bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial)
Authors: Okuma Hitomi S. , Watanabe Keisuke , Tsuchihashi Kenji , Machida Ryunosuke , Sadachi Ryo , Hirakawa Akihiro , Ariyama Hiroshi , Kanai Masashi , Kamikura Masahisa , Anjo Kenta , Hiramitsu Akari , Sekine Shigeki , Okita Natsuko , Mano Hiroyuki , Nishikawa Hiroyoshi , Nakamura Kenichi , Yonemori Kan
Published: October 2023

Purpose:

Mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) are positive predictive markers for immune checkpoint inhibitors. However, data on the activity of nivolumab in advanced dMMR/MSI-H rare cancers and more accurate biomarkers are worth exploring.

Patients and Methods:

We conducted a multicenter phase II, open-label, single-arm clinical trial to explore the effectiveness and safety of nivolumab monotherapy in patients with advanced rare cancers with dMMR/MSI-H, in parallel with immune phenotype analysis, to explore new biomarkers. A Bayesian adaptive design was applied. Characterization of peripheral blood mononuclear cells (PBMC) was characterized by multicolor flow cytometric analysis and CyTOF using samples collected before and after the intervention. The dMMR was identified by the complete loss of MLH1/MSH2/MSH6/PMS2.

Results:

From May 2018 to March 2021, 242 patients were screened, and 11 patients were enrolled, of whom 10 were included in the full analysis. Median follow-up was 24.7 months (interquartile range, 12.4–31.5). Objective response rate was 60% [95% confidence interval (CI), 26.2–87.8] by central assessment and 70% (95% CI, 34.8–93.3) by local investigators. Median progression-free survival was 10.1 months (95% CI, 0.9–11.1). No treatment-related adverse events of grade 3 or higher were observed. Patients with a tumor mutation burden of ≥10/Mb showed a 100% response rate (95% CI, 47.8–100). Responders had increased T-bet+ PD-1+ CD4+ T cells in PBMC compared with nonresponders (P < 0.05).

Conclusions:

The trial met its primary endpoint with nivolumab, demonstrating clinical benefit in advanced dMMR/MSI-H rare solid cancers. Besides, the proportion of T-bet+ PD-1+ CD4+ T-cells may serve as a novel predictive biomarker.
Overweight, Weight Loss, and Self-Reported Global Life Satisfaction: The Lolland-Falster Health Study
Authors: Søby Signe Falcon , Sørensen Thorkild I.A. , Jepsen Randi , Køster-Rasmussen Rasmus
Published: October 2023

Introduction: Obesity is associated with reduced quality of life and reduced life satisfaction, but does weight loss make you happier? The objective of this study was to investigate if body mass index (BMI) is associated with self-reported global life satisfaction, and if weight loss among individuals with overweight is associated with a higher life satisfaction than among weight-stable individuals with overweight. Methods: The participants in the present population-based cohort study from Denmark were 15,213 adults (18 years or older) in the Lolland-Falster Health Study who reported their global life satisfaction with the Cantril Ladder Score (CLS) (scores range from 0, very poor, through 10, very good). The association of BMI and history of weight loss with CLS was assessed by multivariable analyses adjusted for sex, age, educational level, cohabitation, self-reported health, and smoking status. Results: Higher BMI was associated with lower CLS (p < 0.0001). BMI 30–35 was associated with a 0.47 point (95% confidence interval [CI] 0.39; 0.55) lower score and BMI ≥45 with a 1.85 point (CI 1.45; 2.25) lower score, than BMI 18.5–25. History of weight loss was associated with lower CLS among individuals with BMI ≥25 (−0.15 lower CLS, p < 0.005), whereas in the subgroup of individuals with BMI ≥25 and good self-reported health, there was no significant difference in CLS between the weight stable and the weight loss groups (−0.05, p 0.33). Conclusion: This study found that higher BMI was associated with lower CLS. In subjects with BMI ≥25, weight loss was associated with lower CLS compared with stable weight during 5 years. In subjects with BMI ≥25 and good self-reported health, there was no relation between weight loss and CLS. Thus, contrary to our hypothesis, we found that weight loss among participants with overweight was not associated with higher life satisfaction.
Efficacy and Safety of Extracorporeal Shock Wave Therapy in the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Acquired Premature Ejaculation Patients
Authors: Sokmen Dogukan , Comez Yusuf Ilker
Published: October 2023

