabata Tetsuya , Omori Masako , Andou Masaaki
Published: September 2023

Primary extraovarian dysgerminoma (EOD) is a very rare disease. There is no literature about primary EOD involving the uterine cervix. We herein present details of a unique case of primary EOD involving the uterine cervix. A 46-year-old woman with uterine cervical tumor was referred to our institution with atypical genital bleeding. A polypoid tumor localized to the uterine cervix was found. Cervical biopsy detected malignant components of likely nonepithelial cell origin. Preoperative imaging examinations showed a uterine cervical tumor measuring ~5 cm, suggestive of malignancy without distant or lymph node metastases. The patient underwent abdominal radical hysterectomy with pelvic lymph node dissection according to the standard treatment for stage IB3 cervical cancers. The pathological diagnosis was dysgerminoma involving the uterine cervix and the right fallopian tube. Immunohistochemical results were as follows: SALL4 (+), octamer-binding transcription factor 4 (+), D2-40 (+), and c-Kit (+). She received 3 cycles of adjuvant chemotherapy with bleomycin, etoposide, and cisplatin. The disease did not recur up to 14 months after surgery. This is the first-ever published case of primary EOD involving the uterine cervix among previously reported EOD cases. Reported cases of EOD in female genital tract are also reviewed. Our case provides more extensive insights for pathologists to consider the differential diagnosis of cervical lesions. In our case, combination therapy involving a surgical approach—according to cervical cancers and adjuvant chemotherapy as used for ovarian dysgerminomas—was effective. Future verification is needed regarding the best approach for treating uterine cervical dysgerminomas.
Effects of Orbicularis Oculi Flap Suspension on Transcutaneous Lower Blepharoplasty
Authors: Lee Hyunkyu , Shin Hyemi , Baek Sehyun
Published: September 2023

Objective:

The purpose of this study was to analyze the clinical effects of orbicularis oculi muscle suspension in conjunction with transcutaneous blepharoplasty in patients 60 years of age or older.

Methods:

A retrospective study was conducted on patients aged 60 or older who underwent orbicularis oculi flap suspension in conjunction with transcutaneous blepharoplasty to treat lower lid festoons, lower lid fat prolapse, and lid laxity at Korea University Guro Hospital. The outcomes were surgical success rate, recurrence rate, postoperative complications, and patient satisfaction.

Results:

In total, 39 patients (18 males and 21 females) were included, with an average age of 67.5 years (60–86 y) and a follow-up period of 145.7 days (95–195 d). In all patients, eyelid laxity was effectively corrected, and there was no recurrence of eyelid laxity after surgery. Three patients suffered postoperative complications, transient skin edema in 2 patients, and transient ectropion in 1 patient. Subjective satisfaction score following surgery was high, with an average score of 2.56 out of 3 points.

Conclusions:

Orbicularis oculi flap suspension with transcutaneous blepharoplasty can shorten operation time due to surgical ease. It also has the advantage of not involving conjunctival-related complications such as conjunctival edema since it does not pass through the conjunctiva. Finally, it can successfully treat lid laxity and could be used in lower blepharoplasty procedures.
Effects of Pterional and Osteoplastic Craniotomy on Temporalis Muscle and Calvarial Bone Graft Atrophy
Authors: Kalemci Orhan , Kizmazoglu Ceren , Karabay Nuri , Ur Koray , Ozyoruk Safak , Coskun Ege , Ozer Ercan , Erbayraktar Serhat
Published: September 2023

