Rare Combination Research Articles

Dealing with adverse drug reactions in the context of polypharmacy using regression models

Polypharmacy in older adults increases the risk of adverse drug reactions (ADRs), but studying this relationship is complex. In real-world data, the high number of medications, coupled with rare drug combinations, results in high-dimensional datasets that are difficult to analyze using conventional statistical methods. This study applies horseshoe and lasso regression for analyzing rare events in polypharmacy contexts, focusing on severe ADRs such as falls and bleedings. These regression models are executed on a multi-center dataset compiling 7175 cases from the ADRED project to detect potential ADR-associated drugs among 100 most common drugs in emergency department admissions. Positive predictors are classified by using 50% and 90% credibility intervals. This study demonstrates that regression models with horseshoe or lasso priors are effective for analyzing ADRs, providing a comprehensive consideration of multiple factors in large, sparse datasets and improving signal detection in polypharmacy, addressing a significant challenge in pharmacovigilance. Both priors yielded consistent and clinically meaningful results. The horseshoe regression resulted in fewer potential positive predictors overall, which could make it suitable as a diagnostic tool. While these regressions generate valuable information, there are still challenges in setting appropriate thresholds for determining and interpreting the positive results.

«The man of the system»

The article reviews the monograph by I.E. Barykina ("A typical St. Petersburg official" Count Dmitry Andreevich Tolstoy (1823-1889): The experience of the biography of the minister. M.; St. Petersburg, 2022). Noting the merits of the book by I.E. Barykina, the author of the review dwells on the problematic aspects of D.A. Tolstoy's biography. In particular, his role as an official in charge of the Academy of Sciences and Russian universities is considered, as well as a rare combination of the roles of a dignitary and a scientist in the bureaucratic environment of the hero of the reviewed essay.

Vasoactive Intestinal Polypeptide Secreting MS Neuroblastoma

ABSTRACT We present a rare case of a 17-month-old child diagnosed with MS-stage neuroblastoma and associated chronic diarrhea due to elevated vasoactive intestinal peptide (VIP) levels. The unusual occurrence of a VIP-secreting tumor in a patient with MS neuroblastoma is a rare combination, not previously reported in the literature. The patient underwent exploratory laparotomy and excision of the tumor, leading to a significant decline in VIP levels and resolution of symptoms.

Coinfection of pulmonary lophomoniasis, tuberculosis, and hydatid cyst in a pediatric autism patient: a case report and literature review

IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by difficulties in social interaction, communication, and repetitive behaviors or restricted interests. Although research on the link between ASD and parasitic diseases is limited, immune deficiency and inflammation may contribute to the development of parasitic infections.Case reportWe admitted a 14-year-old boy to the hospital who had a known history of ASD because he was presenting with respiratory symptoms, including cough and hemoptysis. During his time in the hospital, after conducting a series of tests and evaluations, we made a critical diagnosis of co-infection of lophomonas, tuberculosis, and hydatid cyst. In response to this diagnosis, we initiated a treatment plan that involved administering appropriate antibiotics as well as preparing for surgical intervention.ConclusionThis case report highlights the complexities and challenges of managing such a rare combination of co-infections with TB, pulmonary hydatid disease and lophomonas in a pediatric patient with underlying developmental considerations such as ASD.

Rare Combination of Congenital Microtia and Limb Malformations: Analysis of Etiology and Treatment.

Congenital microtia is the second most common congenital craniofacial deformity, and limb malformation is the most common birth defect. The combination of the 2 deformities is rare. In this study, the authors present 3 cases with a rare combination of congenital microtia and limb malformations and analyze the etiology and treatment of the malformations. There may be genetic homology between these two malformations, and they can be associated with abnormal ectodermal migration. Level IV-case study.

