bluuebunny/crossref_metadata_2025 huggingface dataset:
Complement Factor I Gene Variant in an Atypical Hemolytic Uremic Syndrome Triggered by Hypereosinophilia Syndrome
Authors: Banjongjit Athiphat , Kittanamongkolchai Wonngarm , Kanjanabuch Talerngsak
Published: October 2023

Atypical hemolytic uremic syndrome (aHUS) is a condition characterized by acute kidney injury (AKI), thrombocytopenia, and microangiopathic hemolytic anemia secondary to complement pathway dysregulation. Several triggers have been identified as causing aHUS in genetically susceptible patients; however, hypereosinophilia syndrome (HES)-triggered aHUS has not been reported. In this article, we present a case of aHUS presented with generalized urticarial rashes and angioedema. The initial investigations revealed hypereosinophilia (maximal absolute eosinophil count of 6,840 cells/µL) with normal bone-marrow analyses; hence, idiopathic HES was diagnosed. During hospitalization, the patient developed convulsion, stuporous, and full-blown thrombotic microangiopathy (TMA), with AKI requiring temporary hemodialysis. A kidney biopsy confirmed the existence of renal TMA. Next-generation sequencing of the coding regions of aHUS-related genes was performed, revealing an underlying complement factor I (CFI) deficiency, a heterozygous variant p.P64L of CFI gene. The patient was successfully treated with high-dose steroids and extended duration of plasmapheresis.
Clostridium difficile Bacteremia as a Rare Presentation of Polymicrobial Pyogenic Liver Abscesses and Its Management Challenges
Authors: Lim Junghyun , Zaw Catherine , Abramson Simon , Lichtenberger Paola N. , John Binu V. , Cuebas-Rosado Lorena
Published: October 2023

Extracolonic manifestations of Clostridium difficile have been rarely reported. We herein report a case of a 60-year-old immunocompetent man presenting with fever, nausea, abdominal pain, and loose stools for 2 weeks. Triple-phase liver computed tomography demonstrated pyogenic liver abscesses and portal pylephlebitis. Blood cultures grew C. difficile and Bacteroides fragilis, and liver abscess cultures grew Proteus mirabilis, Escherichia coli, and the viridans group Streptococci. Antibiotics coverage was selected to direct at all identified organisms. This demonstrates an unusual case of C. difficile bacteremia in a patient with polymicrobial pyogenic liver abscesses and pylephlebitis.
Long-Term Renal Function in Adult Patients with Phenylketonuria
Authors: Prepok Flóra Franciska , Schnabel Karolina Kornélia , Sumánszki Csaba , Barta András Gellért , Tislér András , Reismann Péter
Published: October 2023

Introduction: In phenylketonuria (PKU), toxic phenylalanine (Phe) can harm other organs beyond the brain. Furthermore, the lifelong therapy of PKU consists of consumption of increased amounts of amino-acid mixture that provoke hyperfiltration in the glomeruli. Therefore, the adherence to therapy in PKU might influence the long-term kidney function in PKU patients. Methods: Data from 41 adult, early treated PKU patients were analyzed in this 10-year, retrospective, monocentric study. Two subgroups were created according to their therapy adherence: one with long-term blood Phe levels in the therapeutic range (<600 µmol/L), and one with suboptimal blood Phe levels. Renal function and metabolic parameters were collected over 10 years. Kidney function parameters were compared between the two groups and associations between blood Phe levels and kidney function were tested. Results: After 10 years, serum creatinine levels (p = 0.369) and estimated glomerular filtration rate (eGFR) (p = 0.723) did not change significantly from baseline in the good therapeutic group. The suboptimal therapeutic group’s eGFR decreased in the same period (from 110.4 ± 14 mL/min/1.73 m2 to 94.2 ± 16 mL/min/1.73 m2, p = 0.017). At 10 years, the suboptimal therapeutic group had an increased serum creatinine level (81 ± 14.4 μmol/L vs. 71.5 ± 13 μmol/L, p = 0.038), and a decreased eGFR (94.2 ± 16 mL/min/1.73 m2 vs. 103.3 ± 13 mL/min/1.73 m2p = 0.031) compared to the good adhering group. Significant negative correlation between Phe levels and eGFR (r = −0.41, p = 0.008) was observed. Conclusion: Long-term suboptimal therapy adherence in PKU patients with high blood Phe levels may lead to deterioration in kidney function.
Subphenotypes of Pediatric Acute Kidney Injury
Authors: Menon Shina , Gist Katja M.
Published: October 2023