This study aims to compare the effects of osteoplastic craniotomy on temporalis muscle and bone graft atrophy in patients operated on with a pterional approach to the standard technique. Patients operated on for an intracranial aneurysm with a pterional approach between 2014 and 2018 were studied. Following the exclusion criteria, 36 patients were included in this retrospective study. Temporalis muscle volume and bone graft volume were calculated. The volumes were compared from preoperative and postoperative computed tomography images for temporalis muscle and from early and late postoperative computed tomography images for the bone graft. The osteoplastic craniotomy group (group I) had 17 patients, and the standard craniotomy group had 19 patients (group II). Temporalis muscle volume and bone graft volume decreased statistically significantly in group II after surgery. However, no significant volume difference was found in group I measurements. When compared with the standard technique, osteoplastic craniotomy reduces the likelihood of postoperative temporalis muscle and bone graft atrophy in patients undergoing pterional craniotomy. As a result, the patients’ cosmetic and functional well-being is improved.
How Does Omitting Additional Surgery after Local Excision Affect the Prognostic Outcome of Patients with High-risk T1 Colorectal Cancer?
Authors: Ouchi Akira , Komori Koji , Masahiro Tajika , Toriyama Kazuhiro , Kajiwara Yoshiki , Oka Shiro , Fukunaga Yosuke , Hotta Kinichi , Ikematsu Hiroaki , Tsukamoto Shunsuke , Nagata Shinji , Yamada Kazutaka , Konno Maki , Ishihara Soichiro , Saitoh Yusuke , Matsuda Kenji , Togashi Kazutomo , Ishiguro Megumi , Kuwai Toshio , Okuyama Takashi , Ohuchi Akihiro , Ohnuma Shinobu , Sakamoto Kazuhiro , Sugai Tamotsu , Katsumata Kenji , Matsushita Hiro-o , Nakai Keisuke , Uraoka Toshio , Akimoto Naohiko , Kobayashi Hirotoshi , Ajioka Yoichi , Sugihara Kenichi , Ueno Hideki ,   on behalf of the Study Group for the JSCCR-T study
Published: September 2023

Objective:

To investigate how omitting additional surgery after local excision (LE) affects patient outcomes in high-risk T1 colorectal cancer (CRC).

Summary Background Data:

It is debatable whether additional surgery should be performed for all patients with high-risk T1 CRC regardless of the tolerability of invasive procedures.

Methods:

Patients who had received LE for T1 CRC at the Japanese Society for Cancer of the Colon and Rectum (JSCCR) institutions between 2009 and 2016 were analyzed. Those who had received additional surgical resection and who did not were matched one-on-one by the propensity score (PS)-matching method. A total of 401 PS-matched pairs were extracted from 1,975 patients at 27 JSCCR institutions and compared.

Results:

Regional lymph node metastasis was observed in 31 (7.7%) patients in the LE+surgery group. Comparatively, the incidence of oncologic adverse events was low in the LE-alone group, such as the 5-year cumulative risk of local recurrence (4.1%) or overall recurrence (5.5%). In addition, the difference in the 5-year CSS between the LE+surgery and LE-alone groups was only 1.8% (99.7% and 97.9%, respectively), whereas the 5-year OS was significantly lower in the LE-alone group than in the LE+surgery group (88.5% vs. 94.5%, respectively (P=0.002).

Conclusions:

Those who had been decided to omit additional surgery at the dedicated center for CRC treatment presented a small number of oncologic events and a satisfactory CSS, which may suggest an important role of risk assessment regarding non-oncologic adverse events to achieve a best practice for each individual with high-risk T1 tumors.
Efficacy of Standardized Process Management of Early Postoperative Enteral Nutrition After Laparoscopic Hepatectomy: A Randomized Controlled Trial
Authors: Gao Yun , Wang Fang
Published: September 2023

Background:

We sought to investigate the efficacy of standardized process management of early postoperative enteral nutrition in patients undergoing laparoscopic hepatectomy.

Methods:

From January 2022 to January 2023, a total of 98 patients undergoing laparoscopic hepatectomy in our hospital were enrolled in this prospective study. The participants were allocated into the study group (49 cases, given standardized process management of early postoperative enteral nutrition) and the control group (49 cases, given conventional early postoperative enteral nutrition) based on a random number table. Observation indicators included postoperative recovery, nutritional status, quality of life, and complications.

Results:

The time of first anal exhaust, eating, off-bed, first defecation, and postoperative hospital stay in the 2 groups was significantly shorter than those in the control group (P<0.05). After the intervention, the levels of transferrin, prealbumin, and albumin in the study group were evidently higher than those in the control group (P<0.05). The scores of overall health, body pain, body function, physiological function, vitality, social function, emotional function, and mental health in the study group were significantly higher than those in the control group after intervention (P<0.05).

