Complex Disease Research Articles

Evaluation of ophthalmic vascular and neuroretinal alterations in fibromyalgia syndrome: a cross-sectional comparative study.

Fibromyalgia syndrome (FMS) is a prevalent rheumatic disorder, and its pathogenesis includes genetic, neuroendocrine, and autonomic abnormalities, which may impact ocular structures. The aim was to conduct a comparative analysis of the ophthalmic vasculature and the retinal nerve fiber layer (RNFL) thickness between FMS and control groups using optical coherence tomography (OCT) and OCT angiography (OCTA). This cross-sectional comparative study included 43 FMS patients and 40 healthy controls recruited from a tertiary education and research hospital between January 2024 and May 2024. All patients satisfied the 2016 American College of Rheumatology criteria for FMS and consented. OCT and OCTA were used to assess the RNFL thickness and the retinal microvasculature structure. The Fibromyalgia Impact Questionnaire (FIQ) was performed to evaluate disease severity. The study found significantly higher total retinal parafoveal thickness and foveal density in FMS patients (p = 0.017 and p = 0.044, respectively). Nevertheless, there were no significant differences among the groups concerning total retinal foveal thickness, foveal avascular zone characteristics, superficial and deep capillary plexus densities, choriocapillaris flow area, and outer retinal flow area values (p > 0.05). The RNFL thickness in all quadrants did not reveal significant differences between the groups (p > 0.05). Furthermore, there was no significant correlation between FIQ scores and OCTA parameters or RNFL thickness values (p > 0.05). The study revealed slight differences in retinal parafoveal thickness and foveal density in FMS patients, but no substantial vascular or neurodegenerative alterations were observed compared to healthy controls. These data indicate that FMS may not substantially affect ocular structures, contrary to earlier hypotheses.

Antimelanoma differentiation antigen 5-positive dermatomyositis: an update.

Antimelanoma differentiation antigen 5-dermatomyositis (MDA5-DM) is a complex and serious systemic autoimmune disease that primarily affects the skin and lungs. In this review, we aimed to provide new insights into the clinical features, pathogenesis, and practical management approach for this disease. Although lung lesions are prominent in most patients with MDA5-DM, they are now recognized as heterogeneous diseases. Peripheral blood lymphocyte count can serve as a simple and reliable laboratory parameter for categorizing MDA5-DM into three subgroups: mild, medium, and severe. Recent studies have implicated viral infection, genetic factors, autoimmunity against MDA5, multiple immune cells, and interferons as significant contributors to MDA5-DM pathogenesis. In addition to traditional treatments with glucocorticoids and immunosuppressants, many new approaches, including new biologics and targeted agents, have been explored. Additionally, infection is a common complication of MDA5-DM, and prophylaxis or treatment of the infection is as important as treating the primary disease. Knowledge of clinical characteristics and pathogenesis of MDA5-DM has grown in recent years. Although many new therapeutic approaches have been explored, further studies are required to confirm their efficacy.

Impact of policy change on late-term abortion: a two-decade analysis.

Advances in ultrasound and molecular genetics have changed the field of late termination of pregnancy (LTOP), sparking ethical debates worldwide. In 2007, Israel updated its LTOP policies, requiring a 30% or higher probability of severe handicap for approval of LTOP after 24weeks' gestation. In this retrospective study, we compared LTOP indications and approval rates before (Group 1: 1998-2007) and after (Group 2: 2008-2021) this policy change. Shamir medical records from January 1, 1998 to December 31, 2021 were examined and yielded 4047 abortions, of which 248 were identified as LTOP preformed after 24weeks' gestation. These cases were then categorized into two groups. Data including maternal age, obstetric history, indications for abortion, diagnosis, week of termination, and genetic/sonographic findings were analyzed. The approval rates and indications pre- and post-policy change were compared. Group 1 (LTOP 1998-2007) comprised 95 cases (10.6%), and Group 2 (LTOP 2008-2021) was composed of 153 cases (4.9%). Fetal structural anomalies remained the dominant indication for both groups (67.4 and 65.3%, respectively), with a slight increase in confirmed genetic anomalies from 26.3% (Group 1) to 28% (Group 2). Our findings indicate a decrees in the proportion per year from 10.6 to 4.9% LTOP. Technological advances in genetic evaluation and sonography may have contributed to the early increased detection and decrees in cases reaching LTOP. These results highlight the importance of ongoing ethical reviews and adherence to strict protocols for early detection and termination before 24weeks' gestation.