Acute kidney injury (AKI) is seen frequently in hospitalized patients and is associated with increased risk of mortality and adverse short- and long-term renal and systemic complications. Emerging data suggest that AKI is a heterogenous syndrome with a variety of underlying causes, predisposing illnesses, and range of clinical trajectories and outcomes. This mini-review aims to discuss emerging AKI subphenotype classifications as our understanding of the heterogeneity and underlying pathophysiology has improved.
Case Series of Hepatosplenic T-Cell Lymphoma: A Rare and Aggressive Disease
Authors: Tham Yea Bing , Ahmad Asnawi Asral Wirda , Lau Ngee Siang , Fauzi Alina Md , Syed Abd Kadir Sharifah Shahnaz , Liew Pek Kuen , Tan Sen Mui
Published: October 2023

Hepatosplenic T-cell lymphoma is a rare form of T-cell lymphoma that predominantly emerges from neoplastic proliferation of cytotoxic T cells of γ/δ T-cell receptor-expressing lymphocytes. Isochromosome 7q and trisomy 8 are the most prevalent chromosomal abnormalities associated with hepatosplenic T-cell lymphoma, and most patients have mutations in genes related to chromatin remodeling or the JAK/STAT system. Hepatosplenic T-cell lymphoma can mimic various infectious diseases, immunological conditions, and other malignancies. Patients usually present with nonspecific constitutional symptoms and spleen and liver enlargement, with variable degrees of cytopenia. The rarity of this disease, coupled with the lack of lymph node involvement that is usually seen in lymphomas, causes significant difficulty in diagnosis, which inevitably delays the initiation of treatment. Managing this lymphoma is arduous because of its late presentation and aggressive nature, frequently resulting in rapid progression in its clinical course and refractoriness to conventional chemotherapy. There is a lack of international guidelines for its treatment, and in most cases, treatment is guided by case series. Here, we highlight the clinicopathological features and management of hepatosplenic T-cell lymphoma over a 10-year span in a single hematology referral center and review the literature.
The Role of Erythropoietin Levels in Predicting Long-Term Outcomes following Severe Acute Kidney Injury
Authors: Kusirisin Prit , Thanapongsatorn Peerapat , Chaikomon Kamolthip , Lumlertgul Nuttha , Yimsangyad Khanittha , Leewongworasingh Akarathep , Sirivongrangson Phatadon , Peerapornratana Sadudee , Chaijamorn Weerachai , Avihingsanon Yingyos , Srisawat Nattachai
Published: October 2023

Introduction: Acute kidney injury (AKI) survivors are at an increased risk of chronic kidney disease, end-stage kidney disease, and mortality. Little is known about the effect of erythropoietin (EPO), a kidney-producing hormone, in post-AKI setting. We aimed to investigate the role of EPO as a predictor of long-term outcomes in post-severe AKI survivors. Methods: We performed a retrospective analysis of post-AKI cohort conducted between August 2018 and December 2021. Adults who survived severe AKI stages 2–3 were enrolled. Serum EPO was obtained at 1 month after hospital discharge. We explored whether EPO level could predict long-term kidney outcomes at 12 months including mortality, kidney replacement therapy, doubling serum creatinine, and major adverse kidney events at 365 days. Results: One hundred and twelve patients were enrolled. Median EPO level was significantly higher in non-survivors than survivors (28.9 [interquartile range: 16.2–50.7] versus 11.6 mU/mL [7.5–22.3], p = 0.003). The best EPO level cut-off was 16.2 mU/mL (sensitivity 77.8%, specificity 62.1%). Serum EPO predicted 12-month mortality with an area under the curve (AUC) of 0.69. Combining clinical model using age, baseline, and discharge kidney function with serum EPO improved prediction with AUC of 0.74. Multivariable analysis demonstrated that high-level of EPO group had significantly higher mortality compared with low-level EPO group (15.2% vs. 3.0%, p = 0.020). Hematocrit was significantly lower in high-level EPO group compared with low-level EPO group at 12 months (33.4 ± 1.1% vs. 36.0 ± 0.9%, p = 0.038). Conclusions: Plasma EPO appears to be a useful marker for predicting long-term outcome in post-severe AKI survivors.
Safety of Oral Food Challenge for Individuals with Low Egg White and Ovomucoid-Specific IgE Antibodies
Authors: Ogata Mika , Yoshida Takanobu , Kido Jun , Nishi Natsuko , Shimomura Sachiko , Hirai Nami , Yanai Masaaki , Mizukami Tomoyuki , Nakamura Kimitoshi
Published: October 2023

