BACKGROUND: Caudal regression syndrome (CRS), also known as caudal agenesis, results from abnormal development of the caudal aspect of the spinal cord and vertebral column due to an earlier abnormality of gastrulation.
RESULTS: This report showcases a unique scenario where three siblings, devoid of any prior family history or identifiable risk factors, exhibit symptoms of CRS and receive care at a government-run tertiary facility dedicated to children\'s health. In establishing a concrete diagnosis, we relied on skeletal surveys, comprehensive symptom evaluation, and medical history assessment. Additionally, we recommended further investigation through magnetic resonance imaging and genetic testing to attain a more in-depth understanding and confirmation of the condition. Unfortunately, the financial constraints faced by the parents led to the unfeasibility of pursuing these advanced diagnostic options. Given the rarity of this syndrome and the limited existing literature, our report is a significant contribution. It marks the first comprehensive exploration of CRS from the genetic and familial predisposition perspective, shedding new light on this rare condition.
CONCLUSIONS: This case series pioneers our understanding of the familial and genetic connections between CRS and sacral agenesis. Strikingly, each subsequent generation has experienced more severe manifestations earlier, furnishing compelling evidence that underpins the genetic predisposition to CRS.

Lymphoplasmacytic lymphoma (LPL) is a malignant proliferation of small lymphocytes, lymphoplasmocytoid cells and plasmocytes affecting the bone marrow, lymph nodes and spleen. Its incidence is 1/100,000 and represents 8% of all lymphomas. A total of ~5% of patients with LPL may secrete non-IgM of IgG, IgA, kappa or lambda type or be non-secretory. In the present study, a case of a 62-year-old female patient who was diagnosed with non-IgM LPL with kappa light chain monoclonal paraprotein production and normal serum immunoglobulin levels was reported. The MYD88 L265P mutation was detected by molecular genetic analysis using a sample of the bone marrow. The patient underwent initial treatment with a combination of Bendamustine-Rituximab, and later on, Ibrutinib (a Bruton kinase inhibitor) was added to the treatment protocol. The authors\' aim was to describe a case of a rare type of LPL studied and cured at the University Hospital \'St. Ivan Rilski\', as well as to show the methods used for its diagnosis and their applicability. The difficulty in diagnosing such rare cases of LPL which are associated with marked plasmacytic differentiation and IgA paraprotein secretion resembling plasma cell neoplasia was addressed. From the other side, the characteristic features in favor of LPL diagnosis are the immunophenotype profile of plasmocytes, as well as the presence of MYD88 L265P mutation. Finally, the methods of management and treatment of this type of lymphoma were reported, highlighting the favorable effect of the treatment with Bruton TK inhibitor (Ibrutinib).

Plant cryobanks play a significant role in modern science and breeding. They contribute to the recovery of lost species, the emergence of new plant varieties, and help preserve and explore the diversity of the plant world. The IPPRAS Cryobank collection is constantly supplemented with new samples, while, at the same time, the stored samples are being monitored. In order to test seed germination, seeds of Allium and Veratrum species were thawed. Rare Allium species seeds, such as A. nutans, A. schoenoprasum, and A. victorialis were stored in liquid nitrogen for 17, 19, and 30 years, respectively. Long-term cryopreservation decreased germination rates for A. nutans from 96.55 to 50.00%, for A. schoenoprasum from 72.00 to 62.75%, and for A. victorialis from 90.00 to 83.05%. Seeds of a rare medicinal species, Veratrum lobelianum, were stored in liquid nitrogen for 18 years; the seed germination rate during this storage period has been significantly decreased from 75.00 to 14.81%. V. nigrum seeds were also collected and frozen in liquid nitrogen for 3 days. Short-term cryopreservation did not result in a statistically significant change in germination rates (from 79.71 to 82.69%). The seeds of an endangered ornamental species, Cypripedium calceolus, were collected and kept frozen for 3 days. After cryopreservation, the seeds were planted on three different media, as follows: ½ MS, MS with 10% coconut milk, and BM1. On ½ MS medium, 24.98% seeds formed protocorms, while on MS medium with 10% coconut milk, this number was 10.02%, and on BM1 medium, it was 15.02%, respectively; however, after 2.5 months, all of the protocorms died. Thus, it appears that the existing protocol for seed cryopreservation of C. calceolus needs further improvement. The size, weight, and free water content (WC) of six previously cryopreserved Stipa species and three Allium species were measured. For all the Allium and Stipa species studied, we found no correlation between seed size, WC, and cryotolerance. We also found no correlation between the life form, which reflects the water requirement of the species, and cryotolerance.