Introduction: The aim of this study was to evaluate the efficacy and safety of extracorporeal shock wave therapy (ESWT) in patients with acquired premature ejaculation (APE) due to chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Method: Patients with APE due to CP/CPPS between January 2020 and June 2022 were included in the study. Demographic data of the patients were recorded, and the degree of their symptoms was evaluated with the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), premature ejaculation diagnostic tool (PEDT), and Premature Ejaculation Profile (PEP). The international prostate symptom index (IPSS) was also used for lower urinary tract symptoms (LUTS), and the international erectile function index-erectile function (IIEF-EF) was used to evaluate erectile functions. All patients received treatment with the Medispec Bold Li-ESWT device without using any anesthesia method (12 sessions). The changes in the symptom scores of the patients were evaluated before the treatment and at the 3rd month after the treatment. Results: A total of 42 patients were included in the study. The mean age of the patients was 43.75 ± 12.03 (20–55), and the mean BMI was 23.58 ± 7.61 (18.03–35.98) kg/m2. The patients’ estimated mean intravaginal ejaculation latency time (IELT) before ESWT was 37.98 ± 21.87 s. After a total of 12 sessions of ESWT, the IIEF-EF, IPSS, NIH-CPSI, and PEP index scores of the patients showed significant improvements (p < 0.001 for each). The IELT mean increased to 74.81 ± 46.79 s (p < 0.001). Posttreatment IELT fold increase was determined as 3.25 ± 1.72 fold. A highly significant positive correlation (p = 0.032; r = 0.839) was found between the CPSI score difference and the posttreatment PEP index score. Conclusion: Li-ESWT treatment is an effective and safe treatment with positive effects on both LUTS and premature ejaculation in patients with APE symptoms due to CP/CPPS. Patients who benefit from CP treatment also have longer IELT times.
Laparoscopically Resected Ectopic Hepatocellular Carcinoma Mimicking Subepithelial Tumor of Stomach: A Case Report
Authors: Park Yong-Eun
Published: October 2023

Ectopic hepatocellular carcinoma (HCC) can be defined as an HCC arising from hepatic parenchyma located in an extrahepatic organ or tissue. Fewer than 100 cases of ectopic liver have been reported. In 30 of these cases, HCC was detected in ectopic tissue. The author describes a case of ectopic HCC mimicking subepithelial tumor (SET) of the stomach successfully treated by laparoscopic resection. This case report also provides a pertinent review of the literature. A 61-year-old male was referred to our department for the management of an intra-abdominal mass found on abdominal computed tomography performed at a local medical center due to a 2-month history of vague abdominal pain. Abdominal magnetic resonance imaging and computed tomography showed a 7.2-cm sized heterogenous mass over the left subphrenic space adjacent to the stomach. Esophagogastroduodenoscopy showed a huge subepithelial mass at the fundus of the stomach. Based on the above findings, the diagnosis of SET of the stomach such as gastrointestinal stromal tumor or leiomyoma was suspected. Laparoscopic surgery was performed for definite diagnosis and treatment of the huge SET of the stomach. Histologic diagnosis was ectopic HCC of the trabecular type. Its histologic grade was consistent with Edmondson grade II. Although ectopic HCC is quite rare tumor of the stomach, it should be considered in the differential diagnosis of other abdominal mass-like lesions. Currently, with advances of laparoscopic surgery, laparoscopic resection for complete excision of ectopic HCC is possible with acceptable results.
Supratentorial Collision Tumor of Hemangioblastoma and Metastatic Clear Cell Renal Cell Carcinoma in a Patient with von Hippel-Lindau Disease
Authors: Luo Wenjun , Sun Cuiyun , Yu Shizhu
Published: October 2023

Collision tumors are rarely reported in patients with von Hippel-Lindau (VHL) disease, even though VHL patients often present with multi-organ tumor syndromes, like hemangioblastoma and renal cell carcinoma (RCC). Hemangioblastoma is rarely located in a supratentorial location, and intracranial lateral ventricular is also not a common site of metastasis for RCC. It is extremely rare for the two tumors to collide in the supratentorial area. We report a 64-year-old man with a history of clear cell RCC who presented with a sudden headache. The brain magnetic resonance imaging revealed that there was a cystic-solid mass in the intracranial lateral ventricular trigone. Histopathologically, the tumor consisted of two distinct components, most of which showed the typical morphology of hemangioblastoma. However, there were a few acinar structures composed of clear cells scattered in hemangioblastoma, and these acinar structures were subsequently confirmed as clear cell RCC. The genetic testing confirmed that the patient had VHL disease with de novo somatic mutation. Based on our case report, we systematically reviewed the characteristics of collision tumor composed of hemangioblastoma and metastatic RCC in VHL patients. The special growth site of our case is the first report of this kind of collision tumor, and can also help enrich our understanding of VHL disease and collision tumor.
Sodium Chloride versus Lactose as a Carrier for House Dust Mite Allergen in Allergen Chamber Studies: A Clinical Study to Assess Noninferiority
Authors: Struß Nadja , Dieter Susanne , Schwarz Katharina , Badorrek Philipp , Hohlfeld Jens M.
Published: October 2023

