bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Validation of an Aging-Associated circRNA-miRNA-mRNA Network in Neovascular Age-Related Macular Degeneration
Authors: Wu Jiali , Jiang Yuxin , Sun Junran , Sun Xiaodong
Published: October 2023

Introduction: Neovascular age-related macular degeneration (NVAMD) is a leading cause of severe vision impairment in the elderly. Aging is one of the most pivotal underlying molecular mechanisms of NVAMD. Methods: In this study, we identified the potential aging-related genes involved in NVAMD. Considering that noncoding RNAs are vital regulators of NVAMD progression, we further explored and constructed an aging-originated circRNA-miRNA-mRNA network of NVAMD. Differential expression of 23 aging-associated genes was identified based on sequencing data and the Human Aging Genomic Resources tool at a threshold of p < 0.05, and log2|fold change| > 1. Results: We screened 12 microRNAs (miRNAs) using public datasets and miRNet database. A total of 13 circRNAs were subsequently mined using the starBase tool. Merging these 13 circRNAs, 12 miRNAs, and 15 genes together, we obtained 281 pairs of circRNA-miRNA and 30 pairs of miRNA-mRNA. Conclusion: We created an aging-related circRNA-miRNA-mRNA network, which could be a promising target for future AMD treatments.
Recombinant Human Insulin-Like Growth Factor-1 Treatment of Severe Growth Failure in Three Siblings with STAT5B Deficiency
Authors: Muthuvel Gajanthan , Al Remeithi Sareea Salem , Foley Corinne , Dauber Andrew , Hwa Vivian , Backeljauw Philippe
Published: October 2023

Introduction: Patients with homozygous recessive mutations in STAT5B have severe progressive postnatal growth failure and insulin-like growth factor-I (IGF-I) deficiency associated with immunodeficiency and increased risk of autoimmune and pulmonary conditions. This report describes the efficacy and safety of recombinant human IGF-1 (rhIGF-1) in treating severe growth failure due to STAT5B deficiency. Case Presentation: Three siblings (P1, 4.4 year-old female; P2, 2.3 year-old male; and P3, 7 month-old female) with severe short stature (height SDS [HtSDS] −6.5, −4.9, −5.3, respectively) were referred to the Center for Growth Disorders at Cincinnati Children’s Hospital Medical Center. All three had a homozygous mutation (p.Trp631*) in STAT5B. Baseline IGF-I was 14.7, 14.1, and 10.8 ng/mL, respectively (all < −2.5 SDS for age and sex), and IGFBP-3 was 796, 603, and 475 ng/mL, respectively (all < −3 SDS for age and sex). The siblings were started on rhIGF-1 at 40 μg/kg/dose twice daily subcutaneously (SQ), gradually increased to 110–120 μg/kg/dose SQ twice daily as tolerated. HtSDS and height velocity (HV) were monitored over time. Results: Six years of growth data was utilized to quantify growth response in the two older siblings and 5 years of data in the youngest. Pre-treatment HVs were, respectively, 3.0 (P1), 3.0 (P2), and 5.2 (P3) cm/year. With rhIGF-1 therapy, HVs increased to 5.2–6.0, 4.8–7.1, and 5.5–7.4 cm/year, respectively, in the first 3 years of treatment, before they decreased to 4.7, 3.8, and 4.3 cm/year, respectively, at a COVID-19 pandemic delayed follow-up visit and with decreased treatment adherence. ΔHtSDS for P1 and P2 was +2.21 and +0.93, respectively, over 6 years, but −0.62 for P3 after 5 years and in the setting of severe local lipohypertrophy and suboptimal weight gain. P3 also experienced hypoglycemia that limited our ability to maintain target rhIGF-1 dosing. Conclusion: The response to rhIGF-1 therapy is less than observed with rhIGF-1 therapy for patients previously described with severe primary IGF-I deficiency, including patients with documented defects in the growth hormone receptor, but may still provide patients with STAT5B deficiency with an opportunity to prevent worsening growth failure.
Characteristics of Molecular Genetic Mutations and Their Correlation with Prognosis in Adolescent and Adult Patients with Acute Lymphoblastic Leukemia
Authors: Sun Xue , Liu Xiaoqian , Li Ying , Shi Xue , Li Yahan , Tan Ran , Jiang Yujie , Sui Xiaohui , Ge Xueling , Xu Hongzhi , Wang Xin , Fang Xiaosheng
Published: October 2023

Introduction: The prognosis of acute lymphoblastic leukemia (ALL) in adolescents and adults is poor, and recurrence is an important cause of their death. Changes of genetic information play a vital role in the pathogenesis and recurrence of ALL; however, the impact of molecular genetic mutations on disease diagnosis and prognosis remains unexplored. This study aimed to explore the frequency spectrum of gene mutations and their prognostic significance, along with the minimal residual disease (MRD) level and hematopoietic stem cell transplantation (HSCT), in adolescent and adult patients aged ≥15 years with ALL. Methods: The basic characteristics, cytogenetics, molecular genetics, MRD level, treatment regimen, and survival outcome of patients with untreated ALL (≥15 years) were collected, and the correlation and survival analysis were performed using the SPSS 25.0 and R software. Results: This study included 404 patients, of which 147 were selected for next-generation sequencing (NGS). NGS results revealed that 91.2% of the patients had at least one mutation, and 67.35% had multiple (≥2) mutations. NOTCH1, PHF6, RUNX1, PTEN, JAK3, TET2, and JAK1 were the most common mutations in T-ALL, whereas FAT1, TET2, NARS, KMT2D, FLT3, and RELN were the most common mutations in B-ALL. Correlation analysis revealed the mutation patterns, which were significantly different between T-ALL and B-ALL. In the prognostic analysis of 107 patients with B-ALL, multivariate analysis showed that the number of mutations ≥5 was an independent risk factor for overall survival and the RELN mutation was an independent poor prognostic factor for event-free survival. Discussion: The distribution of gene mutations and the co-occurrence and repulsion of mutant genes in patients with ALL were closely related to the immunophenotype of the patients. The number of mutations ≥5 and the RELN mutation were significantly associated with poor prognosis in adolescent and adult patients with ALL.
Long-Term Progression-Free Survival of a Pre-Treated Patient with Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil
Authors: Michl Gerlinde Maria , Vogt Florian M. , Nouriani Andreas , Ladurner Roland , Kremer Marcus , Reisländer Timo , Michl Marlies
Published: October 2023