BACKGROUND: Artificial intelligence (AI) symptom checker models should be trained using real-world patient data to improve their diagnostic accuracy. Given that AI-based symptom checkers are currently used in clinical practice, their performance should improve over time. However, longitudinal evaluations of the diagnostic accuracy of these symptom checkers are limited.
OBJECTIVE: This study aimed to assess the longitudinal changes in the accuracy of differential diagnosis lists created by an AI-based symptom checker used in the real world.
METHODS: This was a single-center, retrospective, observational study. Patients who visited an outpatient clinic without an appointment between May 1, 2019, and April 30, 2022, and who were admitted to a community hospital in Japan within 30 days of their index visit were considered eligible. We only included patients who underwent an AI-based symptom checkup at the index visit, and the diagnosis was finally confirmed during follow-up. Final diagnoses were categorized as common or uncommon, and all cases were categorized as typical or atypical. The primary outcome measure was the accuracy of the differential diagnosis list created by the AI-based symptom checker, defined as the final diagnosis in a list of 10 differential diagnoses created by the symptom checker. To assess the change in the symptom checker\'s diagnostic accuracy over 3 years, we used a chi-square test to compare the primary outcome over 3 periods: from May 1, 2019, to April 30, 2020 (first year); from May 1, 2020, to April 30, 2021 (second year); and from May 1, 2021, to April 30, 2022 (third year).
RESULTS: A total of 381 patients were included. Common diseases comprised 257 (67.5%) cases, and typical presentations were observed in 298 (78.2%) cases. Overall, the accuracy of the differential diagnosis list created by the AI-based symptom checker was 172 (45.1%), which did not differ across the 3 years (first year: 97/219, 44.3%; second year: 32/72, 44.4%; and third year: 43/90, 47.7%; P=.85). The accuracy of the differential diagnosis list created by the symptom checker was low in those with uncommon diseases (30/124, 24.2%) and atypical presentations (12/83, 14.5%). In the multivariate logistic regression model, common disease (P<.001; odds ratio 4.13, 95% CI 2.50-6.98) and typical presentation (P<.001; odds ratio 6.92, 95% CI 3.62-14.2) were significantly associated with the accuracy of the differential diagnosis list created by the symptom checker.
CONCLUSIONS: A 3-year longitudinal survey of the diagnostic accuracy of differential diagnosis lists developed by an AI-based symptom checker, which has been implemented in real-world clinical practice settings, showed no improvement over time. Uncommon diseases and atypical presentations were independently associated with a lower diagnostic accuracy. In the future, symptom checkers should be trained to recognize uncommon conditions.

UNASSIGNED: Rare cancers are those that exhibit an incidence of less than six per 100,000 in a year. On average, the five-year relative survival for patients with rare cancers is worse than those with common cancers. The traumatic experience of cancer can be further intensified in patients with rare cancers due to the limited clinical evidence and the lack of empirical evidence for informed decision-making. With rare cancers cumulatively accounting for up to 25% of all cancers, coupled with the rising burden of rare cancers on societies globally, it is necessary to determine the psychological outcomes of patients with rare cancers.
UNASSIGNED: This PRISMA-adherent systematic review (PROSPERO: CRD42023475748) involved a systematic search of PubMed, Embase, Cochrane and PsycINFO for all peer-reviewed English language studies published since 2000 to 30th January 2024 that evaluated the prevalence, incidence and risk of depression, anxiety, suicide, and post-traumatic stress disorder (PTSD) in patients with rare cancers. Two independent reviewers appraised and extracted the summary data from published studies. Random effects meta-analyses and meta-regression were used for primary analysis.
UNASSIGNED: We included 32 studies with 57,470 patients with rare cancers. Meta-analyses indicated a statistically significant increased risk-ratio (RR) of depression (RR = 2.61, 95% CI: 1.43-4.77, I2 = 97%) and anxiety (RR = 2.66, 95% CI: 1.27-5.55, I2 = 92%) in patients with rare cancers compared to healthy controls. We identified a high suicide incidence (315 per 100,000 person-years, 95% CI: 162-609, I2 = 95%), prevalence of depression (17%, 95% CI: 14-22, I2 = 88%), anxiety (20%, 95% CI: 15-25, I2 = 96%) and PTSD (18%, 95% CI: 9-32, I2 = 25%). When compared to patients with common cancer types, suicide incidence, and PTSD prevalence were significantly higher in patients with rare cancers. Systematic review found that having advanced disease, chemotherapy treatment, lower income, and social status were risk factors for negative psychological outcomes.
UNASSIGNED: We highlight the need for early identification of psychological maladjustment in patients with rare cancers. Additionally, studies to identify effective interventions are imperative.
UNASSIGNED: This study was supported by the National Medical Research Council Transition Award, SingHealth Duke-NUS Oncology Academic Clinical Programme, the Khoo Pilot Collaborative Award, the National Medical Research Council Clinician Scientist-Individual Research Grant-New Investigator Grant, the Terry Fox Grant and the Khoo Bridge Funding Award.