Introduction: In the Fraunhofer allergen challenge chamber (ACC), a standardized, universal, good manufacturing practice-conforming technology using a spray dried solution of lactose (L) and allergen extract has been established. In this study, we investigated the noninferiority of hypertonic sodium chloride (S) versus L as a carrier for house dust mite (HDM) allergen to simplify manufacturing, reduce costs, and allow for wider use. Methods: Using a participant-blinded, sham exposure-controlled, single-arm, sequential intervention study, we challenged adults with HDM allergic rhinitis five times in the ACC. Participants were first exposed to S, L, and clean air (block 1), followed by S + HDM and L + HDM (block 2). Primary endpoints were mean total nasal symptom score (TNSS) and mean nasal secretion weight. Results: 19 participants were enrolled in the study (10 females; mean age 32 years [22–49], 4 with mild allergic asthma). The safety profile of S + HDM and L + HDM was similar; eight participants experienced mild procedure-related adverse events including tiredness, cough, and dyspnea. Due to dropouts, 13 participants completed the study and were evaluated. Mean TNSS and nasal secretion were as follows: S 0.98, 0.28 g; L 1.1, 0.20 g; clean air 1.1, 0.23 g; S + HDM 5.7, 4.8 g; L + HDM 5.1, 5.1 g. Separate block 1/block 2 MANOVAs with TNSS and nasal secretion as dependent variables revealed no significant differences between the carriers, neither alone and compared with clean air (p = 0.2059, Wilk’s λ = 0.78) nor combined with HDM (p = 0.3474, Wilk’s λ = 0.89). Noninferiority of S was established using a meta-analysis-based minimal clinical important difference of −0.55: mean TNSS difference between S + HDM and L + HDM was 0.62 (90% CI: −0.51 to 1.74). Conclusion: S as an HDM carrier was safe and well tolerated. It was noninferior to L which makes it an adequate and easy-to-use carrier substitute.
Resorcinol 10% as a Promising Therapeutic Option for Mild Hidradenitis Suppurativa: A Prospective, Randomized, Open Study
Authors: Katoulis Alexandros , Efthymiou Ourania , Liakou Aikaterini , Pappa Georgia , Kanelleas Antonios , Koumaki Dimitra , Bozi Evangelia , Sgouros Dimitrios
Published: October 2023

Introduction: Treatment of hidradenitis suppurativa (HS) is challenging, and in Hurley stage I, it is based on topical measures. Our aim was to compare the efficacy and safety of topical resorcinol 10% with topical clindamycin 1% and no therapy, in Hurley stage I HS. Methods: In this open, prospective, randomized trial, we studied 60 Hurley stage I patients with IHS4 ≤10. Group A was treated with topical resorcinol 10%; group B with clindamycin lotion 1%; and group C received no treatment. Patients were evaluated by total lesion count, the International Hidradenitis Suppurativa Severity Score System (IHS4) and the Dermatology Life Quality Index (DLQI) at baseline, 12 and 24 weeks. Self-reported number of flares and adverse events (AEs) were recorded. Results: A significant reduction in the mean total lesion count and DLQI scores were observed in group A, compared to group B at week 12 (p = 0.036, p < 0.001, respectively), and in the mean total lesion count, IHS4, and DLQI scores at week 24 (p = 0.034, p = 0.017, p < 0.001, respectively). Resorcinol 10% was well-tolerated with only mild AEs. Conclusion: Resorcinol 10% may represent a useful alternative for the long-term treatment of mild HS, which is superior to topical clindamycin and has a favorable safety profile.
A Decade of Pathogenesis Advances in Non-Type 2 Inflammatory Endotypes in Chronic Rhinosinusitis: 2012–2022
Authors: Cui Na , Zhu Xuewei , Zhao Chen , Meng Cuida , Sha Jichao , Zhu Dongdong
Published: October 2023

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely, CRS with nasal polyps and CRS without nasal polyps. The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the PubMed and Web of Science databases were searched to conduct a critical analysis of representative literature works on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increase the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied, and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.
The Effect of Postnatal Cytomegalovirus Infection on (Micro)structural Cerebral Development in Very Preterm Infants at Term-Equivalent Age
Authors: Pellkofer Yasmin , Hammerl Marlene , Griesmaier Elke , Sappler Maria , Gizewski Elke Ruth , Kiechl-Kohlendorfer Ursula , Neubauer Vera
Published: October 2023

Introduction: There are some data indicating a negative impact of postnatal cytomegalovirus (CMV) infection on long-term neurodevelopmental outcome of preterm infants. So far, there is only little knowledge about a cerebral imaging correlate of these neurodevelopmental alterations induced by postnatal CMV infection in preterm infants. The aim of the current study was to investigate the effect of postnatal CMV infection on the incidence of brain injury and on microstructural brain maturation in very preterm infants at term-equivalent age. Methods: Infants <32 gestational weeks (02/2011–11/2018) received cerebral MRI including axial diffusion-weighted images at term-equivalent age. All infants were screened for CMV infection using urine/saliva samples, and infection was regarded as acquired postnatal if a sample became positive >5 postnatal days. We compared brain injury as well as fractional anisotropy and apparent diffusion coefficient in 14 defined cerebral regions between infants with and without postnatal CMV infection. Results: 401 infants were eligible, of whom 18 (4.5%) infants had a postnatal CMV infection. There were no significant differences in rates of brain injury or in microstructural brain development between both groups. This applied equally to the subgroup of infants <28 gestational weeks. Conclusion: Although infants with postnatal CMV infection were born more immature and more frequently suffered from complications related to immaturity, we neither observed a higher rate of preterm brain injury nor disadvantageous alterations in microstructural brain maturation at term-equivalent age.
Explorative Clustering of the Nitrogen Balance Trajectory in Critically Ill Patients: A Preliminary post hoc Analysis of a Single-Center Prospective Observational Study
Authors: Nakamura Kensuke , Ogura Kentaro , Nakano Hidehiko , Ikechi Daisuke , Mochizuki Masaki , Takahashi Yuji , Goto Tadahiro
Published: October 2023