Trifluridine/tipiracil is approved for the use in later or last-line setting in previously treated metastatic colorectal cancer (mCRC) patients who progressed on standard anti-tumor drugs including 5-fluorouracil (5-FU), irinotecan, oxaliplatin, anti-VEGF and anti-EGFR antibodies, or who are not considered candidates for those standard therapies. In this report, we describe a 67-year-old male patient with KRAS-mutated mCRC and metachronous liver and lung metastasis who failed prior 5-FU- and irinotecan-containing regimens, but then showed long-term disease control for 31 months on single-agent trifluridine/tipiracil given as second-line treatment. According to our experience, trifluridine/tipiracil is a feasible and effective treatment option in earlier but not necessarily last-line therapy in mCRC patients who are not considered candidates for doublet or triplet chemotherapy. Besides its efficacy, it is associated with maintained quality of life and a manageable toxicity profile. Considering increasing age of mCRC patients and their wish for maintaining an independent lifestyle, further research on the use of trifluridine/tipiracil in earlier lines of systemic mCRC therapy is warranted.
Quartic CAR-T Cell Bridging to Twice Allo-HSCT Therapy in a Patient with Acute Lymphoblastic Leukemia
Authors: Zhang Qing , Dong Yi , Zhai Zhimin , Tao Qianshan
Published: October 2023

Introduction: Chimeric antigen receptor T (CAR-T) cell therapy is an effective bridging treatment for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in relapsed or refractory acute lymphoblastic leukemia (ALL). However, repetitive CAR-T cell therapy and allo-HSCT can only be performed in a few patients because of technical difficulties and patients’ physical, economic, and social conditions. Case Presentation: A 23-year-old female patient with second relapsed B-cell ALL (B-ALL) underwent human-murine chimeric CD19 CAR-T cell therapy twice, human-murine chimeric CD22 CAR-T cell therapy once, and humanized CD19 CAR-T cell therapy once. Moreover, she was sequentially bridged to her mother donor allo-HSCT once and cousin donor allo-HSCT once. Conclusion: Repetitive CAR-T cell therapy bridging to repetitive allo-HSCT is still a safe and active therapeutic strategy for patients with relapsed or refractory ALL.
Fighting Antimicrobial Resistance and Healthcare-Associated Infections in EU-JAMRAI: The One-Health Response from Italy
Authors: Busani Luca , Creti Roberta , Fabbro Elisa , Prestinaci Francesca , Pantosti Annalisa , Marella Anna Maria , Brusaferro Silvio , Sabbatucci Michela
Published: October 2023

Introduction: Antimicrobial resistance (AMR) is a serious health threat, and it has high priority among the European public health agenda. The development and implementation of the National Action Plans (NAPs) with a One-Health perspective to fight AMR was supported in 2017 by the European Union (EU) through a Joint Action on Antimicrobial Resistance and Healthcare Associated Infections (EU-JAMRAI). The Italian National Institute of Health (Istituto Superiore di Sanità), supported by the University of Udine, and the University of Foggia were among the 44 partners involved. This paper describes the results of EU-JAMRAI relevant to Italy and its impact on national policies. Methods: The activities involved national and international experts who worked in groups, either in virtual or face-to-face meetings. Country-to-country visits were organized to assess and compare the national strategies to counteract AMR and to exchange best practices. In addition, qualitative research methods, particularly focus groups (FGs) and structured interviews, were carried out to collect information and opinions from the experts. Results: The Italian team of experts from the Ministry of Health and the University of Foggia visited the Netherlands and hosted the Polish expert team in Italy. In two FG, stakeholders’ opinions from different organizations were collected and analyzed to identify critical areas and provide recommendations to ensure implementation of the NAP and effective One-Health integration. In addition, attitudes of medical professionals toward antimicrobial stewardship were evaluated in a medium/large Italian hospital. Strengths were identified in the multidisciplinary approach and the hospital management’s proactive involvement. As for the veterinary sector, Italy was among the 10 EU countries that did not have any national AMR surveillance in place for animal bacterial pathogens. Consequently, a European surveillance system was proposed with the adhesion of Italy. Regarding research and innovation to fight AMR and healthcare-associated infection, Italy worked with the other European partners to identify national research gaps and opportunities. As a result, recommendations were issued to the authorities to promote research and innovation with a One-Health approach. Conclusions: The Italian participation in the EU JAMRAI provided experience and examples to the Italian government for implementing the NAP and planning the roadmap to fight AMR and helped point out the system’s criticalities. It also supported the promotion of the One-Health integrated vision that was included in the updated NAP.
The Implementation of the International Health Regulations on Vector-Borne Diseases: A Scoping Review of the Qualitative Evidence Performed Worldwide
Authors: Alho Ana Margarida , Quelhas Carlos , Subtil Inês , Adrego Tiago , Durão José
Published: October 2023