Introduction: During an oral food challenge (OFC), there is a risk of adverse reactions, including anaphylaxis. Therefore, the physician should carefully conduct the OFC. This study aimed to evaluate the OFC results in individuals with low levels of egg white (EW)- and ovomucoid (OVM)-specific immunoglobulin E (sIgE) and the safety of a hen’s egg (HE) OFC in these individuals. Methods: A total of 2,058 individuals with low EW- or OVM-sIgE underwent HE-OFC at two institutions in Kumamoto prefecture, located in the western area of Japan, between January 1, 2017, and December 31, 2021, within 1 year of recorded sIgE measurements. The ImmunoCAP systems were used to measure sIgEs. The HE-OFC test was performed according to the 2017 Food Allergy Guidelines in an open and unblinded method. Results: Five hundred and one individuals (24.3%) had low EW-sIgE levels (class 2 or lower), and 926 (45.0%) had low OVM-sIgE levels (class 2 or lower). Individuals with low EW-sIgE had lower total IgE and OVM-sIgE than did those with high EW-sIgE (greater than class 2). Those with low OVM-sIgE had lower total IgE and EW-sIgE than did those with high OVM-sIgE (greater than class 2). Among the individuals with low EW-sIgE, 86.4% (433/501 cases) passed the OFC without symptoms. Among the individuals with low OVF-sIgE, 82.6% (765/926 cases) passed the OFC without symptoms. Conclusion: More than 80% of individuals with suspected IgE-dependent HE allergy and low levels of EW- or OVM-specific IgE were able to consume at least a small amount of HE. As the OFC results are independent of the loading dose in cases with low EW- or OVM-sIgE, a medium-dose HE-OFC may be performed safely in individuals with no history of anaphylaxis.
Plasma Fatty Acid Biomarkers of Dairy Consumption Are Associated with Sex-Dependent Effects on Metabolic Syndrome Components in Mexican Adolescents
Authors: Trejo-Reyes Rebeca , Cantoral Alejandra , Lamadrid-Figueroa Hector , Betanzos-Robledo Larissa , Téllez-Rojo Martha María , Peterson Karen E. , Baylin Ana , Jansen Erica C.
Published: October 2023

Introduction: During adolescence, dairy product intake has shown conflicting associations with metabolic syndrome (MetS) components, which are risk factors for cardiovascular disease (CVD). This study aims to investigate the association between plasma fatty acids (FAs) C15:0, C17:0, and t-C16:1n-7, as biomarkers of dairy intake, with MetS and its components in Mexican adolescents. Methods: A sample of 311 participants from the Early Life Exposure in Mexico City to Environmental Toxicants (ELEMENT) cohort was included in this cross-sectional analysis. FA concentrations were measured in plasma as a percentage of total FA. We used quantile regression models stratified by sex to evaluate the association between FA quantiles and MetS components, adjusting for age, socioeconomic status (SES), sedentary behavior, BMI z-score, pubertal status, and energy intake. Results: We found significant associations between dairy biomarkers and the median of MetS variables. In females, t-C16:1n-7 was associated with a decrease of 2.97 cm in WC (Q4 vs. Q1; 95% CI: −5.79, −0.16). In males, C15:0 was associated with an increase of 5.84 mm/Hg in SBP (Q4 vs. Q1; CI: 1.82, 9.85). For HDL-C, we observed opposite associations by sex. C15:0 in males was associated with decreased HDL-C (Q3 vs. Q1: β = −4.23; 95% CI: −7.98, −0.48), while in females, C15:0 and t-C16:1n-7 were associated with increased HDL-C (Q3 vs. Q1: β = 4.75; 95% CI: 0.68, 8.82 and Q4 vs. Q1: β = 6.54; 95% CI: 2.01, 11.07), respectively. Additionally, in both sexes, different levels of C15:0, C17:0, and t-C16:1n-7 were associated with increased triglycerides (TG). Conclusion: Our results suggest that adolescent dairy intake may be associated in different directions with MetS components and that associations are sex-dependent.
Causes of Death in Cutaneous T-Cell Lymphoma Patients
Authors: Lebas Eve , Collins Patrick , Somja Joan , Nikkels Arjen F.
Published: October 2023

Background: The advancing evolution toward a Th2 immune environment confers a progressive immunosuppression in patients with longstanding cutaneous T-cell lymphoma (CTCL). The conjunction of the disease-related immunosuppression as well as the immunosuppressive character of some CTCL treatments increase the risk of infectious and neoplastic diseases, sometimes with fatal outcomes. Objectives: The aim of the study was to prospectively study the causes of death in a cohort of CTCL patients, in a tertiary university skin cancer center. Methods: All CTCL patients who died between 2008 and 2020 were included. The cause of the death was classified as directly or indirectly related or unrelated to CTCL. Results: Over the study period, 31 (13F/18m) patients with CTCL died (mean age: 75.2 years), mean delay between diagnosis and death: 3.2 years (min: 1, max: 12 years), 58.1% of death causes were classified as indirect (infection), 12.9% directly related (blastic transformation), 22.5% unrelated, and 6.5% of unknown cause. 51.6% of mycosis fungoides (MF) patients who died had early-stage disease (1A–2A) or were on remission. 45.2% of dead patients had advanced-stage MF (2B–4B). Mean CRP level is increased in patients who died from infection whereas LDH level increased in patients with blastosis. A tertiary center is expected to manage of a higher proportion of CTCL patients with advanced-stage disease. Conclusions: As infection represented more than 50% of the causes of death in CTCL patients, particular attention should be given to preventive measures such as anti-infective vaccination. Regular surveillance of CRP and LDH levels could be helpful for follow-up of MF patients, respectively, with regards to infection and blastosis.
SALL4 Phenotype in Four Generations of One Family: An Interplay of the Upper Limb, Kidneys, and the Pituitary
Authors: Kodytková Aneta , Amaratunga Shenali Anne , Zemková Daniela , Maratová Klára , Dušátková Petra , Plachý Lukáš , Průhová Štěpánka , Koloušková Stanislava , Lebl Jan
Published: October 2023