Conclusions:

The standardized process management of early postoperative enteral nutrition showed promising results in effectively improving the nutritional status, rehabilitation, and quality of life, as well as reducing the incidence of related complications among patients undergoing laparoscopic hepatectomy, which supports a wide application in clinical practice.
Fifth-order nonlinear Schrödinger equation as Routhian reduction of the nonlinear Klein–Gordon model
Authors: Sedletsky Yu. V. , Gandzha I. S.
Published: September 2023

We consider the nonlinear Klein–Gordon model with polynomial nonlinearity involving odd and even powers. We elaborate a hybrid Hamiltonian and Lagrangian approach, which is generally referred to as Routh’s procedure, to describe the nonlinear modulation of wave packets assuming the wave field envelope to be a slow function of time and coordinate. An extended fifth-order nonlinear Schrödinger equation is obtained from the Routhian equation for a complex canonical variable that couples the wave field and its momentum. This canonical variable is expressed in terms of the amplitude of fundamental harmonic and its derivatives with respect to coordinate. The resulting fifth-order nonlinear Schrödinger equation is demonstrated to be a Hamiltonian system under a certain constraint imposed on its model parameters. When compared with other techniques used to derive high-order nonlinear Schrödinger models, our approach preserves the Hamiltonian structure of the governing equations for the fundamental harmonic, while the input of higher harmonics is taken into account by means of variational principle applied to the averaged Routhian. In this way, it represents the most general tool for the reduction of nonlinear wave equations to high-order envelope models for slowly modulated wave packets.
Stability of longitudinal sediment waves formed by turbidity currents: linear and weakly nonlinear perspectives
Authors: Mahato Rajesh K. , Ali Sk Zeeshan , Dey Subhasish
Published: September 2023

We perform the linear and weakly nonlinear stability analyses of longitudinal sediment waves triggered by the interaction of turbidity currents with an erodible bed. The mathematical framework is based on the two-dimensional flow equations, advection–diffusion equation for sediment concentration and Exner equation for bed evolution. Using the standard linearization, the linear analysis offers the resonant wavenumber that maximizes the growth rate of sediment waves. We study the influence of the key parameters, such as the gravitational parameter, longitudinal bed slope, Rouse number, shear Reynolds number, relative roughness number and erosion coefficient, on the growth rate, resonant wavenumber and phase velocity. The results reveal that the longitudinal sediment waves migrate both upstream and downstream. By plotting the gravitational parameter against the dimensionless wavenumber, we obtain a stability diagram that accurately captures the experimental data plots within the unstable zone. Additionally, we explore the perturbation fields of velocity components, pressure and sediment concentration. Employing the centre manifold projection, the weakly nonlinear analysis provides the equilibrium amplitude of sediment waves and its sensitivity to the key parameters. The predicted wavelength and amplitude of sediment waves are comparable with field observations in the Atlantic Ocean, the Sea of Japan and the Pacific Ocean.
The CD46 ectodomain participates in human cytomegalovirus infection of epithelial cells
Authors: Parsons Andrea J. , Stein Kathryn R. , Atanasoff Kristina E. , Ophir Sabrina I. , Casado Jailene Paredes , Tortorella Domenico
Published: September 2023

Human cytomegalovirus (HCMV) primary infections are typically asymptomatic in healthy individuals yet can cause increased morbidity and mortality in organ transplant recipients, AIDS patients, neonates, and the elderly. The successful, widespread dissemination of this virus among the population can be attributed in part to its wide cellular tropism and ability to establish life-long latency. HCMV infection is a multi-step process that requires numerous cellular and viral factors. The viral envelope consists of envelope protein complexes that interact with cellular factors; such interactions dictate virus recognition and attachment to different cell types, followed by fusion either at the cell membrane or within an endocytic vesicle. Several HCMV entry factors, including neuropilin-2 (Nrp2), THBD, CD147, OR14I1, and CD46, are characterized as participating in HCMV pentamer-specific entry of non-fibroblast cells such as epithelial, trophoblast, and endothelial cells, respectively. This study focuses on characterizing the structural elements of CD46 that impact HCMV infection. Infectivity studies of wild-type and CD46 knockout epithelial cells demonstrated that levels of CD46 expressed on the cell surface were directly related to HCMV infectivity. Overexpression of CD46 isomers BC1, BC2, and C2 enhanced infection. Further, CD46 knockout epithelial cells expressing CD46 deletion and chimeric molecules identified that the intact ectodomain was critical for rescue of HCMV infection in CD46 knockout cells. Collectively, these data support a model that the extracellular domain of CD46 participates in HCMV infection due to its surface expression.
Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia
Authors: Goda Chinmayee , Kulkarni Rohan , Rudich Alexander , Karunasiri Malith , Balcioglu Ozlen , Al-Marrawi Yzen , Korn Erin , Kanna Sanjay , Garfinkle Elizabeth A.R. , Mundy-Bosse Bethany , Zhang Bin , Marcucci Guido , Mardis Elaine R , Garzon Ramiro , Miller Katherine E , Dorrance Adrienne M
Published: September 2023