Introduction: The International Health Regulations were created by the World Health Organization with the purpose of preventing the international spread of diseases. The 196 signatory countries are bound by this international agreement. In this article, we conducted a scoping review of the literature concerning the implementation and operationalization of measures at both the continental and national levels to prevent the spread of vector-borne diseases. The purpose was to understand the main strategies and policies adopted, as well as how they have been operating. Methods: Out of an initial search on PubMed™, SCOPUS™, and Web of Science™ using combinations of “International Health Regulations” and “vector-borne diseases”, 75 references were obtained, of which 27 were included after careful qualitative analysis. Results: Publication dates of included articles ranged from 1996 to 2022. Four major categories of measures were identified: (a) surveillance and epidemic intelligence; (b) Declaration of Public Health Emergency of International Concern; (c) measures in Points of Entry; and (d) vaccination status. Implemented measures were found in all continents: Africa, Oceania (Australia), Asia (China, India, Taiwan), Europe (Ireland, the Netherlands, and Mediterranean countries), North America (USA), and South America (Brazil). Yellow fever, Zika, Dengue, and Chikungunya were the most cited vector-borne diseases but Crimean-Congo hemorrhagic fever, Japanese encephalitis, Lyme disease, Malaria, Leishmaniasis, Tick-borne encephalitis, and West Nile fever were also mentioned. Conclusion: There are severe asymmetries across countries on the implementation of international regulations with regards to vector-borne diseases, particularly on the issue of surveillance systems. State Parties should consider the lessons learned from the pandemic and perfect their core capacities to prevent future outbreaks of infectious diseases.
Prenatal Diagnosis of a de novo 2q14.3-q22.1 Deletion with Complex Chromosomal Rearrangement
Authors: Wu Yong , Liao Chuanning , Xie Yamei , Wang Lingxi
Published: October 2023

Introduction: Chromosomal aberrations due to complex chromosomal rearrangements (CCRs) can cause abnormal phenotypes if accompanied by microdeletions or microduplications near the breakpoint, or gene breaks. Case Presentation: We report a prenatal diagnostic case of 2q14.3-q22.1 deletion with ultrasound suggestive of absent nasal bone accompanied by CCRs involving 6 chromosomes. Cytogenetic analysis revealed a karyotype of 46,XY,der(1)t(1;2)(p13.3;p11.2),der(2)t(1;2)inv(2)(q12q14.2)del(2)(q14.3q22.1),t(12;16)(q21.2;q12.1),t(13;21)(q32;q22.1). Chromosomal microarray analysis identified a 14.90 Mb deletion on 2q14.3q22.1. The copy number variant was de novo, as determined by karyotype analysis of the parents’ peripheral blood G-banding. Conclusion: The region contains haploinsufficient genes that can cause different phenotypes, mainly associated with neurodevelopmental and autism spectrum disorders. However, the genotype-phenotype correlation is limited in prenatal evaluation. Therefore, the combined use of multiple diagnostic techniques has an important role in the assessment of CCRs and genetic counseling.
The Risk of Developing Disabling Crohn’s Disease: Validation of a Clinical Prediction Rule to Improve Treatment Decision Making
Authors: Bastida Paz Guillermo , Merino Ochoa Olga , Aguas Peris Mariam , Barreiro-de Acosta Manuel , Zabana Yamile , Ginard Vicens Daniel , Ceballos Santos Daniel , Muñoz Núñez Fernando , Monfort i Miquel David , Catalán-Serra Ignacio , García Sánchez Valle , Loras Alastruey Carmen , Lucendo Villarín Alfredo , Huguet Jose Maria , de la Coba Ortiz Cristóbal , Aldeguer Manté Xavier , Palau Canós Antonio , Domènech Morral Eugeni , Nos Pilar ,   GETECCU Group (Spanish Working Group on Crohn’s Disease and Ulcerative Colitis)
Published: October 2023

Background: Crohn’s disease (CD) is characterized by the development of complications over the course of the disease. It is crucial to identify predictive factors of disabling disease, in order to target patients for early intervention. We evaluated risk factors of disabling CD and developed a prognostic model. Methods: In total, 511 CD patients were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to identify demographic, clinical, and biological risk factors. A predictive nomogram model was developed in a subgroup of patients with noncomplicated CD (inflammatory pattern and no perianal disease). Results: The rate of disabling CD within 5 years after diagnosis was 74.6%. Disabling disease was associated with gender, location of disease, requirement of steroids for the first flare, and perianal lesions. In the subgroup of patients (310) with noncomplicated CD, the rate of disabling CD was 80%. In the multivariate analysis age at onset <40 years (OR = 3.46, 95% confidence interval [CI] = 1.52–7.90), extensive disease (L3/L4) (OR = 2.67, 95% CI = 1.18–6.06), smoking habit (OR = 2.09, 95% CI = 1.03–4.27), requirement of steroids at the first flare (OR = 2.20, 95% CI = 1.09–4.45), and albumin (OR = 0.59, 95% CI = 0.36–0.96) were associated with development of disabling disease. The developed predictive nomogram based on these factors presented good discrimination, with an area under the receiver operating characteristic curve of 0.723 (95% CI: 0.670–0.830). Conclusion: We identified predictive factors of disabling CD and developed an easy-to-use prognostic model that may be used in clinical practice to help identify patients at high risk and address treatment effectively.
Clinico-Radio-Pathologic Correlation of Leukostasis in Acute Myeloid Leukemia with FLT3 Mutation
Authors: Bello Elisa , Liao Haihui , Patel Shyam A.
Published: October 2023