Background: The nitrogen balance estimates a protein net difference. However, since it has a number of limitations, it is important to consider the trajectory of the nitrogen balance in the clinical course of critically ill patients. Objectives: We herein exploratively classified the nitrogen balance trajectory using a machine learning method. Method: This is a post hoc analysis of a single-center prospective study for the patients admitted to our Emergency and Critical Center ICU. The nitrogen balance was evaluated with 24-h urine collection from ICU days 1–10 with 9 points. K-means clustering was performed to classify the nitrogen balance trajectory. We also evaluated factors associated with uncovered clusters. Results: Seventy-six eligible patients were included in the present study. After clustering, the nitrogen balance trajectory was classified into 4 classes. Class 1 was trajected as a negative balance over 10 days (24 patients). Class 2 had a positive conversion on day 3 or 4 (8 patients). Class 3 had a positive conversion on day 8 or 9 (28 patients). Class 4 initially had a positive balance and then converted to a negative balance (16 patients). Sepsis complication and steroid use were associated with negative nitrogen balance trajectory. Class 2 was associated with lower length of hospital stay and femoral muscle volume loss, however, frequently had frailty and sarcopenia on admission. Active nutrition therapy intention was not correlated with positive trajectory. Conclusions: The nitrogen balance trajectory in critically ill patients may be classified into 4 classes for clinical practice. Among patients emergently admitted to the ICU, the positive conversion of the nitrogen balance might be delayed over 10 days.
Frontiers in Endoscopic Treatment for Gastroesophageal Reflux Disease
Authors: Ota Kazuhiro , Takeuchi Toshihisa , Higuchi Kazuhide , Sasaki Shun , Mori Yosuke , Tanaka Hironori , Hakoda Akitoshi , Sugawara Noriaki , Iwatsubo Taro , Nishikawa Hiroki
Published: October 2023

Background: The 3rd edition of the evidence-based clinical practice guidelines for gastroesophageal reflux disease (GERD) 2021 from the Japanese Society of Gastroenterology states that the treatment strategy for potassium-competitive acid blocker (PCAB)-refractory GERD remains unclear. Furthermore, even if GERD improves with the administration of an acid secretion inhibitor, it is feared that GERD may flare up after discontinuation of the drug, resulting in some cases in which patients are forced to take vonoprazan semipermanently (the so-called PCAB-dependent cases). From a global perspective, PCAB is not yet used in all countries and regions, and measures that can be taken now for cases in which a conventional proton pump inhibitor (PPI) is inadequately effective need to be devised. Summary: Endoscopic treatment for GERD may be effective in cases where conventional proton pump inhibitors are ineffective; however, there are insufficient long-term studies to corroborate this, and its cost effectiveness is unknown. Other treatment options for PCAB or PPI-refractory GERD include surgical procedures (Nissen and Toupet operations), which have a longer history than endoscopic treatment for GERD. However, their long-term results are not as good as those of acid secretion inhibitors, and they are not cost effective. Endoscopic treatment for GERD may fill gaps in inadequate surgical treatment. In April 2022, endoscopic anti-reflux mucosal resections (ARMS [anti-reflux mucosectomy] and ESD-G [endoscopic submucosal dissection for GERD]) were approved for reimbursement, making endoscopic treatment of GERD possible throughout Japan. Key Messages: It is important to identify the background factors in cases in which endoscopic treatments are effective.
Comparison between MRI and the Combination of 2D and 3D US in the Prenatal Diagnosis of Closed Spina Bifida
Authors: Zhang Weiping , Wang Jingling , Wu Hui , Chen Li
Published: October 2023

Introduction: Closed spina bifida (CSB) is a rare condition with a challenging prenatal diagnosis. Herein, we assess the conventional two-dimensional (2D) ultrasound (US) combined with three-dimensional (3D) ultrasound (US) and magnetic resonance imaging (MRI) in the prenatal diagnosis of CSB. Methods: In this retrospective study, we included 20 cases of fetal CSB confirmed by postnatal MRI, post-mortem pathological examination, or postpartum surgery. Prenatal 2D US complemented with the 3D US was performed in all fetuses to evaluate the characteristics of the conus, vertebral arch, and scoliosis. Moreover, MRI was performed to establish the split vertebrae, with or without a bulging mass. Thereafter, we compared the performance of the US and MRI. Results: Diagnosis accuracy of US was comparable with MRI (70% vs. 75%, κ = 0.62); US detected more cases with interpediculate distance ≥95% (55% vs. 35%, κ = 0.22) than MRI. On the other hand, MRI had a superior capacity for identifying vertebral arch fissures (20% vs. 35%, κ = 0.39). MRI and ultrasound had good agreement in the conus medullaris (65% vs. 70%, κ = 0.42) and scoliosis (45% vs. 35%, κ = 0.59). Both US and MRI detected 1 (5.0%) case with “lemon sign” and “banana sign.” The missed diagnosis rates of US and MRI were 15% (3/20) and 5% (1/20), respectively. The misdiagnosis rates of US and MRI were 15.0% (3/20) and 20.0% (4/20), respectively. Conclusion: Both MRI and 2D US combined with the 3D US had excellent performance in prenatal diagnosis of CSB.
Regulation of Skeletal Muscle Resistance Arteriolar Tone: Integration of Multiple Mechanisms
Authors: Halvorson Brayden D. , Bao Yuki , Ward Aaron D. , Goldman Daniel , Frisbee Jefferson C.
Published: October 2023