Introduction: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. Case Presentation: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, −2.2 SDS; length 47 cm, −2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 μg/L (−1.0 SD), and growth hormone (GH) after stimulation 6.2 μg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly – a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother’s and father’s heights are 152.3 cm (−2.4 SD) and 177.8 cm (−0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; −2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather’s mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (−2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (−0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. Conclusion: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.
Family Aggregation of Hematological Malignancies Discovered from an Acute Myeloid Leukemia Patient with STK11 and THBD Gene Mutation
Authors: Zhang Nan , Miao Xiao-juan , Shuai Yan-rong , Yao Hao , Fan Fang-Yi , Liu Yi-lan
Published: October 2023

Acute myeloid leukemia (AML) is a large class of heterogeneous hematological malignancies with the highest incidence rate in acute leukemia. Its pathogenesis is still unclear, which may be related to genetics. According to the latest AML NCCN guidelines, genes involved in AML family genetic changes include RUNX1, ANKRD26, CEBPA. Finding new genes related to AML genetics is of great significance for predicting the prognosis of patients, developing targeted drugs, and selecting transplant donors. Here, we report a case of adult female AML patient whose three relatives suffered from hematological malignancies, including Waldenstrom macroglobulinemia, NK/T-cell lymphoma, and angioimmunoblastic T-cell lymphoma. The screen for genetic susceptibility genes related to blood and immune system diseases was carried out, and the result showed that the patient herself, her son, her daughter, and her two cousins all had STK11 p.F354L and/or THBD p.D486Y mutations. At present, there is no research or case report on the relationship between STK11/THBD and family aggregation of hematological malignancies. We report for the first time that an AML patient with STK11 and THBD mutations has a family aggregation of hematological malignancies, and consider that STK11 and THBD may be related to family genetic changes which ultimately cause the family aggregation of hematological malignancies.
Apalutamide-Induced Toxic Epidermal Necrolysis in a Caucasian Patient with Metastatic Castration-Sensitive Prostate Cancer: A Case Report and Review of the Literature
Authors: Flynn Calvin R. , Liu Shun-Chieh , Byrne Berbie , Ralph James , Paz Gabriela , Anwar Salman , Buchalter Jemma , Fitzpatrick Orla M. , Markham Trevor , Donnellan Paul
Published: October 2023

Apalutamide is a novel nonsteroidal androgen receptor inhibitor that has been shown to improve outcomes for patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer when combined with androgen deprivation therapy. Apalutamide-induced skin rash occurred commonly in clinical trials, with 23.8–27.1% of patients experiencing a rash of any grade, and 5.2–6.3% experiencing a rash of grade three or higher. There were no cases of severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) reported in clinical trials; however, there are rare cases reported in the literature with the majority occurring in Asian patients. An 83-year-old Caucasian male was commenced on apalutamide, combined with degarelix, for the management of metastatic castration-sensitive prostate cancer. During week five of apalutamide treatment, the patient developed a widespread erythematous maculopapular rash. On presentation, the rash affected 80% of his body surface area (BSA) and a diagnosis of a severe cutaneous drug eruption was made. He was commenced on methylprednisolone (MP) therapy. Despite 5 days of MP, the rash continued to deteriorate involving 95% of his BSA. Nikolsky’s sign was positive. A diagnosis of overlap SJS/TEN was made, supported by skin biopsy. His SCORTEN score was three. He was then commenced on intravenous immunoglobulin and transferred to the intensive care unit. Over the coming days, the rash began to stabilise, and his steroid dose was weaned. He was discharged from hospital 38 days after rash onset. We report the first suggested case of apalutamide-induced SJS/TEN in a Caucasian patient. We discuss other cases of apalutamide-induced SCARs reported in the literature. Risk factors seem to include low body weight and Japanese race, as well as short time to onset of rash.
Effects of Catecholamines on Blood Flow in Preterm Infants: A Subanalysis of PICC-MBF Trial
Authors: Ishiguro Akio , Kabe Kazuhiko
Published: October 2023