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

Despite being the second largest family of flowering plants, orchids represent community structure variation in plant-microbial associations, contributes to niche partitioning in metacommunity assemblages. Yet, mycorrhizal communities and interactions remain unknown for orchids that are highly specialized or even obligated in their associations with their mycorrhizal partners. In this study, we sought to compare orchid mycorrhizal fungal (OMF) communities of three co-occurring hemiepiphytic Vanilla species (V. hartii, V. pompona, and V. trigonocarpa) in tropical forests of Costa Rica by addressing the identity of their OMF communities across species, root types, and populations, using high-throughput sequencing. Sequencing the nuclear ribosomal internal transcribed spacer (nrITS) yielded 299 fungal Operational Taxonomic Units (OTUs) from 193 root samples. We showed distinct segregation in the putative OMF (pOMF) communities of the three coexisting Vanilla hosts. We also found that mycorrhizal communities associated with the rare V. hartii varied among populations. Furthermore, we identified Tulasnellaceae and Ceratobasidiaceae as dominant pOMF families in terrestrial roots of the three Vanilla species. In contrast, the epiphytic roots were mainly dominated by OTUs belonging to the Atractiellales and Serendipitaceae. Furthermore, the pOMF communities differed significantly across populations of the widespread V. trigonocarpa and showed patterns of distance decay in similarity. This is the first report of different pOMF communities detected in roots of wild co-occurring Vanilla species using high-throughput sequencing, which provides evidence that three coexisting Vanilla species and their root types exhibited pOMF niche partitioning, and that the rare and widespread Vanilla hosts displayed diverse mycorrhizal preferences.

Structural variations (SV) are large (>50 base pairs) genomic rearrangements comprising deletions, duplications, insertions, inversions, and translocations. Studying SVs is important because they play active and critical roles in regulating gene expression, determining disease predispositions, and identifying population-specific differences among individuals of diverse ancestries. However, SV discoveries in the Indian population using whole-genome sequencing (WGS) have been limited. In this study, using short-read WGS having an average 42X depth of coverage, we identify and characterize 36,210 SVs from 529 individuals enrolled in population-based cohorts in India. These SVs include 24,574 deletions, 2,913 duplications, 8,710 insertions, and 13 inversions; 1.26% (456 out of 36,210) of the identified SVs can potentially impact the coding regions of genes. Furthermore, 56 of these SVs are highly intolerant to loss-of-function changes to the mapped genes, and five SVs impacting ADAMTS17, CCDC40, and RHCE are common in our study individuals. Seven rare SVs significantly impact dosage sensitivity of genes known to be associated with various clinical phenotypes. Most of the SVs in our study are rare and heterozygous. This fine-scale SV discovery in the underrepresented Indian population provides valuable insights that extend beyond Eurocentric human genetic studies.

A 23-year-old female patient presented with radicular back pain, perineal numbness, and urinary retention. The patient was diagnosed with cauda equina syndrome and magnetic resonance imaging (MRI) of the spine revealed an enhancing osseous lumbar lesion causing severe central stenosis. A core needle biopsy of the lumbar spine showed microscopic features compatible with a small round blue cell tumor. CD99 and FLI1 were positive in the tumor cells. Next-generation sequencing demonstrated a EWSR1::FLI1 fusion. Given these findings, the spine lesion was diagnosed as Ewing sarcoma. The patient underwent surgical decompression of L2. On further workup, an MRI revealed an ill-defined enhancing mass of the right distal femur. This area was biopsied, demonstrating a fibro-osseous lesion with osteoblast proliferation containing nuclear atypia, low mitotic activity, and SATB2 positivity, diagnosed as low-grade central osteosarcoma (LGCOS). The patient underwent resection, which showed a classic LGCOS by histomorphology. Although fluorescence in-situ hybridization study for MDM2 gene amplification was negative, the overall findings are most consistent with LGCOS. These neoplasms are considered to be synchronous due to the presentation of each entity within 6 months. Considering the aggregate yearly incidence of Ewing sarcoma (approximately 1 case per 750 000 per year) and LGCOS (approximately 1 case per 10 million per year), the aggregate yearly probability of developing both of these genetically unrelated tumors in a single individual is 1 per 7.5 trillion per year, and it is likely such an event has never happened in the past.

Vagococcus fluvialis infection is rare in humans, and there is limited research on the clinical manifestations and antimicrobial susceptibility testing of Vagococcus fluvialis infection. Here, We isolated Vagococcus fluvialis from the urine samples of bladder cancer patients at Hunan Provincial People\'s Hospital, and it is the first reported case of Vagococcus fluvialis isolated from the urine. The fully automated microbial identification system and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) identified the bacterium as Vagococcus fluvialis with a confidence level of 99.9%. The VITEK-2Compact fully automated microbial susceptibility analysis system indicated that it was most sensitive to tigecycline, vancomycin, quinupristin/dalfopristin, linezolid, and showed moderate sensitivity to erythromycin, levofloxacin, ciprofloxacin, ampicillin/sulbactam, and tetracycline. Additionally, it exhibited synergy when combined with high-level gentamicin and vancomycin, showing sensitivity. However, it displayed poor activity against penicillin and furanth. According to our knowledge, this is the first study to isolate and identify Vagococcus fluvialis from the urine of bladder cancer patients and the systematically reviewed other reported Vagococcus infections on human, which provide an experimental basis for guiding the rational use of drugs in the clinical treatment and diagnose of Vagococcus fluvialis infection and related pathogenic mechanism research. Meanwhile, we have systematically reviewed other reported.