Intractable & rare diseases research最新文献

As the aging population increases globally, health-related issues caused by frailty are gradually coming to light and have become a global health priority. Frailty leads to a significantly increased risk of falls, incapacitation, and death. Early screening leads to better prevention and management of frailty, increasing the possibility of reversing it. Developing assessment tools by incorporating disease states of older adults using effective interventions has become the most effective approach for preventing and controlling frailty. The most direct and effective tool for evaluating debilitating conditions is a frailty screening tool, but because there is no globally recognized gold standard, every country has its own scale for national use. The diversity and usefulness of the frailty screening tool has become a hot topic worldwide. In this article, we reviewed the frailty screening tool published worldwide from January 2001 to June 2023. We focused on several commonly used frailty screening tools. A systematic search was conducted using PubMed database, and the commonly used frailty screening tools were found to be translated and validated in many countries. Disease-specific scales were also selected to fit the disease. Each of the current frailty screening tools are used in different clinical situations, and therefore, the clinical practice applications of these frailty screening tools are summarized graphically to provide the most intuitive screening and reference for clinical practitioners. The frailty screening tools were categorized as (ⅰ) Global Frailty Screening Tools in Common; (ⅱ) Frailty Screening Tools in various countries; (ⅲ) Frailty Screening Tools for various diseases. As science and technology continue to advance, electronic frailty assessment tools have been developed and utilized. In the context of Coronavirus disease 2019 (COVID-19), electronic frailty assessment tools played an important role. This review compares the currently used frailty screenings tools, with a view to enable quick selection of the appropriate scale. However, further improvement and justification of each tool is needed to guide clinical practitioners to make better decisions.

To analyze the outcome in patients who have undergone multivisceral resection (MVR) for locally advanced gastrointestinal stromal tumors (GISTs), and identify the risk factors for tumor recurrence and postoperative morbidity. Sixty-four patients who operated for locally advanced GISTs with MVR in PPeking University Cancer Hospital Sarcoma Center (PUCHSC) between 2013 and 2021 were identified. Clinicopathologic characteristics, surgical outcomes, recurrence, and 5-year recurrence-free and overall survival were evaluated. The mean age of the patients was 60 years. Mean tumor size was 11.1 cm. Complete resection was achieved in all patients. The estimated 5-year recurrence-free and overall survival were 86.6% and 90.0%, respectively. Independent factor of recurrence following surgery was mitotic count on multivariate analysis. Overall postoperative morbidity was 53.1% (n = 34). Severe morbidity was 21.9% (n = 14). The most common severe complication was clinically relevant pancreatic fistula (n = 12, 18.8%), followed by anastomotic leakage (n = 4, 6.3%) and Intraabdominal abscess (n = 4, 6.3%). Multivariate analysis showed that preoperative imatinib therapy could reduce overall morbidity. Long operation time, combined colectomy and pancreatectomy were independent risk factors for postoperative severe morbidity. Compared to partial pancreatectomy, pancreaticoduodenectomy (PD) was significantly increased the incidence of severe morbidity. In conclusion, compared to systemic therapy alone, the outcome of locally advanced GISTs after MVR was more favorable. Despite the high overall morbidity, the postoperative severe morbidity and mortality of MVR were acceptable. Preoperative imatinib therapy should be recommended whenever possible. Combined pancreatectomy and colectomy are associated with significant postoperative severe morbidities. PD should be thoroughly discussed and be subject to MDT approach before surgery.

This study aimed to depict the emotional journey of Japanese patients with specific intractable diseases facing challenges associated with a delayed diagnosis. Specifically, our focus was on elucidating the emotional journey of patients and identifying the unmet needs caused by a delayed diagnosis. We conducted a web-based survey targeting 179 patients with 11 specified intractable diseases. They reported their emotional states during each journey phase using a 10-point scale. The results revealed that the period from noticing bodily changes to clinic visits was characterized by the most negative emotional states. Furthermore, the patients experienced a gradual shift towards positive emotional states as they decided to complete a consultation at a specialized hospital. They reached their most positive emotional states when they received a definitive diagnosis, subsequent treatment, and care. The thematic classification of emotional changes at the time of definitive diagnosis showed that "relief" was the most prevalent emotion (41.9%), followed by "no change" (19.9%), "anxiety" (14.0%), "shock" (13.4%), and "resignation" (6.5%). Additionally, when classifying the thematic changes in emotions during the period of bodily changes and clinic visits, "frustration" was the most common (51.3%), followed by "fear and anxiety" (43.6%). Patients tended to be most psychologically distressed during the period leading up to the definitive diagnosis. These results reveal that patients with intractable diseases are seeking a fast and accurate diagnosis, and that achieving these is a key unmet need for the patients.