Introduction: This study evaluated the correlation between skin blood flow and systemic blood flow and whether skin blood flow can determine the circulatory effects of dopamine and dobutamine on blood flow in very low birth weight (VLBW) infants. Methods: This study was a subanalysis of the PICC-MBF randomized controlled trial. The correlation between skin blood flow and echocardiographic findings was examined. Changes in skin blood flow and blood pressure before and after initiation or dose increase of dopamine and dobutamine were also evaluated. Results: Two hundred and thirty-four participants underwent echocardiography. Skin blood flow was significantly correlated with supra vena cava (SVC) flow (r = 0.31, p < 0.001). Receiver operator characteristic analysis revealed that skin blood flow <17 mL/min effectively detected SVC flow <41 mL/min (area under the curve = 0.83, p < 0.001). Dobutamine significantly increased skin blood flow after initiation or dose increase (p = 0.033) without increasing blood pressure. However, dopamine significantly increased both skin blood flow (p = 0.010) and blood pressure (p < 0.001). Conclusions: Our findings indicated that skin blood flow could be used as a surrogate marker of systemic blood flow in VLBW infants and revealed differences in the effects of dopamine and dobutamine on circulation.
Clinical Experience of Two Sutureless Intrascleral Fixation Techniques for Secondary Intraocular Lens Implantation
Authors: Januschowski Kai , Rickmann Annekatrin , Boden Karl T. , Ehrlich-Treuenstätt Gregor V. , Wakili Philip , Bisorca-Gassendorf Lukas
Published: October 2023

Introduction: The aim of this study was to evaluate the outcome of the modified Carlevale intraocular lens (IOL) fixation technique, using two different vitrectomy ports (23- vs. 27-gauge) as anchor fixation. Methods: Retrospective, consecutive study of 282 eyes (282 patients) who underwent a secondary IOL implantation using the Carlevale IOL (Soleko IOL Division, Italy) with two anchor haptics for intrascleral implantation with either 23- or 27-gauge (G) port. Results: Transient post-operative ocular hypotonia (intraocular pressure ≤5 mm Hg) was observed less in the 27-G group (13 vs. 4 patients, p = 0.057) three requiring additional tunnel sutures (2 cases for 23-G; 1 case 27-G). Post-operative vitreous haemorrhage was recorded more often in the 23-G group (8 vs. 1 patient, p = 0.034), but all cases in both groups resolved without intervention. Visual acuity did improve post-operatively in the two groups. No post-operative complications such as retinal detachment, endophthalmitis, and IOL-dislocation tilt were observed in the follow-up. Conclusion: The 27-G modified technique for sutureless intrascleral implantation is simple and effective and causes less post-operative hypotony.
Interoceptive and Affective Alterations in Body Integrity Dysphoria: An Online Self-Reporting Study
Authors: Capodici Alessandro , Pennisi Antonio , Rizzo Gaetano , Falzone Alessandra , Vicario Carmelo Mario
Published: October 2023

Introduction: Body integrity dysphoria (BID) is a rare condition in which individuals experience a long-lasting desire to achieve a specific physical disability. In this study, we tested the hypothesis of interoceptive and affective abnormalities in BID, in line with the evidence of structural and functional alteration of the interoceptive-affective neural system in these individuals. Method: Our study involved 68 participants with BID (mean age: 35.6, SD: 16.4). Among these participants, 47 expressed a desire for amputation, 14 desired paralysis, 3 sought sensory deprivation, and 3 desired a combination of these forms. For comparisons, we recruited a control group of 79 participants (mean age: 35.2, SD: 15.8). We administered assessment measures to investigate alexithymia level (TAS-20), disgust sensitivity (DS-R), interoceptive awareness (MAIA-2), and (affective and cognitive) empathy (QCAE). We also administered the Short Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) to identify psychiatric comorbidities. Subgroups with low O-LIFE scores (BID = 31; controls = 43) and subgroups with high O-LIFE scores (BID = 37; controls = 36) were derived through a median-split procedure. Results: Within the BID low O-LIFE group, we found reduced interoceptive sensibility, reduced disgust sensitivity, and increased difficulty in identifying feelings, which refers to a dimension of the alexithymia trait. Within the BID high O-LIFE group, we observed a reduced disgust sensitivity and interoceptive sensibility, accompanied by a diminished score in cognitive empathy. Conclusion: Our study suggests that BID can be associated with altered interoceptive and affective processing.
PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy
Authors: Guo Peiyu , Li Hua , Wang Xuming , Li Xingguo , Li Xi
Published: October 2023

Introduction: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β). Methods: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo. Results: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545. Conclusion: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.
Functional Dyspepsia: Current Understanding and Future Perspective
Authors: Oshima Tadayuki
Published: October 2023