The systemic complications of acute hematologic emergencies account for the high mortality rates seen during inpatient management. Perhaps the most challenging diagnostic entity among all hematologic emergencies is leukostasis. In acute myeloid leukemia (AML), myeloid blasts are often highly adherent to the endothelial vasculature, and high peripheral blood blast count in excess of 100,000 cells per microliter can predispose patients to pulmonary and neurologic complications, leading to rapid clinical deterioration even before a formal diagnosis of leukostasis is made. The mobilization of appropriate healthcare personnel in the inpatient setting at inopportune times sometimes poses a major barrier to the successful treatment of patients with leukostasis, and patients can pass away quickly. In this report, we describe clinico-radio-pathologic correlations of leukostasis using pre- and post-mortem analysis in a patient with AML with a FLT3-TKD mutation, and we describe the current literature on best management approaches based on recent evidence, including consideration of first-line FLT3 (CD135) inhibitors such as quizartinib.
Combination of Donor Lymphocyte Infusion and Blinatumomab for B-Cell Lymphoblastic Lymphoma Relapse after Allogeneic Stem-Cell Transplantation
Authors: Mori Jinichi , Shingai Naoki , Kobayashi Takeshi , Doki Noriko
Published: October 2023

A woman in her forties with relapsed B-cell lymphoblastic lymphoma was treated with blinatumomab, but the drug proved ineffective. Salvage therapy with clofarabine induced a complete remission, and she received an allogeneic stem-cell transplantation (allo-SCT) from an HLA-matched sibling donor. However, her disease relapsed only 4 months after the allo-SCT. Three courses of combination therapy with donor lymphocyte infusion (DLI) and blinatumomab were administered, and the tumor progression was well controlled for 6 months, leading to a second allo-SCT from an HLA-haploidentical donor. The remission was persistent for approximately 1 year, but the disease relapsed in her central nervous system, and she eventually died. Our case demonstrated the efficacy and safety of concomitant use of DLI and blinatumomab. This combination presumably enhanced a graft-versus-lymphoma effect of allogeneic T-cells without provoking graft-versus-host disease.
Therapeutic Exercise on Metabolic and Renal Outcomes in Patients with Chronic Kidney Disease: A Narrative Review
Authors: Febles Raúl Morales , Miranda Domingo Marrero , Perera Coriolano de la Concepción Cruz , Martín Laura Díaz , Rodríguez-Rodríguez Ana Elena , González Martín Amelia Remedios , Sánchez Báez Daniel Javier , Porrini Esteban
Published: October 2023

Background: Chronic kidney disease (CKD) affects 11–13% of the world population. The main risk factors for CKD include diabetes, hypertension, and obesity. Metabolic syndrome (MS) is associated with the onset of CKD in the nondiabetic population. Obesity and MS are also risk factors for a worse progression of established CKD. Therapeutic exercise is an effective option to treat and manage obesity, MS, and diabetes in the general population. However, the evidence on the effect of exercise on patients with CKD, obesity, and MS is scarce. Summary: We evaluated available evidence on the effect of therapeutic exercise in patients with CKD, excluding dialysis, particularly in improving the metabolic risk factors and main renal outcomes: renal function loss and albuminuria/proteinuria. This review includes prospective studies and clinical trials. A total of 44 studies were analysed in 1,700 subjects with renal disease (2–5), including patients with renal transplantation. Most studies did not prove a major effect of exercise on albuminuria/proteinuria, glomerular filtration rate (GFR), obesity, or MS. These results are intriguing and deserve attention. The exploratory nature of most studies, including a low number of cases and short follow-up, might explain the lack of efficacy of exercise in our analysis. Specific aspects like the type of exercise, frequency, intensity, duration, accommodation during follow-up, individualization, safety, and adherence are crucial to the success of therapeutic exercise. The beneficial role of exercise in patients with CKD remains to be determined. Key Messages: Key messages of this review are as follows. (1) The effect of therapeutic exercise on renal and metabolic outcomes in patients with CKD remains to be determined. (2) According to the evidence selected, therapeutic exercise seems to be safe to treat patients with CKD. (3) Most studies are exploratory by nature, with results that need further investigation. (4) Therapeutic exercise is a complex procedure that must be specifically designed to treat patients with CKD.
Plica Neuropathica in 2 Hispanic Patients
Authors: Asz-Sigall Daniel , Ramos-Cavazos César , Gay-Muñoz Paulina Mariel , González-Gutiérrez Jessica , Guerrero-Álvarez Alejandra , Corona-Rodarte Eduardo
Published: October 2023