Rare Combination of Multiple Endocrine Neoplasia 1 with Medullary Thyroid Carcinoma and Clinical Value of 68Ga-DOTATATE PET/CT in Diagnosing Different Lesions and Exploring Theranostic Strategy

AbstractMultiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the presence of hyperplastic or neoplastic tumors in the parathyroid, pituitary, and gastroenteropancreatic endocrine tissues. The presence of lesions in at least two out of the three glands (pituitary, parathyroid, and pancreas) is indicative of MEN1 syndrome. Medullary thyroid carcinoma (MTC) is a type of tumor that originates from the parafollicular C cells of the thyroid gland. It is frequently found as part of MEN2 syndrome. MEN1 with MTC is a relatively uncommon occurrence. We report a rare case of MTC that later on developed parathyroid carcinoma, pituitary microadenoma, pancreatic neuroendocrine tumor (NET), and duodenal NET. The case was identified as part of MEN1 syndrome using exome sequencing and somatostatin receptor–based functional imaging 68Ga-DOTATATE positron emission tomography/computed tomography was employed for exploring theranostic strategy in the management of the patient.

Rare case of medial Hoffa fracture with ipsilateral femur shaft fracture with unusual mechanism of injury

Hoffa’s fracture is a rare fracture which involves coronal fracture of the distal femur involving one or both the condyles. We report a rare combination of Hoffa fracture with ipsilateral femur shaft fracture with an unusual mechanism of injury. This case report will help increase awareness about such combined fracture pattern and eventually avoid missing these important intra-articular injuries- Hoffa’s fracture. In a patient with ipsilateral femur shaft fracture and in polytrauma patients, diagnosis of Hoffa’s fracture is very challenging because of presence of other long bone fracture and injuries. Missed Hoffa’s fracture in a patient with ipsilateral femur shaft fracture may restrict post-operative knee range of motion, knee pain, increased risk of early arthritis and joint deformity and stiffness.

San Martín's accurate longitude measurements on Magellan's circumnavigation: luck or mastery?

Abstract During the 1519–1522 Magellan expedition, the astronomer Andrés de San Martín made two remarkably accurate longitude measurements, an order of magnitude better than what was typical for the 16th century. How he managed to do so remained shrouded in mystery for the past 500 years. Using modern ephemerides, we have retraced San Martín's observations and calculated their error signatures, clarifying the method he used (a simplified version of lunar distances) and why two out of his six measurements were accurate (a rather fortuitous cancellation of errors). It would be rash to dismiss San Martín's work as sheer luck though, as he was an exceedingly rare combination of a capable astronomer and a knowledgeable mariner.

Phenotypic Evaluation of Rare Cystic Fibrosis Transmembrane Conductance Regulator Mutation Combinations in People with Cystic Fibrosis in Queensland, Australia.

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with 'rare' CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have 'rare' CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority.