Background: Functional dyspepsia (FD) is a common disorder characterized by chronic or recurrent upper abdominal pain or discomfort without any structural abnormalities in the gastrointestinal tract. FD is categorized into two subgroups based on symptoms: postprandial distress syndrome (PDS) and epigastric pain syndrome. Summary: The pathophysiology of FD involves several mechanisms. Delayed gastric emptying is observed in approximately 30% of FD patients but does not correlate with symptom patterns or severity. Impaired gastric accommodation is important in the pathophysiology, particularly for PDS. Visceral hypersensitivity, characterized by heightened sensitivity to normal activities, contributes to the perception of discomfort or pain in FD. Alterations to the duodenal mucosa, including impaired mucosal barrier function and low-grade inflammation, are also implicated in the pathogenesis of FD. Microbial dysbiosis and psychological factors such as stress can further exacerbate symptoms. Treatment options include dietary modifications, establishing a physician-patient relationship, acid suppressants, prokinetics, neuromodulators, and behavioral therapies. Dietary recommendations include eating smaller, more frequent meals, and avoiding trigger foods. Acid suppressants are used as the first-line treatment. Prokinetics and neuromodulators aim to improve gastric motility and central pain processing, respectively. Behavioral therapies, including cognitive behavioral therapy and hypnotherapy, have shown benefits for refractory FD. Severe and refractory cases may require combination therapies or experimental treatments. Key Messages: FD is a disorder of gut-brain interaction involving diverse pathophysiological mechanisms. Individualized treatment based on symptoms and responses to interventions is crucial. Further research is needed to improve the understanding of FD and advance the development of effective therapies.
The Effect of Iron Overload on the Mobilization of Peripheral Blood Hematopoietic Stem Cells in Pediatric Patients with Thalassemia Major
Authors: Van Timothee Bindanda Mvuama , Du Jing , Ren Yuqiong , He Yuelin , Ruan Yongsheng , Liu Xuan , Chen Libai , Wen Jianyun , Ding Rongfang , Yu Li , Liu Qiujun , Liu Xiaoting , Liao Jianyun , Peng Zhiyong , Wu Xuedong , Li Chunfu , Feng Xiaoqin
Published: October 2023

Introduction: The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with β-thalassemia major (TM). Methods: We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload was measured by magnetic resonance imaging (MRI) T2*. Results: The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI and lower leukapheresis product white blood cell count and CD34+ cell levels (all, p < 0.05). Conclusion: Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload, in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.
Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson’s Disease and Amyotrophic Lateral Sclerosis
Authors: Aslam Ayesha , Sarmad Eisham , Nawaz Ahmad , Numan Ahsan , Ahmad Azba , Hassan Muhammad
Published: October 2023

The Parkinson’s disease-amyotrophic lateral sclerosis (ALS) complex typically manifests as levodopa-responsive parkinsonism, followed by ALS. It is extremely rare for Parkinson’s disease and ALS to coexist without other neurological disorders. Named after the scientists who first described this overlap of two neurodegenerative conditions, it is referred to as Brait-Fahn-Schwartz disease. Given its variable presentation, increasing rarity, and lack of any diagnostic test, it poses a diagnostic challenge for physicians. We present a case of a 55-year-old Pakistani male experiencing progressive quadriparesis with spastic lower limbs and flaccid upper limbs, in addition to the cardinal features of idiopathic Parkinson’s disease. Since there is currently no cure available for either Parkinson’s disease or ALS, all available treatment focuses on improving quality of life, which we achieved in our patient. This case is unique in being the first incidence of Parkinson’s disease-ALS complex in a novel geographic region such as Pakistan, where genetic testing and cost constraints limit the diagnosis of rare disorders. The coexistence of extrapyramidal symptoms and pyramidal symptoms is uncommon. In such situations, physicians may overlook one group of symptoms, potentially leading to a misdiagnosis. This case highlights the value of a thorough physical examination and electrodiagnostic studies and suggests the association between Parkinson’s disease and ALS. This case demonstrates the significance of understanding when Parkinson’s disease symptoms start to appear in patients with ALS and the need to start dopaminergic therapy in those who had Parkinson’s disease features before ALS to alleviate the suffering of an individual and enhance quality of life.
Trends in Preterm Body Composition and Neurodevelopmental Outcomes after Discharge
Authors: Lach Laura E. , Chetta Katherine E. , Gregoski Mathew J. , Katikaneni Lakshmi D.
Published: October 2023

Introduction: Body composition, specifically fat-free mass (FFM), of preterm infants is associated with improved neurodevelopmental outcomes. Little is known about body composition of preterm infants after discharge. Preterm body composition was measured by air displacement plethysmography (ADP) at two time points, inpatient (35–40 weeks postmenstrual age [PMA]) and outpatient (48–58 weeks PMA), with neonatal factors and neurodevelopmental testing at 4–6 months corrected age. We hypothesized increased FFM is positively associated with neurodevelopment. Methods: From 2007 to 2011, 510 infants admitted to the Medical University of South Carolina’s neonatal intensive care unit underwent ADP. A total of 379 of 510 (74%) had anthropometrics at birth, an ADP scan with FFM, fat mass, fat percent z-scores, and an outpatient neurodevelopmental evaluation (CAT/CLAMS, Peabody Gross Motor). Variables were compared using multivariate analyses for body composition measurements. Results: The infants were 32 ± 4.8 weeks gestational age at birth with an average birth weight of 1,697 ± 932 g. Most (56%) infants received maternal milk at discharge. CAT, CLAMS, and gross motor scores had positive correlations with FFM z-scores at inpatient and outpatient ADP (p < 0.05). Receiving maternal milk at discharge was positively associated with cognitive (β = 0.22, p < 0.05) and language scores (β = 0.26, p < 0.05). Conclusion: Increased FFM is associated with improved cognitive, language, and gross motor testing. Maternal milk was positively associated with language and cognitive scores.
Recurrent Fluconazole-Induced Fixed Drug Eruption of the Digit with Nail Matrix Involvement: A Case Report and Review of the Literature
Authors: Hernandez Loren E. , Jadoo Arvin , Morrison Brian
Published: October 2023