Introduction: Plica neuropathica (PN) is a rare, acquired, and irreversible condition characterized by the formation of a compacted mass of tangled hair held together by a hard keratin cement. Case Presentation: In case 1, a 50-year-old woman with history of contact dermatitis of the scalp presented with hair tangling and difficulty combing. Physical examination revealed a matted mass of hair with a dirty appearance and non-scarring alopecia. Case 2 involved a 46-year-old woman who experienced spontaneous hair matting after using various products, resulting in a dreadlock-like appearance. Clinical examination showed a compact and matted mass of hair with irregular twists, dirt, and yellowish exudate. Conclusion: PN’s exact pathogenesis is not fully understood, but it is believed to involve physical and chemical insults to the hair shaft. Risk factors include self-neglect, hair felting or rubbing, certain substances, religious practices, chemotherapy, immunosuppressive drugs, infections, and contact dermatitis. Trichoscopy can provide valuable clues for an accurate diagnosis, such as fractured hairs, bent hair shafts, trichorrhexis nodosa, retained telogen hairs, and twisted hairs. Treatment involves cutting the matted hair, and early-stage manual separation may be beneficial.
Regulation of T Helper Cell Type 2 Immune Response by Controlling Beta-2 Adrenergic Receptor in Dendritic Cells of Patients with Allergic Rhinitis
Authors: Yeon Ji Woo , Kim Byoungjae , Byun Junhyoung , Jung Semyoung , Park Jaehyung , Han Munsoo , Baek Seung-Kuk , Kim Tae Hoon
Published: October 2023

Introduction: Allergic diseases are mediated by T helper cell type 2 (Th2) cells, which are differentiated by dendritic cells (DCs). Recently, it was reported that cAMP concentration in DCs is important for inducing allergic responses. However, the regulatory function of cAMP in DCs in Th2 immune responses is unclear. It was hypothesized that the regulation of G protein-coupled receptors (GPCRs) to increase cAMP levels in DCs would reduce Th2 immune responses. Methods: Human DCs from patients with allergic rhinitis (AR) and from healthy controls were subjected to next-generation sequencing (NGS) to identify potential GPCR. To investigate the functions of GPCR agonists, the in vitro co-culture experiment that THP-1 cells were differentiated into DCs and cultured with human CD4+ T-cells and an AR animal in vivo model were used. Results: Among the GPCRs, the beta-2 adrenergic receptor (ADRB2) of allergic DCs was significantly increased by NGS analysis. The expression of ADRB2 was also increased in Der p 1-treated DCs, which was reduced by treatment with the ADRB2 agonist salbutamol. Salbutamol treatment induced cAMP production in THP-1 derived DCs. In an in vitro co-culture experiment, salbutamol-treated DCs reduced the secretion of Th2 cytokine. In an in vivo AR animal experiment, salbutamol-administered mice showed reduced allergic behavior and Th2 cytokine expression in the nasal mucosa. Conclusions: The regulation of ADRB2 with salbutamol alleviated the allergic response in vitro DC-T cell co-culture and in vivo AR animal models, suggesting that ADRB2 is a therapeutic target for AR and that ADRB2 agonists may be a promising medication for AR.
Spirochetosis Mimicking Acute Appendicitis: Clinical Report and Review of the Literature
Authors: Lüthy Magdalena , Käser Samuel A. , Wagener Carolin , Fahrner René
Published: October 2023

Introduction: Intestinal spirochetosis is sometimes found by chance in histological specimen of routine endoscopies. There are only a few cases described in the literature that spirochetosis of the appendix was mimicking acute appendicitis. We present a case of pseudoappendicitis with the histological finding of spirochetes and review the current literature. Case Presentation: A 72-year-old woman presented with pain of the lower right abdomen and previous systemic corticoid therapy. In clinical examination, there was a tenderness and pain in the right lower quadrant, and inflammation values were elevated. An abdominal computed tomography scan revealed no obvious inflammation of the appendix. A diagnostic laparoscopy was performed and revealed a macroscopically uninflamed appendix which was removed. Histology revealed spirochetosis of the appendix but no typical signs of appendicitis. The patient was treated with antibiotics for 5 days and was discharged without abdominal pain. In a clinical control 6 weeks later, the abdominal pain had disappeared and the patient was in good clinical condition. Discussion: Intestinal spirochetosis is randomly found in histological specimen during routine endoscopies, even in asymptomatic patients. There are only a few cases described with spirochetosis of the appendix causing pain and mimicking appendicitis; hence, this entity is an important differential diagnosis of pain in the right lower quadrant of the abdomen.
Higher Prevalence and Severity of Eosinophilic Otitis Media in Patients with Asthma-COPD Overlap Compared with Asthma Alone
Authors: Sato Emiri , Seo Yukako , Tagaya Etsuko , Yagi Osamitsu , Yamamura Yukie , Nonaka Manabu
Published: October 2023