8411 Ectopic ACTH-dependent Cyclical Cushing’s Syndrome- the Art of Hide-and-seek

Abstract Disclosure: H. Mon: None. A. Kapoor: None. S. Qureshi: None. M. Martineau: None. K. Meeran: None. Case report: A 72-years-old lady was admitted with hypokalaemia, hyperglycaemia with metabolic alkalosis with background hypertension, type2 diabetes, osteoporosis and right-sided breast cancer treated with chemotherapy and radiotherapy 3years ago. She was previously seen in Endocrinology Clinic for similar episode and deemed not having Cushing’s or Conn’s syndrome on workup. During this admission, although there was no obvious Cushingoid appearance, there was refractory hypokalaemia. On further exploration, there were previous admissions with similar episodes in UK and in her home country, within the same year, a few months apart. Therefore, endocrinology workup was conducted for suspected cyclical Cushing’s syndrome. It demonstrated raised 24-hour urinary free cortisol of 5643 nmol/24hour (reference range 0-164 nmol/24hours), unsuppressed low dose dexamethasone suppression test with cortisol level of 800 nmol/L and increased ACTH level of 429 ng/L. MRI (pituitary) showed no pituitary lesion with probable empty sella and CSF filled. However, CT (thorax) showed enlarging lesion (previously from 1cm to 1.6cm) in the left lower lobe, concerning lung metastasis or primary lung malignancy. PET scan showed left lower lobe nodule having low-grade activity with likelihood of indolent malignancy and appearances of physiologic adrenal hyperplasia. Management: Given persistently high cortisol levels during admission with ongoing hyperglycaemia and refractory hypokalaemia, metyrapone was started and titrated accordingly. Her clinical condition including potassium and cortisol levels effectively responded to metyrapone. Gallium scan was booked for detail localization with ongoing lung MDT (multidisciplinary team meeting) and neuroendocrine tumour MDT.However, after starting metyrapone, she had type 1 respiratory failure, not responding to initial antibiotics. After excluding other possible respiratory aetiologies, empirical treatment for Pneumocystosis pneumonia (PCP) was initiated, after which blood test for Beta-D-glucan was found out to be significantly raised, supporting the presumptive diagnosis. Conclusion: Our case highlighted the following interesting points 1. diagnostic challenges, due to the fluctuating nature of cyclical Cushing’s syndrome, presenting with recurrent hypokalaemia. 2. the interesting nature of likely ACTH-dependent cyclical Cushing’s syndrome, progressing into florid Cushing’s syndrome, with efficacy to metyrapone 3. rare and compelling combination of 3 conditions of Cyclical Cushing’s syndrome, being ectopic ACTH-dependent and complicated by Pneumocystosis pneumonia (PCP). Presentation: 6/1/2024

Gene Analysis of Combined Dual Rare Thalassemia

To retrospectively analyze the detection and diagnosis process of two cases with double rare thalassemia genotypes, explore the causes of missed diagnosis and misdiagnosis of rare thalassemia, and improve the diagnosis level of rare thalassemia. Base on the family history, hematological phenotype and hemoglobin electrophoretic analysis results, the common genotypes of α and β-thalassemia were detected by PCR+diversion hybridization. DNA sequencing technology was used for rare α and β protein genes sequencing. Both subjects were combined with double rare thalassemia genotypes, and both rare thalassemia gene combinations were reported for the first time. One of them was αβ complex thalassemia with αα*53_55 del TCC/αα heterozygous merger βIVS II-2(-T)/βN heterozygous, the other was ααIVS-II-55(T→G) in α1/αα4.2-Q double azygous heterozygous α-thalassemia, among which αα*53_55 del TCC/αα genotype was also reported for the first time. The reported rare gene type αα*53_55 del TCC/αα and two cases of rare gene combinations enriches the spectrum of gene mutations in the Chinese population, and provides richer molecular information for thalassemia diagnosis and eugenics counseling.

Stokes and anti-Stokes emission characteristics of Er3+/Yb3+ co-doped zinc tellurite glasses under 377 and 1550 nm excitations for solar energy conversion application

One of the best rare earth combinations for down- and up-converting the solar photons is Er3+/Yb3+. Therefore, at present, by using the traditional melt quench technique, zinc tellurite glasses doped with Er3+ and Er3+/Yb3+ were characterised. Several methods of down-conversion that result in the emission of 1000 nm from the acceptor (Yb3+) under excitation of donor (Er3+) were studied. On the other hand, the impact of acceptor (Yb3+) concentration and excitation pump power on the excited state absorption and its influence on the up-conversion emission (1000 nm) properties were investigated in detail under 1535 nm excitation. The studies on emission and decay results are discovered to be very significant. Suggesting that these glasses when used as conversion layers, can append the conversion efficiency of Si-based solar cells.

Global Avian Functional Diversity Depends on the World's Most Widespread and Distinct Birds.