With the increasing application of artificial intelligence (AI) in medicine and healthcare, AI technologies have the potential to improve the diagnosis, treatment, and prognosis of rare diseases. Presently, existing research predominantly focuses on the areas of diagnosis and prognosis, with relatively fewer studies dedicated to the domain of treatment. The purpose of this review is to systematically analyze the existing literature on the application of AI in the treatment of rare diseases. We searched three databases for related studies, and established criteria for the selection of retrieved articles. From the 407 unique articles identified across the three databases, 13 articles from 8 countries were selected, which investigated 10 different rare diseases. The most frequently studied rare disease group was rare neurologic diseases (n = 5/13, 38.46%). Among the four identified therapeutic domains, 7 articles (53.85%) focused on drug research, with 5 specifically focused on drug discovery (drug repurposing, the discovery of drug targets and small-molecule inhibitors), 1 on pre-clinical studies (drug interactions), and 1 on clinical studies (information strength assessment of clinical parameters). Across the selected 13 articles, we identified total 32 different algorithms, with random forest (RF) being the most commonly used (n = 4/32, 12.50%). The predominant purpose of AI in the treatment of rare diseases in these articles was to enhance the performance of analytical tasks (53.33%). The most common data source was database data (35.29%), with 5 of these studies being in the field of drug research, utilizing classic databases such as RCSB, PDB and NCBI. Additionally, 47.37% of the articles highlighted the existing challenge of data scarcity or small sample sizes.

Previous studies have indicated an elevated risk of infertility in certain birth defects, including congenital heart disease (CHD), hypospadias, cryptorchidism, and disorders of sexual development (DSD). Although the identification of chromosomal abnormalities or chromosomal aberrations (CAs) is crucial for the diagnosis of these conditions, the assessment of CAs in these disorders remains unclear, and few large-scale studies have been conducted at multiple centers. The aim of the current study was to systematically evaluate the prevalence of CAs in CHD, hypospadias, cryptorchidism, and DSD. Studies reporting CAs in these birth defects were retrospectively analyzed from 1991- 2023, using online databases such as PubMed and Google scholar as well as preprints and references from related literature. Comprehensive screening, data acquisition, and systematic assessments of the identified literature were performed. Ultimately, searches yielded a total of 7,356 samples from 14 published articles on CHD, 298 hypospadias cases from 4 published articles, 1,681 cryptorchidism cases from 4 published articles, and 2,876 DSD cases from 7 published articles. Carrier rates of CAs varied widely among these studies and conditions. A retrospective analysis revealed that CHD was associated with the highest carrier rate (26%) for CAs, followed by DSD (21%), hypospadias (9%), and cryptorchidism (5%). A subtype analysis of CAs indicated a higher prevalence of numerical abnormalities among the reported cases. Therefore, considering CAs in birth defects associated with infertility is imperative. This provides a foundation for the further clinical implementation of chromosomal screening and enhancing high-risk screening for individuals in the real world.

Interferon-inducible transmembrane (IFITM) are a family of small proteins localized to plasma and endolysosomal membranes. Their functions beyond restricting viral entry and replication have been revealed in recent years. IFITM5 is involved in bone mineralization and is an osteogenic cell surface marker. IFITM1 and 3 interact with desmin and myosin, and are involved in myogenic differentiation. This study found upregulation of Ifitm2 during osteogenic differentiation of C3H10T1/2 cells. This positively correlated to the expression of osteogenic differentiation markers Col1a1, Alp, Runx2, and Ocn. Knockdown of Ifitm2 by siRNAs inhibited osteogenic differentiation, calcium deposition, and osteogenic marker expression of C3H10T1/2 cells. The osteoblast transcriptome revealed that knocking down Ifitm2 affected the expression Wnt signaling pathway-related genes, including Wnt family members, their receptors Lrp, Frizzled, and Lgr, and transmembrane molecule Rnf43 that suppresses the Wnt signaling pathway. Luciferase assays indicated enhancement of canonical Wnt signaling pathways by Ifitm2 overexpression. Furthermore, IFITM2 was colocalized in the metaphyseal bone and growth plate of the mouse tibial bone with SP7, a transcription factor essential for osteoblast differentiation and bone formation. These findings reveal a possible novel function and potential mechanisms of Ifitm2 in osteogenic differentiation.