Introduction: Eosinophilic otitis media (EOM) is well-known to frequently co-exist with adult-onset asthma. Both diseases are similar type 2 inflammation and are considered to have a “one airway, one disease” relationship. Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO), characterized by airway obstruction caused by airway wall thickening (AWT), is a severe condition with a higher incidence of mortality compared to asthma alone or COPD alone. Based on the “one airway, one disease” concept, we hypothesized that the inflammatory pathophysiology of EOM differs depending on its comorbidity with ACO or with asthma alone. Methods: A total of 77 chronic rhinosinusitis (CRS) patients with asthma were enrolled in this study. The subjects were divided into 2 groups: a group with comorbid asthma alone (asthma group; 46 patients), and a group with comorbid ACO (ACO group; 31 patients). The 2 groups were compared and assessed with regard to various factors, including the patients’ clinical characteristics, prevalence rate of EOM, EOM severity, EOMs relationships with smoking and AWT, and the eosinophil and neutrophil cell counts in the middle ear effusion (MEE). Results: The ACO group included significantly more males (p < 0.05), was significantly older (p < 0.05), and showed significantly lower lung function values (FEV1 [L], FEV1 [%pred]) (p < 0.01) compared with the asthma group. The ACO group also had a significant history of smoking as shown by the Brinkman index (p < 0.01) and greater AWT as assessed by high-resolution computed tomography (p < 0.05). The EOM prevalence rate was significantly higher in the ACO group (p < 0.05), especially with increased ACO severity (p < 0.05). The EOM severity was also significantly higher in the ACO group (p < 0.05) and also correlated with the ACO severity (p < 0.05). The pretreatment ear clinical characteristics score and the average air conduction hearing level were significantly higher in the ACO group (p < 0.05). The eosinophil percentage in the MEE/otorrhea was significantly lower in the ACO group (25.3%) than in the asthma group (54.7%) (p < 0.05). Conversely, the neutrophil percentage was significantly higher in the ACO group (75.7% vs. 41.9%) (p < 0.05). Conclusions: Our findings suggest that, in CRS patients with asthma, comorbidity with ACO may be a clinical factor leading to increased EOM prevalence and severity, as well as a higher neutrophil infiltration percentage in the middle ear. Cessation of smoking and early therapeutic intervention for ACO may mitigate progression of bronchial remodeling (i.e., reduce AWT) and help reduce the prevalence and severity of EOM.
Isolation and Cultivation of Vascular Smooth Muscle Cells from the Mouse Circle of Willis
Authors: Chang Wei , Li Yajuan , Liu Fengzhou , Zang Kehai , Zhang Peiran , Qu Shuai , Zhao Jingyu , Xue Junhui
Published: October 2023

Introduction: Culturing cerebrovascular smooth muscle cells (CVSMCs) in vitro can provide a model for studying many cerebrovascular diseases. This study describes a convenient and efficient method to obtain mouse CVSMCs by enzyme digestion. Methods: Mouse circle of Willis was isolated, digested, and cultured with platelet-derived growth factor-BB (PDGF-BB) to promote CVSMC growth, and CVSMCs were identified by morphology, immunofluorescence analysis, and flow cytometry. The effect of PDGF-BB on vascular smooth muscle cell (VSMC) proliferation was evaluated by cell counting kit (CCK)-8 assay, morphological observations, Western blotting, and flow cytometry. Results: CVSMCs cultured in a PDGF-BB-free culture medium had a typical peak-to-valley growth pattern after approximately 14 days. Immunofluorescence staining and flow cytometry detected strong positive expression of the cell type-specific markers alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain 11 (SMMHC), smooth muscle protein 22 (SM22), calponin, and desmin. In the CCK-8 assay and Western blotting, cells incubated with PDGF-BB had significantly enhanced proliferation compared to those without PDGF-BB. Conclusion: We obtained highly purified VSMCs from the mouse circle of Willis using simple methods, providing experimental materials for studying the pathogenesis and treatment of neurovascular diseases in vitro. Moreover, the experimental efficiency improved with PDGF-BB, shortening the cell cultivation period.
Anterior Skull Base Abnormalities in Congenital Anosmia
Authors: Yan Xiaoguang , Benkhatar Hakim , Chao Yun-Ting , Georgiopoulos Charalampos , Hummel Thomas
Published: October 2023

Introduction: The structures of the skull and the brain are related to each other. Prior work in individuals with isolated congenital anosmia (ICA) showed that these individuals were characterized by olfactory bulb (OB) defects. The aim of this study was to compare the morphological pattern of the anterior skull base surrounding the OB between individuals with ICA and normosmic controls. We meant to investigate whether these features can help distinguish abnormalities from normal variation. Methods: We conducted a retrospective study to acquire T2-weighted magnetic resonance images from individuals diagnosed with ICA (n = 31) and healthy, normosmic controls matched for age and gender (n = 62). Between both groups, we compared the depth and width of the olfactory fossa, the angle of the ethmoidal fovea, as well as the angle of the lateral lamella of the cribriform plate. Within the ICA group, we further performed subgroup analyses based on the presence or absence of the OB, to investigate whether the morphology of the anterior skull base relates to the presence of OBs. The diagnostic performance of these parameters was evaluated using receiver operating characteristic analysis. Results: Individuals with ICA exhibited a flattened ethmoid roof and shallower olfactory fossa when compared to controls. Further, the absence of the OB was found to be associated with a higher degree of flattening of the ethmoid roof and a shallow olfactory fossa. We reached the results in the following areas under the receiver operating characteristic curves: 0.80 – angle of fovea ethmoidalis, 0.76 – depth of olfactory fossa, 0.70 – angle of lateral lamella of the cribriform plate for significant differentiation between individuals with ICA and normosmic controls. Conclusion: Individuals with ICA exhibited an unusual anterior skull base surrounding the OB. This study supports the idea of an integrated development of OB and anterior skull base. Hence, the morphological pattern of the anterior skull base surrounding the OB helps distinguish individuals with ICA from normosmic controls and may therefore be useful for the diagnosis of ICA, although it is certainly not an invariable sign of congenital anosmia.
Recurrent Acute on Chronic Respiratory Failure in Stiff Person Syndrome
Authors: Bheemavarapu Bhumika , Singh Arkaja , Jayaraj Ranjini Nived , Meda Venkata Sai Abhilash , Patil Dhrumil
Published: October 2023