The relationship between global trait distinctiveness and geographic range size is an emerging pattern of interest in macroecology. Early observations suggested that the relationship was positive, implying that globally widespread species hold the rarest combinations of traits. Here, we formally describe and test the relationship in the world's birds and consider its implications for global functional diversity and redundancy. We demonstrate that the relationship is best described as triangular with a positive upper boundary, with its linear model significance lost when including phylogenetic effects. The triangular relationship is formed by groups of phylogenetically related widespread species with moderate and high trait distinctiveness. Decomposing the relationship further using quantile regression highlights the unique traits of these widespread birds. Overall, the triangular relationship emphasises that while not all widespread species have rare trait combinations, those that do should not be overlooked in conservation efforts, regardless of their current threat status.

Влияние абиотических факторов на продуктивность тростника Phragmites australis в озёрах юга Западной Сибири

The article presents the results of studying phytomass, stem height and density of thickets (herbage) of Phragmites australis, one of the most common aerial-aquatic plant in the south of Western Siberia. This region is distinguished by a rare combination of chloride, sulfate and soda lakes in a relatively small space. As an eurybiont, reed is highly resistant to water and soil salinity, but high salinity adversely affects its growth and development. The aim of the work was to assess the degree of abiotic factors (pH, mineralization) effect on the quantitative characteristics of reed growing in water bodies with different water mineralization: from 0.005 to 387.6 g/L. In total, we studied 59 freshwater, brackish-water (oligo-, meso- and polyhaline) and hypersaline water bodies, located in various natural zones (southern taiga, forest, forest-steppe, steppe and dry-steppe) in the south of Western Siberia. The studies were carried out in late July – early August from 2012 to 2020 during the period of maximum vegetation of plants. As a result of the studies, it is shown that the optimal for reed growth and development is water mineralization from 0.5 to 5.0 g/L, when the highest values of biomass and plant height are observed. A model based on redundancy analysis (RDA) was built and a correlation analysis was carried out to assess the dependence of phytomass, shoot height and herbage density on abiotic factors. We took into account pH, salinity, and Ca2+, Na+, Mg2+, K+, HCO3-, Cl- and SO42- content. We found that pH and determined by Ca2+ water hardness are the limiting factors in freshwater lakes. In brackish-water meso- and polyhaline, as well as in saline hyperhaline water bodies reed phytomass is affected by a whole range of factors, while shoot height is affected by pH, chlorides, and water hardness, and grass stand density is affected by chlorides and sulfates.

Clinical case of plurihormonal pituitary adenoma (STH/ACTH/TSH/FSH/LH-secreting), diagnostic pitfalls

According to numerous studies, the most common pituitary tumors are prolactinomas, reaching 60% of all clinically significant adenomas, the next in order are non-functional pituitary adenomas, somatotropinomas, corticotropinomas and thyrotropinomas. Plurigormonal tumors occur in less than 1% of all pituitary adenomas. The most common form of mixed secretion adenoma in this patient population, derived from the Pit-1 cell line, produces various combinations of hormones: growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH). This article presents a patient with a plurihormonal two-component pituitary macroadenoma with a rare and exceptional combination of secreted hormones - GH / adrenocorticotropic hormone (ACTH) / TSH / follicle-stimulating hormone (FSH) / luteinizing hormone (LH) with minimal nonspecific clinical manifestations such as diabetes mellitus and poorly controlled arterial hypertension.

Concurrent Esophageal Leiomyoma and Helicobacter pylori Infection

Esophageal leiomyomas are rare benign tumors arising from smooth muscle cells in the esophagus. Despite their rarity, they present unique diagnostic and management challenges due to varied symptomatology and anatomical locations. Here, we present a case of a 40-year-old male with unresolved dysphagia and epigastric pain referred for esophagogastroduodenoscopy (EGD). EGD revealed a medium-sized submucosal mass at the gastroesophageal junction, partially obstructing the lumen. Concurrently, severe chronic active gastritis with Helicobacter pylori (H. pylori) infection was confirmed upon gastric biopsy. Subsequent evaluation included endoscopic ultrasound (EUS), which identified a likely benign esophageal leiomyoma. Although a surgical referral was recommended, the patient was deferred. This case highlights the importance of EGD in diagnosing esophageal leiomyomas and uncovering incidental findings that can significantly influence patient management. The rare presentation of this leiomyoma at the gastroesophageal junction, combined with the co-occurrence of severe H. pylori-induced gastritis and chronic GERD, introduces new considerations for understanding the pathophysiology of esophageal tumors. The rare combination of these factors highlights the need for further research into their interactions, providing novel insights that could influence future diagnostic strategies and therapeutic approaches for similar cases.