Introduction: Fixed drug eruptions (FDEs) are cutaneous hypersensitivity reactions due to an offending drug and are rarely associated with nail involvement. Moreover, FDEs associated with fluconazole use are sparsely reported in literature. Case Presentation: We report a case of a recurrent FDE with involvement of one finger and corresponding Beau’s lines due to fluconazole use. The diagnosis of FDE secondary to fluconazole use was confirmed histopathologically, with improvement after the application of twice daily 0.05% clobetasol propionate ointment. Conclusion: FDEs are hypersensitivity reactions that occur after exposure to an offending drug. FDEs uncommonly affect the nail matrix and are often not caused by fluconazole. It is important for dermatologists to assess for changes in the nail plate when evaluating a patient with FDE and evaluate all medications a patient is taking.
Kaposi Sarcoma of the Nail Unit: A Case Report and Review of the Literature
Authors: Krygier Jonathan , Sass Ursula , Meiers Isabelle , Marneffe Alice , de Vicq de Cumptich Marine , Richert Bertrand
Published: October 2023

Introduction: Kaposi sarcoma is an angioproliferative neoplasm. Its manifestations are well known but nail involvement seems extremely underreported. Case Presentation: A 55-year-old man presented with a 6-month history of a growing subungual tumor affecting the third right toe. After surgical excision, histological examination revealed a Kaposi sarcoma. Discussion: We report a case of Kaposi sarcoma with nail involvement of only one toe as the first and unique manifestation, which is exceptional.
Urological Tumor: A Narrative Review of Tertiary Lymphatic Structures
Authors: Shen Chong , Zhang Dong-Li , Cheng Xiao-Long , Zhang Wei-Chuan , Zhao Jian-Jun
Published: October 2023

Background: Tertiary lymphoid structures (TLSs), as ectopic lymphoid-like tissues, are highly similar to secondary lymphoid organs and are not only involved in chronic inflammation and autoimmune responses but are also closely associated with tumor immunotherapy and prognosis. The complex composition of the urological tumor microenvironment not only varies greatly in response to immunotherapy, but the prognostic value of TLSs in different urological tumors remains controversial. Summary: We searched PubMed, Web of Science, and other full-text database systems. TLSs, kidney cancer, uroepithelial cancer, bladder cancer, and prostate cancer as keywords, relevant literature was searched from the time the library was built to 2023. Systematically explore the role and mechanism of TLSs in urological tumors. It includes the characteristics of TLSs, the role and mechanism of TLSs in urological tumors, and the clinical significance of TLSs in urological tumors. Key Messages: The prognostic role of TLSs in different urological tumors was significantly different. It is not only related to its enrichment in the tumor but also highly correlated with the location of the tumor. In addition, autoimmune toxicity may be a potential barrier to its role in the formation of TLSs through induction. Therefore, studying the mechanisms of TLSs in autoimmune diseases may help in the development of antitumor target drugs.
Blood Pressure and Mortality in the 4D Study
Authors: Yazdani Babak , Kleber Marcus E. , Delgado Graciela E. , Yücel Gökhan , Asgari Aruscha , Gerken Andreas L.H. , Daschner Clara , Ayasse Niklas , März Winfried , Wanner Christoph , Krämer Bernhard K.
Published: October 2023

Introduction: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear. Methods: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers. Results: Mean age was 66.3 years, mean blood pressure 146/76 mm Hg, mean time suffering from diabetes 18.1 years, and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP, and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we also did not detect any significant mortality prediction for PP, SBP, DBP, or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70–80 mm Hg. Discussion: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and CVM that may no longer be significantly modulated by blood pressure control.
Geometric versus Hemodynamic Indexes for Rupture-Destined Aneurysms: A Retrospective Cohort and a Repeated-Measures Study
Authors: Lee Chan-Hyuk , Kwak Hyo Sung , Kang Hyun-Seung , Jung Keun-Hwa , Jeong Seul-Ki
Published: October 2023