Stiff person syndrome (SPS) is an extremely rare disease that presents with episodic painful muscle spasms and progressive muscle rigidity. Recent evidence suggests that SPS can rarely manifest with life-threatening respiratory complications. However, the pathophysiology behind respiratory failure in SPS is still not clearly understood. Here, we explored an extremely rare case of a 36-year-old African-American female with SPS presenting with multiple episodes of respiratory failure events for the past 9 years. She had an in-situ tracheostomy and was admitted to the hospital for tracheostomy evaluation and decannulation. 11 years ago she initially presented with gait abnormalities, stiffness, and spastic episodes. She was diagnosed 1 year later with SPS after detecting elevated anti-glutamic acid decarboxylase antibody levels in her blood. Through this report, we were able to follow a very rare case of SPS that presented with multiple episodes of respiratory failure. We pointed out the importance of early start and regular administration of diazepam, baclofen, and IVIg in not only controlling the symptoms and progression of the disease but also in preventing further respiratory failure and possible sudden death.
Pembrolizumab-Induced Rhabdomyolysis in a Clear Cell Renal Cell Carcinoma Patient: A Case Report
Authors: Altermanini Mohammad , Ali Khaled , Alwassiti Wisam , Almohtasib Suliman , Omar Nabil E. , Zafar Abdulaziz
Published: October 2023

Pembrolizumab is one of the approved treatments for many types of cancer including clear cell renal cell carcinoma (ccRCC). It has improved the prognosis of renal cell carcinoma, yet has many possible immune-related side effects. We discuss a rare case of rhabdomyolysis in an ccRCC patient treated with pembrolizumab. The case was complicated with acute kidney injury and severe hypothyroidism, which can be attributed to pembrolizumab.
Effect of Needle-To-Puncture Time on Reperfusion Outcome in Acute Ischemic Stroke
Authors: Chen Chih-Hao , Bala Fouzi , Najm Mohamed , Alhabli Ibrahim , Singh Nishita , Kashani Nima , McDonough Rosalie V. , Horn MacKenzie , Stang Jilian , Demchuk Andrew M. , Menon Bijoy K. , Hill Michael D. , Almekhlafi Mohammed A.
Published: October 2023

Introduction: The aim of the study was to investigate the impact of time interval between start of intravenous thrombolysis (IVT) to start of endovascular thrombectomy (EVT) on stroke outcomes. Methods: Data from the Quality Improvement and Clinical Research (QuICR) provincial stroke registry from Alberta, Canada, were used to identify stroke patients who received IVT and EVT from January 2015 to December 2019. We assessed the impact of the time interval between IVT bolus to EVT puncture (needle-to-puncture times [NPT]) on outcomes. Radiological outcomes included successful initial recanalization (revised Arterial Occlusive Lesion 2b–3), successful initial and final reperfusion (modified thrombolysis in cerebral infarction 2b–3). Clinical outcomes were 90-day modified Rankin Scale (mRS) and mortality. Results: Of the 680 patients, 233 patients (median age: 73, 41% females) received IVT + EVT. Median NPT was 38 min (IQR, 24–60). Arrival during working hours was independently associated with shorter NPT (p < 0.001). Successful initial recanalization and initial and final reperfusion were observed in 12%, 10%, and 83% of patients, respectively. NPT was not associated with initial successful recanalization (OR 0.97 for every 10-min increase of NPT, 95% CI: 0.91–1.04), initial successful reperfusion (OR 1.01, 95% CI: 0.96–1.07), or final successful reperfusion (OR: 1.03, 95% CI: 0.97–1.08). Every 10-min delay in NPT was associated with lower odds of functional independence at 90 days (mRS ≤2; OR: 0.93; 95% CI, 0.88–0.97). Patients with shorter NPT (≤38 min) had lower 90-day mRS scores (median 1 vs. 3; OR: 0.54 [0.31–0.91]) and had lower mortality (6.1% vs. 21.2%; OR, 0.23 [0.10–0.57]) than the longer NPT group. Conclusion: Shorter NPT did not impact reperfusion outcomes but was associated with better clinical outcome.
Risk Factors for Fractures in Renal Transplantation: A Population-Based Cohort Study
Authors: Tsai Hsin-Lin , Lin Tzu-Ching , Lin Niang-Cheng , Yang Hui-Hsin , Chang Jei-Wen
Published: October 2023