A rare combined variation of left renal vasculature in a human cadaver: embryological basis and clinical significance.

Classically, a single renal artery supplies, and a single renal vein drains each kidney. The morphology and variations in the renal vascular structures are of great importance when performing any type of renal surgery. The present case describes a rare combination of renal vasculature variation in a formalin-fixed, Chinese male cadaver. In this case, the left kidney is drained by a main renal vein (MRV) and an inferior renal vein (IRV), the latter might be the remnant of the left dorsal renal vein during the embryonic period. Two sets of renal arteries are present in this case, possibly due to persistent mesonephric arteries during embryonic development. Describing such anatomical variations is not only of academic interest but also important to help radiologists with the correct interpretation of image examinations and for surgeons to be prepared in advance.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype

BackgroundChromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty.ResultsWe identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene.ConclusionThis report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Multi-Label Conditional Generation From Pre-Trained Models.

Although modern generative models achieve excellent quality in a variety of tasks, they often lack the essential ability to generate examples with requested properties, such as the age of the person in the photo or the weight of the generated molecule. To overcome these limitations we propose PluGeN (Plugin Generative Network), a simple yet effective generative technique that can be used as a plugin for pre-trained generative models. The idea behind our approach is to transform the entangled latent representation using a flow-based module into a multi-dimensional space where the values of each attribute are modeled as an independent one-dimensional distribution. In consequence, PluGeN can generate new samples with desired attributes as well as manipulate labeled attributes of existing examples. Due to the disentangling of the latent representation, we are even able to generate samples with rare or unseen combinations of attributes in the dataset, such as a young person with gray hair, men with make-up, or women with beards. In contrast to competitive approaches, PluGeN can be trained on partially labeled data. We combined PluGeN with GAN and VAE models and applied it to conditional generation and manipulation of images, chemical molecule modeling and 3D point clouds generation.

ALMA reveals a dust-obscured galaxy merger at cosmic noon

Context. Galaxy mergers play a critical role in galaxy evolution. They alter the size, morphology, dynamics, and composition of galaxies. Galaxy mergers have so far mostly been identified through visual inspection of their rest-frame optical and near-IR (NIR) emission. Dust can obscure this emission, however, resulting in the misclassification of mergers as single galaxies and in an incorrect interpretation of their baryonic properties. Aims. Having serendipitously discovered a dust-obscured galaxy merger at z = 1.17, we aim to determine the baryonic properties of the two merging galaxies, including the star formation rate (SFR) and the stellar, molecular gas and dust masses. Methods. Using Band 3 and 6 observations from the Atacama Large Millimeter and submillimeter Array (ALMA) and ancillary data, we studied the morphology of this previously misclassified merger. We deblended the emission, derived the gas masses from CO observations, and modeled the spectral energy distributions to determine the properties of each galaxy. Using the rare combination of ALMA CO(2–1), CO(5–4) and dust-continuum (rest-frame 520 μm) observations, we provide insight into the gas and dust content and into the properties of the interstellar medium of each merger component. Results. We find that only one of the two galaxies is highly obscured by dust, but both are massive (> 1010.5 M⊙) and highly star forming (SFR = 60 − 900 M⊙/yr), have a moderate-to-short depletion time (tdepl < 0.7 Gyr) and a high gas fraction (fgas ≥ 1). Conclusions. These properties can be interpreted as the positive impact of the merger. With this serendipitous discovery, we highlight the power of (sub)millimeter observations to identify and characterise the individual components of obscured galaxy mergers.