Mutations in hematopoietic stem/progenitor cells (HSPCs) can remain dormant within the bone marrow (BM) for decades before leukemia onset. Understanding the mechanisms by which these mutant clones eventually slead to full blown leukemia is of critical importance to develop strategies to eliminate these clones before they achieve their full leukemogenic potential. Recent data suggest that leukemic stem cells (LSCs) induce alterations within BM microenvironment (BMM) favoring LSC growth over normal HSCs. However, the cross talk between preleukemic stem cells (pLSC) and BMM is not completely understood. We hypothesize that pLSC induces critical changes within the BMM that are critical for leukemogenesis. To address this question, we are using our previously developed murine model of AML that highly recapitulates the human disease, develops AML sporadically with a preleukemic phase in which mice display normal white blood counts (WBCs) and absence of blasts in the BM. Thus, this is an excellent model to evaluate changes in the BMM that occurs during progression into AML. Using this model we performed single cell RNA-sequencing on cells from the BMM compared to wild-type (WT) controls. Overall, we defined the transcriptional profiles of pre-leukemic BMM cells and observed decreased percentages of normal BMM cells such as LepR+ mesenchymal stem cells (MSCs) and endothelial cells (ECs), known to regulate normal HSC function. Concomitantly, we found increases in CD55+ fibroblasts and NG2+ pericytes, that might play a more important role in regulation of pre-LSCs. Preleukemic CD55+ fibroblasts had a higher proliferation rate and showed significant down-regulation of several collagen genes known for regulating extra cellular matrix (ECM) including:Col1a1, Col1a2, Col3a1, Col4a1, andCol6a1,suggesting that ECM remodeling occurs in the early stages of leukemogenesis. Importantly, co-culture assays found that pre-leukemic CD55+ BM fibroblasts expanded pre-LSCs significantly over normal HSCs. In conclusion, we have identified distinct changes in the preleukemic BMM and identified a novel CD55+ fibroblast population that is expanded in preleukemic BMM that promote the fitness of pre-LSCs over normal HSCs.

STATEMENT OF SIGNIFICANCE

We have identified changes in the BMM landscape that define a preleukemic BM niche which includes the expansion of a novel CD55+ fibroblast population. These data suggest that a distinct preleukemic BM niche exists and preferentially supports LSC survival and expansion over normal HSCs to promote leukemogenesis.
An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying translocation RCC
Authors: Ganpat Maroussia M.P. , Morales-Rodriguez Francisco , Pham Nhung , Lijnzaad Philip , de Souza Terezinha , Derakshan Sepide , Fumagalli Arianna , Zeller Peter , Balwierz Aleksandra , Ayyildiz Dilara , van den Heuvel-Eibrink Marry M. , de Krijger Ronald R. , van Oudenaarden Alexander , Margaritis Thanasis , de Sousa Lopes Susana M. Chuva , Drost Jarno
Published: September 2023

Translocation renal cell carcinoma (tRCC) is a rare, aggressive type of kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members, TFE3 or, in rare cases, TFEB. The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. Here, we utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expression of one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion expressing tubuloids adopt a tRCC-like phenotype and gene expression signaturein vitroand grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis reveals that SFPQ-TFE3 reprograms gene expression signatures by aberrant, gain-of-function genome-wide DNA binding. Combining these analyses with single-cell mRNA readouts reveals an epithelium-to-mesenchymal differentiation trajectory underlying tRCC transformation, potentially caused by deregulated Wnt signaling. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation, thereby facilitating the development of new therapeutic interventions.