Obstructive Sleep Apnea and Short-Term Outcomes After Pediatric Cardiac Surgery.

Obstructive sleep apnea (OSA) has been associated with negative cardiovascular effects and negative outcomes following cardiovascular surgery in the adult population. Our objective was to evaluate if there is a similar association in children. Single center retrospective matched cohort study, we collected data on patients aged 1-18 who were admitted to the cardiac intensive care unit (CICU) between Jan 2012 and Dec 2021. We used a 3:1 propensity score matching for cases not diagnosed with OSA. Primary outcome was a composite variable: "adverse outcome," consisting of prolonged hospital and CICU stay, prolonged duration of mechanical ventilation, need for extracorporeal membrane oxygenation, and death. The study comprised 80 patients diagnosed with OSA and 240 patients without a diagnosis of OSA before cardiac surgery. The median age was 5.3years (IQR 2.7-11.2). There were 184 (57.5%) males, and 102 (31.9%) had chromosomal and genetic abnormalities. There was a difference in "adverse outcome" between the OSA and non-OSA groups [34 (42.50%) vs 68 (28.33%), p = 0.027]. Moreover, bivariate analysis revealed that CICU length of stay, and chromosomal anomalies were statistically different between the groups. By logistic regression the composite variable "adverse outcome" remained associated to the OSA group (p = 0.009) with an adjusted odds ratio (OR) of 4.09 (1.83-9.18), p < 0.001. Children diagnosed with OSA had a higher risk of "adverse outcome" following cardiac surgery. The risk disappeared if the patient had Tonsillectomy and Adenoidectomy before cardiac surgery. Further studies should explore a proactive treatment for OSA in pediatric patients who need cardiac surgery.

Characterisation of Canine and Feline Breast Tumours, Their Metastases, and Corresponding Primary Cell Lines Using LA-REIMS and DESI-MS Imaging

Breast cancer, a complex disease with a significant prevalence to form metastases, necessitates novel therapeutic strategies to improve treatment outcomes. Here, we present the results of a comparative molecular study of primary breast tumours, their metastases, and the corresponding primary cell lines using Desorption Electrospray Ionisation (DESI) and Laser-Assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) imaging. Our results show that ambient ionisation mass spectrometry technology is suitable for rapid characterisation of samples, providing a lipid- and metabolite-rich spectrum within seconds. Our study demonstrates that the lipidomic fingerprint of the primary tumour is not significantly distinguishable from that of its metastasis, in parallel with the similarity observed between their respective primary cell lines. While significant differences were observed between tumours and the corresponding cell lines, distinct lipidomic signatures and several phospholipids such as PA(36:2), PE(36:1), and PE(P-38:4)/PE(O-38:5) for LA-REIMS imaging and PE(P-38:4)/PE(O-38:5), PS(36:1), and PI(38:4) for DESI-MSI were identified in both tumours and cells. We show that the tumours’ characteristics can be found in the corresponding primary cell lines, offering a promising avenue for assessing tumour responsiveness to therapeutic interventions. A comparative analysis by DESI-MSI and LA-REIMS imaging revealed complementary information, demonstrating the utility of LA-REIMS in the molecular imaging of cancer.

Using Microfluidics to Align Matrix Architecture and Generate Chemokine Gradients Promotes Directional Branching in a Model of Epithelial Morphogenesis.

The mechanical cue of fiber alignment plays a key role in the development of various tissues in the body. The ability to study the effect of these stimuli in vitro has been limited previously. Here, we present a microfluidic device capable of intrinsically generating aligned fibers using the microchannel geometry. The device also features tunable interstitial fluid flow and the ability to form a morphogen gradient. These aspects allow for the modeling of complex tissues and to differentiate cell response to different stimuli. To demonstrate the abilities of our device, we incorporated luminal epithelial cysts into our device and induced growth factor stimulation. We found the mechanical cue of fiber alignment to play a dominant role in cell elongation and the ability to form protrusions was dependent on cadherin-3. Together, this work serves as a springboard for future potential with these devices to answer questions in developmental biology and complex diseases such as cancers.