Introduction: Physiological system complexity represents an imposing challenge to gaining insight into how arteriolar behavior emerges. Further, mechanistic complexity in arteriolar tone regulation requires that a systematic determination of how these processes interact to alter vascular diameter be undertaken. Methods: The present study evaluated the reactivity of ex vivo proximal and in situ distal resistance arterioles in skeletal muscle with challenges across the full range of multiple physiologically relevant stimuli and determined the stability of responses over progressive alterations to each other parameter. The five parameters chosen for examination were (1) metabolism (adenosine concentration), (2) adrenergic activation (norepinephrine concentration), (3) myogenic activation (intravascular pressure), (4) oxygen (superfusate PO2), and (5) wall shear rate (altered intraluminal flow). Vasomotor tone of both arteriole groups following challenge with individual parameters was determined; subsequently, responses were determined following all two- and three-parameter combinations to gain deeper insight into how stimuli integrate to change arteriolar tone. A hierarchical ranking of stimulus significance for establishing arteriolar tone was performed using mathematical and statistical analyses in conjunction with machine learning methods. Results: Results were consistent across methods and indicated that metabolic and adrenergic influences were most robust and stable across all conditions. While the other parameters individually impact arteriolar tone, their impact can be readily overridden by the two dominant contributors. Conclusion: These data suggest that mechanisms regulating arteriolar tone are strongly affected by acute changes to the local environment and that ongoing investigation into how microvessels integrate stimuli regulating tone will provide a more thorough understanding of arteriolar behavior emergence across physiological and pathological states.
RhoA/ROCK Signaling Is Involved in Pathological Retinal Neovascularization
Authors: Tang Fen , Huang Kongqian , Peng Biyan , Deng Wen , Su Ning , Xu Fan , Zhang Mingyuan , Zhong Haibin
Published: October 2023

Objective: The aim of the study was to evaluate the effect of the RhoA/ROCK inhibitor Fasudil on retinal neovascularization (NV) in vivo and angiogenesis in vitro. Methods: C57BL/6 was used to establish an OIR model. First, RhoA/ROCK expression was first examined and compared between OIR and healthy controls. Then, we evaluated the effect of Fasudil on pathological retinal NV. Whole-mount retinal staining was performed. The percentage of NV area, the number of neovascular tufts (NVT), and branch points (BP) were quantified. Finally, human umbilical vein endothelial cells (HUVECs) were used to investigate the effect of Fasudil on angiogenesis. Results: Real-time PCR and Western blotting showed that ROCK expression in retinal tissue was statistically upregulated in OIR. Furthermore, we found that Fasudil attenuated the percentage of NV area, the number of NVT, and BP significantly. In addition, Fasudil could suppress the proliferation and migration of HUVECs induced by VEGF. Conclusions: RhoA/ROCK might be involved in the pathogenesis of OIR. And its inhibitor Fasudil could suppress retinal NV in vivo and angiogenesis in vitro. Fasudil may be a potential treatment strategy for retinal vascular diseases.
Usefulness and Educational Benefit of a Virtual Scale Endoscope in Measuring Colorectal Polyp Size
Authors: Takehara Yudai , Yamashita Ken , Morimoto Shin , Tanino Fumiaki , Yamamoto Noriko , Kamigaichi Yuki , Tanaka Hidenori , Takigawa Hidehiko , Yuge Ryo , Urabe Yuji , Oka Shiro
Published: October 2023

Introduction: The virtual scale endoscope (VSE) is a newly introduced endoscope that helps endoscopists in measuring colorectal polyp size (CPS) during colonoscopy by displaying a virtual scale. This study aimed to determine the usefulness of the VSE for CPS measurement and the educational benefit of using VSE images to improve CPS estimation accuracy. Methods: This study included 42 colorectal polyps in 26 patients treated at Hiroshima University Hospital. In study 1, CPS measured using a VSE before endoscopic mucosal resection was compared with CPS measured on resected specimens, and the agreement between the two measurement methods was evaluated via Bland-Altman analysis. In study 2, 14 endoscopists (5 beginners, 5 intermediates, and 4 experts) took a pre-test to determine the size of 42 polyps. After the pre-test, a lecture on CPS measurement using VSE images was given. One month later, the endoscopists took a post-test to compare CPS accuracy before and after the lecture. Results: In study 1, Bland-Altman analysis revealed no fixed or proportional errors. The mean bias ±95% limits of agreement (±1.96 standard deviations) of the measurement error was −0.05 ± 0.21 mm, indicating that the agreement between two measurement methods was sufficient. In study 2, the accuracy of CPS measurement was significantly higher among beginners (59.5% vs. 26.7%, p < 0.01) and intermediates (65.2% vs. 44.3%, p < 0.05) in the post-test than in the pre-test. Conclusion: The VSE accurately measures CPS before resection, and its images are useful teaching tools for beginner and intermediate endoscopists.
Scleroderma Secondary to Pembrolizumab: A Case Report and Review of 19 Cases of Anti-PD-1-Induced Scleroderma
Authors: Farrugia Stephanie , Mercieca Liam , Betts Alexandra , Refalo Nick , Boffa Michael J.
Published: October 2023