Extrahepatic portal vein obstruction (EHPVO) is a rare disease. Most EHPVO patients are usually referred to a gastroenterologist for intestinal bleeding and hypersplenic thrombocytopenia; however, hypercoagulative diseases may be occult in these patients and require anticoagulation. The purpose of this study was to elucidate the clinical characteristics of EHPVO. We conducted a retrospective analysis of the hospital database, evaluating the medical records of 15 patients (7 males, 8 females, mean age of onset 42.0 years, range 5-74 years). Thirteen of 15 EHPVO patients (86.7%) had intestinal varices. These included 10 esophageal (66.7%), 12 gastric (80.0%), and 6 ectopic varices (40.0%). Nine (60.0%) of 15 had a history of intestinal bleeding. Regarding comorbidities, 5 of 15 (33.3%) suffered from vascular diseases, including acute myocardial infarction, cerebral infarction, pulmonary embolism, Budd-Chiari syndrome, and mesenteric vein thrombosis. The former 3 vascular commodities manifested at less than 32 years of age. Four patients (26.7%) with JAK2V617F mutation were diagnosed as myeloproliferative neoplasm (MPN). 72.3% of EHPVO patients without MPN experienced thrombocytopenic state. No EHPVO patients with MPN experienced thrombo-leukocytopenia. The elevation of white blood cell and platelet counts, and decrease of protein S were seen in EHPVO with MPN, compared with EHPVO without MPN. EHPVO is frequently associated with underlying hypercoagulative factors, causing a dilemma between thrombotic complications and portal hypertensive bleeding. Most EHPVO patients experience an evident thrombocytopenic state due to severe hypersplenism; however, hypersplenic hematologic changes are eliminated in EHPVO with MPN. MPN should be suspected in EHPVO patients negative for thrombo-leukocytopenia.

Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS. In this work, we report a boy who presented with intracranial hemorrhage (ICH) as an initial symptom and detects a novel pathogenic synonymous mutation in his WAS gene. His mother was a carrier of the mutant gene. The mutation, located at position c.273 (c.273 G>A) in exon 2, is a synonym mutation and predicted to affect protein expression by disrupting gene splicing. This study summarizes the diagnosis and treatment process of the patient and expands the genetic spectrum of WAS.

Varicella zoster virus (VZV) causes chickenpox at the primary infection and then becomes latent in the spinal dorsal root ganglia; VZV can reactivate with aging, immunosuppression, stress, and other factors, occurring as herpes zoster (HZ) at 1-2 skin segments. HZ peripheral nerve complications caused by VZV reactivation include Hunt syndrome, segmental HZ paresis, post-herpetic neuralgia, and Guillain-Barré syndrome (GBS). We have encountered the rare HZ complications of upper-limb paresis, myeloradiculitis, and polyradiculoneuritis: an adult woman with upper-limb paresis consistent with the nerve root on segments above the thoracic HZ dermatome; another woman exhibiting ascending myeloradiculitis originating at the Th11-12 roots; an elderly woman with ascending VZV polyradiculoneuritis resembling GBS; an adult with VZV quadriplegia with disseminated HZ; and an elderly patient with VZV-associated polyradiculoneuritis. The three polyradiculoneuritis cases may be a new subtype of HZ peripheral neuropathy, but the pathophysiology for these HZ peripheral nerve complications unrelated to HZ dermatomes is unclear. We analyzed host factors, skin lesions, neurological and virological findings, and MRI results including 3D NerveVIEW in 15 Japanese patients treated at our facility for HZ peripheral neuropathy, including six differing from the HZ dermatome. Based on the clinical findings including MRI results of spinal ganglia and roots, we identified four possible routes for the patterns of VZV spread: (i) ascending spinal roots, (ii) ascending spinal cord, (iii) polyradiculopathy, and (iv) intrathecal spread. The incidence of HZ is increasing with the aging of many populations, and clinicians should be aware of these HZ neuropathies.