Retrospective Single Nucleotide Polymorphism Analysis of Host Resistance and Susceptibility to Ovine Johne’s Disease Using Restored FFPE DNA

Johne’s disease (JD), also known as paratuberculosis, is a chronic, untreatable gastroenteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. Evidence for host genetic resistance to disease progression exists, although it is limited due to the extended incubation period (years) and diagnostic challenges. To overcome this, previously restored formalin-fixed paraffin embedded tissue (FFPE) DNA from archived FFPE tissue cassettes was utilized for a novel retrospective case-control genome-wide association study (GWAS) on ovine JD. Samples from known MAP-infected flocks with ante- and postmortem diagnostic data were used. Cases (N = 9) had evidence of tissue infection, compared to controls (N = 25) without evidence of tissue infection despite positive antemortem diagnostics. A genome-wide efficient mixed model analysis (GEMMA) to conduct a GWAS using restored FFPE DNA SNP results from the Illumina Ovine SNP50 Bead Chip, identified 10 SNPs reaching genome-wide significance of p &lt; 1 × 10−6 on chromosomes 1, 3, 4, 24, and 26. Pathway analysis using PANTHER and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was completed on 45 genes found within 1 Mb of significant SNPs. Our work provides a framework for the novel use of archived FFPE tissues for animal genetic studies in complex diseases and further evidence for a genetic association in JD.

Three Familial Cases of Stickler Syndrome: A Case Report

Purpose: Stickler syndrome, a hereditary connective tissue disorder characterized by mutations in collagen genes, presents with progressive ophthalmopathy and diverse systemic manifestations. Here, we present three familial cases of Stickler syndrome, emphasizing the importance of early detection through clinical investigations and genetic testing.Case summary: Two generations of a family, a mother and her two daughters, were evaluated for Stickler syndrome. All three exhibited bilateral retinal lattice degeneration, perivascular retinal degeneration, and vitreous liquefaction. The daughters shared characteristic facial features, including a flattened face, broad nasal bridge, and micrognathia. Clinical symptoms and examination findings led to diagnoses of Stickler syndrome. Subsequent genetic testing in five family members confirmed a COL2A1 mutation in the three affected individuals.Conclusions: Stickler syndrome carries a high risk of vision loss from ocular complications, necessitating early detection and intervention. In addition, the presence of systemic manifestations, such as musculoskeletal joint disorders, mitral valve prolapse, hearing loss, and cleft palate, emphasizes the importance of prompt detection through appropriate clinical investigations and genetic testing.

Exome sequencing confirms the clinical diagnosis of both joubert syndrome and klinefelter syndrome with keratoconus in a han Chinese family

IntroductionJoubert syndrome a rare genetic disorder, is characterized by abnormalities in the development of the central nervous system with “molar signs” on magnetic resonance imaging of the brain and accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. Keratoconus (KC) is a kind of genetically predisposed eye disease that causes blindness characterized by a dilated thinning of the central or paracentral cornea conically projected forward, highly irregular astigmatism, and severe visual impairment. Klinefelter syndrome is caused by an extra X chromosome in the cells of male patients, and the main phenotype is tall stature and dysplasia with secondary sex characteristics. This study was intended to identify the genetic etiology and determine the clinical diagnosis of one Han Chinese family with specific clinical manifestations of keratoconus and multiorgan involvement.MethodsA comprehensive ocular and related general examination was performed on one patient and his asymptomatic parents and brother. Pathogenic genes were tested by exome sequencing. CNV-seq was used to verify the copy number variation, and peripheral blood was cultured for karyotype analysis. The pathogenicity of the identified variant was determined subject to ACMG guidelines. The Gene Expression Omnibus (GEO) dataset of keratoconus-related genes in the NCBI database was obtained to analyze the differentially expressed genes in corneal tissues of the keratoconus group and the normal control group, and analysis of protein-protein interaction networks (PPI) was performed.ResultsProband, a 25-year-old male, had sudden loss of vision in the left eye for 1 week. Best corrected visual acuity (BCVA): 0.5 (−1.00DS/-5.00DC*29°) in the right eye, counting fingers/40 cm in the left eye. Slit-lamp microscopy of the right eye showed mild anterior protrusion of the cornea and thinning of the cone-topped cornea. The left eye showed marked thinning of the central region of the cornea, rounded edema in the form of a cone-like bulge, epithelial bullae, edema and turbidity of the stroma, and bulging of the Descemet’s membrane. Cranial magnetic resonance imaging (MRI) revealed changes in the midbrain and cerebellum, with a “molar sign” and a “bat-winged” ventriculus quartus cerebri. General check-up: 168 cm in height, decreased muscle tone in all four limbs, knee jerk elicited, negative Babinski sign, abdominal reflexes elicited, finger-to-nose test positive, intentional tremor evident in both hands, positive Romberg’s sign, instability of gait, level I intellectual disability, poor adaptive behavior, communication disorders, teeth all dentures, a peculiar face with blepharophimosis, wide inner canthus distance, mild ptosis, severe positive epicanthus, high palatal arches, exotropia, hypotrichosis of beard and face, inconspicuous prominentia laryngea, and short upper and lower limbs. Exome sequencing detected compound heterozygous frameshift variants M1:c.9279dup:p.His3094Thrfs*18 and M2:c.6515_6522del:p.Lys2172Thrfs*37 in the patient’s CPLANE1 gene and the presence of duplication-type CNV on the X chromosome. Sanger sequencing showed that the mother and father carried the M1 and M2 variants, respectively, and the younger brother carried the M2 variant, which was a novel variant. CNV-seq analysis showed the presence of a duplication-type CNV Xp22.33-Xq28 (2757837-156030895) of approximately 155 Mb on the X chromosome of the proband, which was a de novo variant and carried by neither of the parents. The two heterozygous frameshift variants and duplication-type CNV were pathogenic according to the ACMG guidelines. Differential expression analysis of keratoconus-related genes showed that CPLANE1 was upregulated in the corneal tissues of keratoconus patients compared with normal controls, and such a difference was statistically significant (p = 0.000515, &amp;lt;0.05). PPI analysis showed that the CPLANE1-NPHP3 complex protein acted as a bridge between cilia and extracellular matrix tissue. According to the genetic test results and clinical phenotype analysis, the family was finally diagnosed with Joubert syndrome combined with Keratoconus and Klinefelter syndrome.DiscussionIn this study, we report a proband in a Han Chinese family with both Joubert syndrome and X-linked Klinefelter syndrome as well as keratoconus, and the phenotype spectrum of CPLANE1-Joubert syndrome may be expanded accordingly. Meanwhile, the significance of exome sequencing was emphasized in aiding the clinical diagnosis of complex cases, which is difficult to make.