Immune checkpoint inhibitors are increasingly being used to treat various malignancies. Despite their efficacy, they are known to potentially cause immune-related adverse effects, including dermatological manifestations. A rare cutaneous immune-related adverse effect is scleroderma, which has been reported to occur with anti-programmed cell death-1 (PD-1) agents such as pembrolizumab and nivolumab. This may present with skin tightening and hardening at any point during or after immunotherapy. We present the case of a 54-year-old Caucasian woman who, following 16 doses of pembrolizumab for breast cancer, developed clinical features of scleroderma confirmed on histology. She was initially treated with oral corticosteroids, followed by oral psoralen-UVA, with poor response, but eventually improved with methotrexate. A literature review revealed 12 other cases of scleroderma following pembrolizumab treatment and 6 cases of scleroderma following nivolumab treatment. Males and females were both affected, and their ages ranged from 33 to 81 years. Scleroderma developed at different stages of pembrolizumab or nivolumab therapy. Although scleroderma is not commonly drug-induced, anti-PD-1 agents may be a rare cause and it is important to elicit an accurate drug history, including immunotherapy, in such cases.
The Relationship between Allergic Disease and Sexual Dysfunction: A Scoping Review
Authors: Chiang Ting-Yi , Lee Hsiang-Ying , Chien Wei-Chen , Su Hsiao-Chun , Su Yung-Chun , Lin Chung-Wei
Published: October 2023

Introduction: Sexual dysfunction (SD) and allergic disease are common health concerns worldwide and bear a potential relationship. This scoping review is conducted to analyze the currently available data regarding the associations between these two health issues. Methods: A comprehensive literature search was performed in the databases of PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to retrieve studies that were published before January 2023. A narrative synthesis was conducted to analyze the effects of allergic diseases on SD based on the evaluation of the Female Sexual Function Index (FSFI) and International Index of Erectile Function (IIEF). Results: Twelve observational studies were included after the selection process. The results generally suggested lower FSFI or IIEF scores in patients with asthma, allergic rhinitis, allergic rhinoconjunctivitis, and urticaria compared to the healthy control groups. The underlying factors of this relationship could be inflammation, psychological factors, hormonal changes, sleep disorders, sexual behavior-related allergic reactions, social economic status, and the use of medications. Conclusion: SD and allergic disease are interrelated based on the extant literature. This scoping review provides insights into the clinical implications of both entities, while more research studies are warranted to further elucidate this complex relationship.
Pan-Cancer Analysis of the Prognostic and Immunological Role of SMG5: A Biomarker for Cancers
Authors: Yang Leteng , Wei Jie , Ma Xiaoya , Cheng Rui , Zhang Huan , Jin Tianbo
Published: October 2023

Introduction: SMG5 is involved in tumor cell development and viewed as a potential target for immunotherapy. The purpose of this study was to systematically analyze the expression level, function, and prognostic value of SMG5 in pan-cancers. Methods: Differential expression of SMG5 in normal and tumor tissues was analyzed using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Database (GTEx) data. Survival analysis was performed by Kaplan-Meier method and Cox risk regression. The relationship between SMG5 expression and lymphocyte abundance, tumor cell immune infiltration level, molecular and immune subtypes as well as immune checkpoints was analyzed by tumor-immune system interactions database (TISIDB), Tumor Immune Estimation Resource (TIMER), and Sangerbox databases. The correlation between SMG5 and immune scores was studied using the Estimation of Stromal and Immune Cells in Malignant Tumours using Expression (ESTIMATE) data algorithm. Further, drug sensitivity analysis of SMG5 with low-grade glioma (LGG) was conducted using the CellMiner database. Results: SMG5 was highly expressed in 23 tumors and only had a significant impact on the prognosis of patients with LGG only. In addition, in tumor microenvironment and tumor immune analysis, we found that the level of immune infiltration, tumor mutational load, microsatellite instability, and immune checkpoints of LGG were significantly correlated with SMG5 expression. Furthermore, SMG5 was significantly associated with immune scores, stromal scores, and sensitivity of some drugs in LGG. Conclusion: SMG5 is differentially expressed in several cancers and is significantly associated with prognosis, immune microenvironment, and immune checkpoints in LGG patients. Therefore, SMG5 could be a potential pan-cancer biomarker and an immunotherapeutic target for LGG.
An Analysis of the Content and Recommendations of 700 American Tattoo Aftercare Instructions
Authors: Liszewski Walter , Newcomer Jack , Laumann Anne E. , Leger Marie C. , Farah Ronda S.
Published: October 2023