Introduction: A proper stratification of intracranial aneurysms is critical in identifying rupture-destined aneurysms and unruptured intracranial aneurysms. We aimed to determine the utility of geometric and hemodynamic indexes in differentiating two types of aneurysms and to examine the characteristics of natural evolutionary changes of unruptured aneurysms. Methods: Rupture-destined aneurysm refers to an aneurysm that undergoes subsequent aneurysmal subarachnoid hemorrhage (SAH). On the other hand, an unruptured intracranial aneurysm is characterized by an aneurysm that does not experience rupture during serial time-of-flight magnetic resonance angiography (TOF-MRA). In addition to geometric indexes, signal intensity gradient (SIG), an in vivo approximated wall shear stress from TOF-MRA, was measured in aneurysms. The difference between the maximum and minimum values of SIG in an aneurysm compared to parent arterial values was designated as the delta-SIG ratio. Results: This study analyzed 20 rupture-destined aneurysms in 20 patients and 45 unruptured intracranial aneurysms in 41 patients with follow-up TOF-MRA. While geometric indexes did not show differences between the two groups, the delta-SIG ratio was higher in the rupture-destined aneurysms (1.5 ± 0.6 vs. 1.1 ± 0.3, p = 0.032). The delta-SIG ratio showed a higher area under the receiver operating characteristic curve for SAH than the size ratio (0.72 [95% CI, 0.58–0.87] vs. 0.56 [95% CI, 0.41–0.72], p = 0.033). The longitudinal re-examination of TOF-MRA in the unruptured intracranial aneurysms revealed evidence of aneurysmal growth, while concurrently exhibiting hemodynamic stability. Conclusion: The delta-SIG ratio showed higher discriminatory results between the two groups compared to geometric indexes. Aneurysmal rupture risk should be assessed by considering both geometric and hemodynamic information. This study was registered on ClinicalTrials.gov (NCT05450939).
Regulatory Qualification of a Cross-Disease Digital Measure: Benefits and Challenges from the Perspective of IMI Consortium IDEA-FAST
Authors: Nobbs David , Piwko Wojciech , Bull Christopher , Cormack Francesca , Ahmaniemi Teemu , Holst Sebastian C. , Chatterjee Meenakshi , Maetzler Walter , Avey Stefan , Ng Wan Fai ,   IDEA-FAST Consortium
Published: October 2023

Background: Innovative Medicines Initiative (IMI) consortium IDEA-FAST is developing novel digital measures of fatigue, sleep quality, and impact of sleep disturbances for neurodegenerative diseases and immune-mediated inflammatory diseases. In 2022, the consortium met with the European Medicines Agency (EMA) to receive advice on its plans for regulatory qualification of the measures. This viewpoint reviews the IDEA-FAST perspective on developing digital measures for multiple diseases and the advice provided by the EMA. Summary: The EMA considered a cross-disease measure an interesting and arguably feasible concept. Developers should account for the need for a strong rationale that the clinical features to be measured are similar across diseases. In addition, they may expect increased complexity of study design, challenges when managing differences within and between disease populations, and the need for validation in both heterogeneous and homogeneous populations. Key Messages: EMA highlighted the challenges teams may encounter when developing a cross-disease measure, though benefits potentially include reduced resources for the technology developer and health authority, faster access to innovation across different therapeutic fields, and feasibility of cross-disease comparisons. The insights included here can be used by project teams to guide them in the development of cross-disease digital measures intended for regulatory qualification.
Management of Status Epilepticus by Different Pediatric Departments: Neurology, Intensive Care, and Emergency Medicine
Authors: Dedeoglu Özge , Akça Halise , Emeksiz Serhat , Kartal Ayşe , Kurt Neşe Çıtak
Published: October 2023

Introduction: The aim of this study was to explore the differences in status epilepticus (SE) management among pediatric neurology, emergency medicine, and intensive care specialists in Turkey. Methods: A 22-item questionnaire regarding first-, second-, and third-line management strategies of SE including demographic characteristics and common etiologies according to the specialty of participants was mailed to 370 specialists working in Turkey. Results: A total of 334 participants (response rate 90%) comprising 136 pediatric neurologists, 102 pediatric emergency medicine specialists, and 96 pediatric intensive care specialists completed the survey. While intensive care specialists frequently managed SE due to metabolic and autoimmune reasons, the most common etiologies encountered by emergency medicine specialists were epilepsy and infections. More than half of the intensive care specialists (64.6%) reported using non-BZD antiseizure medications in the 5th minute of the seizure. Most of the neurologists (76.4%) preferred to administer intravenous (IV) levetiracetam infusion as a second-line agent. About half of intensive care specialists and neurologists tried immunomodulatory therapies in super-refractory SE. Intensive care and emergency medicine specialists were less likely to favor ketogenic diet and pyridoxine therapy for the treatment of super-refractory SE. The rate of requesting EEG monitoring to recognize nonconvulsive SE (NCSE) was found to be very low except for neurologists. Conclusion: There was no consensus among neurologists, intensive care specialists, and emergency medicine specialists in the management of SE in Turkey. Familiarity with particular antiseizure medications and the etiologies they manage seem to be the most important factors influencing the attitudes.