Introduction: Kidney transplant recipients are at an increased risk of fractures, and targeted preventive strategies are needed. Therefore, in this retrospective cohort study, we investigated a large population-based cohort to identify the transplant recipient-specific risk factors for fractures in Taiwanese kidney transplant recipients. Methods: We conducted a retrospective cohort study using the National Health Insurance Research Database. Patients who underwent renal transplantation between 2003 and 2015 were identified and followed until December 31, 2015, to observe the development of fractures. Variables associated with the development of post-transplant fractures were identified by calculating hazard ratios in a Cox regression model. Results: 5,309 renal transplant recipients were identified, of whom 553 (10.4%) were diagnosed with post-transplant fractures. Independent predictors of post-transplant fractures included an age at transplant ≥65 years (p < 0.001), female sex (p < 0.001), fractures within 3 years prior to transplantation (p < 0.001), and diabetes mellitus (p < 0.001). In addition, daily prednisolone doses >2.9–5.3 mg/day (p < 0.001), >5.3–8.7 mg/day (p < 0.001), and >8.7 mg/day (p < 0.001) were also independent predictors of post-transplant fractures. Conversely, the use of peritoneal dialysis before renal transplantation (p = 0.021), hypertension (p = 0.005), and the use of tacrolimus (p < 0.001), azathioprine (p = 0.006), mycophenolate mofetil/mycophenolic acid (p = 0.002), mTOR inhibitors (p = 0.004), and calcium supplements (p = 0.009) were inversely correlated with post-transplant fractures. Conclusion: We recommend minimizing daily glucocorticoids as early and as far as possible in conjunction with immunosuppressive regimens such as tacrolimus, azathioprine, mycophenolate mofetil/mycophenolic acid, mTOR inhibitors, and calcium supplements, especially in older female recipients and in recipients with diabetes and a history of prior fractures.
The Effect of Hemodialysis on Spectral and Temporal Processing Abilities and Speech Perception in Noise among Individuals with Chronic Kidney Disease
Authors: Kumar Kaushlendra , Sengolraj Livingston , Kalaiah Mohan Kumar
Published: October 2023

Introduction: The effect of chronic kidney disease (CKD) on hearing is well documented in the literature. Several studies have investigated the effect of hemodialysis on the peripheral auditory system among individuals with CKD. However, studies investigating the effect of hemodialysis on speech perception and auditory processing abilities are limited. The present study investigated the effect of hemodialysis on few auditory processing abilities and speech perception in noise among adults with CKD. Methods: A total of 25 adults with CKD undergoing hemodialysis regularly participated in the study. Spectral ripple discrimination threshold (SRDT), gap detection threshold (GDT), amplitude-modulation detection threshold (AMDT), and speech recognition threshold in noise (SRTn) were measured before and after hemodialysis. Paired samples “t” test was carried out to investigate the effect of hemodialysis on thresholds. Results: Results showed a significant improvement for SRDT, GDT, AMDT, and SRTn after hemodialysis among individuals with CKD. Discussion: Hemodialysis showed a positive effect on speech perception in noise and auditory processing abilities among individuals with CKD.
The Initial Journey of Patients with Metastatic Pancreatic Cancer (PaCTO Project): A Nationwide Survey among Portuguese Specialist Physicians
Authors: Barros Anabela G. , Mansinho Hélder , Couto Nuno , Teixeira Manuel R. , Tonin Fernanda S. , Francisco Rudolfo , Duarte-Ramos Filipa
Published: October 2023

Introduction: We aimed to characterize the initial healthcare journey of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients in Portugal, including healthcare provision and factors affecting therapeutic decisions, namely BRCA mutations testing. Methods: This is a descriptive cross-sectional, web-based survey using a convenience sampling approach. Portuguese oncologists and pathologists that routinely work with mPDAC patients from the different geographical regions and settings were invited to participate in the study via email (December 2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR) (Stata v.15.0). Results: Seventy physicians participated in the study (43 oncologists, 27 pathologists). According to the responses, a median of 28 patients per center (IQR 12–70) was diagnosed with PDAC in the previous year; 22 of them referring (IQR 8–70) to mPDAC. The pointed median time from patients’ first hospital admission until disease diagnosis/staging is between 2 and 4 weeks. Endoscopic ultrasound with fine-needle biopsy is available in most hospitals (86%). Around 50% of physicians request BRCA testing; the assessment of additional biomarkers besides BRCA is requested by 40% of professionals. Half of them stated that BRCA testing should be requested earlier–upon histological diagnosis, especially because the median time for results is of 4.0 weeks (IQR 4–8). PARP inhibitors such as olaparib, when available, would be the therapy of choice for most oncologists (71%) if no disease’ progression occurs after 4 months. Treatments’ selection is usually grounded on clinical criteria (e.g., performance status, liver function). Around 45% of patients use FOLFIRINOX/mFOLFIRINOX as the first-line therapy. Gemcitabine + nab-paclitaxel is used by 35% of patients as the second-line therapy. Conclusions: Physicians in Portugal support the increasing role of patient-tailored treatments in mPDAC, whose selection should be grounded on tumoral subtyping and molecular profiling. Further efforts to develop multidisciplinary teams, standardized clinical practice, and optimize the implementation of new target therapies are needed.
Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial
Authors: Lee Su Won , Lyu Yee Ran , Yang Won Kyung , Kim Seung Hyung , Kim Si Yeon , Kang Weechang , Jung In Chul , Lee Beom joon , Choi Jun Yong , Lee Mee Young , Park Yang Chun
Published: October 2023

Background: Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment. Methods: We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on. Conclusion: This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA.
Extracorporeal Techniques in Kidney Failure
Authors: Meijers Bjorn , Vega Almudena , Juillard Laurent , Kawanishi Hideki , Kirsch Alexander H. , Maduell Francisco , Massy Ziad A. , Mitra Sandip , Vanholder Raymond , Ronco Claudio , Cozzolino Mario ,   on behalf of the Nomenclature Standardization Faculty
Published: October 2023

During the last decades, various strategies have been optimized to enhance clearance of a variable spectrum of retained molecules to ensure hemodynamic tolerance to fluid removal and improve long-term survival in patients affected by kidney failure. Treatment effects are the result of the interaction of individual patient characteristics with device characteristics and treatment prescription. Historically, the nephrology community aimed to provide adequate treatment, along with the best possible quality of life and outcomes. In this article, we analyzed blood purification techniques that have been developed with their different characteristics.