Background: Tattoo aftercare instructions describe how to care for a new tattoo. Unfortunately, tattoo artists often base their advice on personal experience rather than best practices in medical wound management. The diversity of recommendations in these instructions is currently unknown. Objectives: Our review was performed to determine current recommendations in tattoo aftercare instructions in the United States. Methods: Using a Google search, a total of 700 aftercare instructions from all 50 states and Washington D.C. were collected and their contents analyzed. Results: Most instructions encouraged washing new tattoos with antibiotic soaps, including chlorhexidine, and 14.9% encouraged using topical antibiotics. Few instructed individuals to wash their hands before touching a healing tattoo. A total of 70 moisturizers were recommended. Of these, 22 were niche products made specifically for tattoo aftercare. Only a subset of instructions provided parameters about when to contact the tattooist (49.9%) and/or a physician (19.4%) should there be a complication in the healing process. Conclusion: The content and recommendations of the 700 instructions vary tremendously. Many lacked instructions on appropriate hygiene and when to seek medical care. As skin and wound care experts, there may be an opportunity for the dermatology community to partner with tattooists to create more useful evidence-based tattoo aftercare practices.
Cognitive Impairment Is Associated with New-Onset Stroke: Evidence from a Nationwide Prospective Cohort Study
Authors: Qiao Tian , Lu Hongzhuan , Wang Xianghua , Wang Xiang
Published: October 2023

Introduction: Stroke is closely related to cognitive function, and many patients experience cognitive impairment after stroke; however, whether cognitive impairment is associated with an increased risk of stroke remains inconclusive. This study aims to investigate whether cognitive impairment is associated with new-onset stroke (first ever nonfatal stroke) using a national prospective study. Methods: Data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018 were used. A total of 11,961 Chinese participants aged ≥45 years without a history of stroke were included in the present study and divided into a cognitive impairment group and a normal group according to the baseline cognitive score. Logistic regression analysis was used to analyse the association between baseline cognitive function and new-onset stroke. Results: During the 6.96-year follow-up period, 875 participants experienced new-onset stroke. Compared with the cognitively normal group, the odds ratio (95% confidence intervals) for new-onset stroke in the cognitively impaired group was 1.21 (1.04, 1.40) when not adjusted for confounders and 1.22 (1.01, 1.48) after adjusting for established confounding factors, including demographic data, medical history, physical examination, and laboratory indicators. Conclusion: Cognitive impairment was associated with new-onset stroke among middle-aged and elderly Chinese individuals. Further studies should be carried out to confirm the causal relationship between cognitive impairment and stroke.
The Global Prevalence and Severity of Dental Caries among Racially Minoritized Children: A Systematic Review and Meta-Analysis
Authors: Nath Sonia , Sethi Sneha , Bastos João L. , Constante Helena M. , Mejia Gloria , Haag Dandara , Kapellas Kostas , Jamieson Lisa
Published: October 2023

Racially minoritized children often bear a greater burden of dental caries, but the overall magnitude of racial gaps in oral health and their underlying factors are unknown. A systematic review and meta-analysis were conducted to fill these knowledge gaps. We compared racially minoritized (E) children aged 5–11 years (P) with same-age privileged groups (C) to determine the magnitude and correlates of racial inequities in dental caries (O) in observational studies (S). Using the PICOS selection criteria, a targeted search was performed from inception to December 1, 2021, in nine major electronic databases and an online web search for additional grey literature. The primary outcome measures were caries severity, as assessed by mean decayed, missing, and filled teeth (dmft) among children and untreated dental caries prevalence (d > 0%). The meta-analysis used the random-effects model to calculate standardized mean differences (SMD) and 95% confidence intervals (95% CI). Subgroup analysis, tests for heterogeneity (I2, Galbraith plot), leave-one-out sensitivity analysis, cumulative analysis, and publication bias (Egger’s test and funnel plots) tests were carried out. The New Castle Ottawa scale was used to assess risk of bias. This review was registered with PROSPERO, CRD42021282771. A total of 75 publications were included in the descriptive analysis. The SMD of dmft score was higher by 2.30 (95% CI: 0.45, 4.15), and the prevalence of untreated dental caries was 23% (95% CI: 16, 31) higher among racially minoritized children, compared to privileged groups. Cumulative analysis showed worsening caries outcomes for racially marginalized children over time and larger inequities in dmft among high-income countries. Our study highlights the high caries burden among minoritized children globally by estimating overall trends and comparing against factors including time, country, and world income. The large magnitude of these inequities, combined with empirical evidence on the oral health impacts of racism and other forms of oppression, reinforce that oral health equity can only be achieved with social and political changes at a global level.
Impact of Oophorectomy on Survival and Improving Nutritional Status in Ovarian Metastasis from Colorectal Adenocarcinoma
Authors: Miyagawa Yusuke , Kitazawa Masato , Tokumaru Shigeo , Nakamura Satoshi , Koyama Makoto , Yamamoto Yuta , Miyazaki Satoru , Hondo Nao , Soejima Yuji
Published: October 2023

Introduction: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer. Methods: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient’s symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5–109) months. Results: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p < 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110–2,607) preoperatively and 6,095.2 (1,612.3–14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis. Conclusions: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients’ symptoms and nutritional status and may result in improved prognosis.
Differential G Protein-Coupled Estrogen Receptor-1 Regulation of Counter-Regulatory Transmitter Marker and 5′-AMP-Activated Protein Kinase Expression in Ventrolateral versus Dorsomedial Ventromedial Hypothalamic Nucleus
Authors: Bheemanapally Khaggeswar , Briski Karen P.
Published: October 2023

Introduction: The ventromedial hypothalamic nucleus (VMN) is an estrogen receptor (ER)-rich structure that regulates glucostasis. The role of nuclear but not membrane G protein-coupled ER-1 (GPER) in that function has been studied. Methods: Gene silencing and laser-catapult microdissection/immunoblot tools were used to examine whether GPER regulates transmitter and energy sensor function in dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN counter-regulatory nitrergic and γ-Aminobutyric acid (GABA) neurons. Results: Intra-VMN GPER siRNA administration to euglycemic animals did not affect VMNdm or -vl nitrergic neuron nitric oxide synthase (nNOS), but upregulated (VMNdm) or lacked influence on (VMNvl) GABA nerve cell glutamate decarboxylase65/67 (GAD) protein. Insulin-induced hypoglycemia (IIH) caused GPER knockdown-reversible augmentation of nNOS, 5′-AMP-activated protein kinase (AMPK), and phospho-AMPK proteins in nitrergic neurons in both divisions. IIH had dissimilar effects on VMNvl (unchanged) versus VMNdm (increased) GABAergic neuron GAD levels, yet GPER knockdown affected these profiles. GPER siRNA prevented hypoglycemic upregulation of VMNvl and -dm GABA neuron AMPK without altering pAMPK expression. Conclusions: Outcomes infer that GPER exerts differential control of VMNdm versus -vl GABA transmission during glucostasis and is required for hypoglycemic upregulated nitrergic (VMNdm and -vl) and GABA (VMNdm) signaling. Glycogen metabolism is reported to regulate VMN nNOS and GAD proteins. Data show that GPER limits VMNvl glycogen phosphorylase (GP) protein expression and glycogen buildup during euglycemia but mediates hypoglycemic augmentation of VMNvl GP protein and glycogen content; VMNdm glycogen mass is refractory to GPER control. GPER regulation of VMNvl glycogen metabolism infers that this receptor may govern local counter-regulatory transmission in part by astrocyte metabolic coupling.
Troponin T and N-Terminal Pro-Brain Natriuretic Peptide Are Associated with Long-Term All-Cause Mortality in Patients with Post-Sternotomy Mediastinitis following Coronary Artery Bypass Grafting: A 15-Year Follow-Up Study
Authors: Risnes Ivar , Aukrust Pål , Lundblad Runar , Ueland Thor , Rynning Stein Erik , Solheim Eivind , Saeed Sahrai
Published: October 2023

Background: Deep sternal wound/mediastinitis is a rare but feared complication in coronary artery bypass grafting (CABG) patients and seems to increase the risk of cardiac death, and is also associated with the risk of early internal mammary artery (IMA) graft obstruction. The pathological mechanism explaining the link between mediastinitis and IMA graft obstruction and the impact on mortality is complex, multifactorial, and not fully investigated. Objectives: Mediastinitis has been associated with increased concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T (TnT) at mid-term follow-up, representing persistent low-grade myocardial injury and impaired cardiac function. However, whether mediastinitis is associated with all-cause mortality, or whether the association is driven by these cardiac-specific biomarkers (NT-proBNP and TnT), is not investigated. Methods: The present study provides the longest and most complete follow-up data in 82 patients undergoing CABG, including 41 with post-sternotomy mediastinitis. Results: The annualized incidence rate of mediastinitis was 0.14%/year and remained stable at 0.14% throughout the study period. During a mean follow-up of 12.7 ± 3.5 years, a total of 42 deaths occurred (27 [65.9%] in mediastinitis and 15 [36.6%] in non-mediastinitis group, p = 0.008). No association was found between IMA or saphenous vein graft obstruction with all-cause mortality. Mediastinitis was associated with a 1.9-fold increased risk of all-cause mortality. However, in the multivariable-adjusted models, age and higher TnT and NT-proBNP levels, but not mediastinitis per se were associated with all-cause mortality. Conclusions: Mediastinitis after CABG surgery was associated with a poor prognosis during a 15-year follow-up, showing a nearly two-fold higher frequency of all-cause mortality compared with non-mediastinitis group, with the differences in mortality rate occurring primarily after 10 years. The association between mediastinitis and all-cause mortality was modulated by subclinical myocardial damage and stretch, reflected by elevated TnT and NT-proBNP, measured at 2.7-year follow-up, underscoring that these could represent prognostic markers in CABG patients.