Screening and the analysis of genotypic and phenotypic characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Fujian province, China

IntroductionGlucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked hereditary disorder in southern China. However, the incidence rate of G6PD deficiency and the frequency of the most common G6PD gene variants vary widely. The purpose of this study was to investigate the prevalence, genotype, and phenotypic features of G6PD deficiency in neonates in Fujian province, southeastern China.MethodsThis retrospective cohort study enrolled 2,789,002 newborns (1,521,431 males and 1,267,571 females) based on the newborn screening program for G6PD deficiency in Fujian Province between January 2010 and December 2021.ResultsOf the 2,789,002 newborns enrolled, 26,437 cases were diagnosed (22,939 males and 3,498 females), and the estimated prevalence of G6PD deficiency in Fujian province was 0.95%. The prevalence was significantly higher among males (1.51%) than in females (0.28%) (p &amp;lt; 0.00001). Among the 3,198 patients with G6PD deficiency, 3,092 cases (2,145 males and 947 females) were detected to have G6PD gene variants. The top six prevalent genotypes identified represented 90.84% (2095/3,198) of the total and included c.1376G &amp;gt; T (44.93%), c.1388G &amp;gt; A (18.42%), c.1024C &amp;gt; T (9.32%), c.95A &amp;gt; G (8.69%), c.392G &amp;gt; T (5.25%), and c.871G &amp;gt; A (4.22%). The frequency of genotypes with c.1388G &amp;gt; A, c.1024C &amp;gt; T, and c.871G &amp;gt; A was higher in males in the Fujian province than in females, while the frequency of genotypes with c.1376G &amp;gt; T was lower. Furthermore, when comparing the enzyme activities of the top six prevalent genotypes, there were significant differences in the enzyme activities among the genotypes of male hemizygotes and female heterozygotes. According to the new classification of G6PD variants proposed by the World Health Organization (WHO), the variants with c.1376G &amp;gt; T, c.95A &amp;gt; G, and c.871G &amp;gt; A were recognized as Class A, while the c.392G &amp;gt; T, c.1388G &amp;gt; A, and c.1024C &amp;gt; T were recognized as Class B.DiscussionTo the best of our knowledge, this study is the first to systematically describe the overview of epidemiological characteristics of newborn G6PD deficiency in Fujian province, China, including the screening rate, incidence rate, and variant spectrum. Additionally, we elucidated the relationship between the distribution of enzyme activity with specific mutations and their WHO classification patterns. Our results could provide strategies for screening, diagnosis, and genetic counseling of G6PD deficiency in this area.

Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7

Disease-causing bi-allelic DNA variants in CCDC39 and CCDC40 are frequent causes of the hereditary disorder of primary ciliary dyskinesia (PCD). The encoded proteins form a molecular ruler complex, crucial for maintaining the 96 nm repeat units along the ciliary axonemes. Defects of those proteins cause a stiff, rapid, and flickery ciliary beating pattern, recurrent respiratory infections, axonemal disorganization, and abnormal assembly of GAS8, CCDC39, and DNALI1. We performed molecular characterization of the defects in the 96 nm axonemal ruler due to disease-causing variants in CCDC39 and CCDC40 and analyzed the effect on additional axonemal components. We identified a cohort of 51 individuals with disease-causing variants in CCDC39 and CCDC40 via next-generation sequencing techniques and demonstrated that the IDA heavy chains DNAH1, DNAH6, and DNAH7 are conspicuously absent within the respiratory ciliary axonemes by immunofluorescence analyses. Hence, we show for the first time that the centrin2 (CETN2) containing IDAs are also affected. These findings underscore the crucial role of CCDC39 and CCDC40 in the assembly and function of IDAs in human respiratory cilia. Thus, our data improve the diagnostics of axonemal ruler defects by further characterizing the associated molecular IDA defects.

The synergy of artificial intelligence and personalized medicine for the enhanced diagnosis, treatment, and prevention of disease.

The completion of the Human Genome Project in 2003 marked the beginning of a transformative era in medicine. This milestone laid the foundation for personalized medicine, an innovative approach that customizes healthcare treatments. Central to the advancement of personalized medicine is the understanding of genetic variations and their impact on drug responses. The integration of artificial intelligence (AI) into drug response trials has been pivotal in this domain. These technologies excel in handling large-scale genomic datasets and patient histories, significantly improving diagnostic accuracy, disease prediction and drug discovery. They are particularly effective in addressing complex diseases such as cancer and genetic disorders. Furthermore, the advent of wearable technology, when combined with AI, propels personalized medicine forward by offering real-time health monitoring, which is crucial for early disease detection and management. The integration of AI into personalized medicine represents a significant advancement in healthcare, promising more accurate diagnoses, effective treatment plans and innovative drug discoveries. As technology continues to evolve, the role of AI in enhancing personalized medicine and transforming the healthcare landscape is expected to grow exponentially. This synergy between AI and healthcare holds great promise for the future, potentially revolutionizing the way healthcare is delivered and experienced.

Contemporary Role of Positron Emission Tomography (PET) in Endocarditis: A Narrative Review

Endocarditis, a serious infectious disease, remains a diagnostic challenge in contemporary clinical practice. The advent of advanced imaging modalities has contributed significantly to the improved understanding and management of this complex disease. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging has shown remarkable potential in improving the diagnostic accuracy of endocarditis. In the update of the Modified Duke Criteria, in 2023, The International Society for Cardiovascular Infectious Diseases (ISCVID) Working Group recognized specific 18F-FDG PET/CT findings as a major diagnostic criterion, particularly in patient with prosthetic valve endocarditis. The ability of PET to visualize metabolic activity allows for the identification of infective foci and could differentiate between infective and non-infective processes. This review examines the clinical utility of PET in differentiating infective endocarditis from other cardiovascular pathologies, highlighting its sensitivity and specificity in detecting native and prosthetic valve infections, including patients with transcatheter aortic valve implantation (TAVI), cardiac implantable devices (CIEDs), and left ventricular assistance devices (LVAD). Also, practical aspects and indications are illustrated to optimize the quality of imaging and reduce potential false positive results. In conclusion, the current use of PET in endocarditis has become a valuable diagnostic tool; as technological advances continue, PET will play an increasingly important role in the multidisciplinary approach to the management of endocarditis.

Comparison of patients with chronic and episodic migraine with healthy individuals by brain volume and cognitive functions

Objectives: Migraine is a complex neurological disease. In addition to headache, individuals with migraine may develop structural changes inside the brain and cognitive impairment. There is increased evidence associated with impairments in brain volume and cognitive functions in patients with migraine. The present study aimed to investigate the impairment in memory function in individuals with migraine using brain magnetic resonance imaging, volume measurement, and neuropsychological tests. Methods: The study included 20 patients with episodic migraine, 20 patients with chronic migraine, and 20 healthy controls. Subcortical volumes of all participants were measured by FreeSurfer, an automatic segmentation method. The Wechsler Memory Scale-Revised Form (WMS-R), Stroop test, Raven’s Standard Progressive Matrices, Verbal Fluency Test, and Lines Orientation Test were applied in all the study participants. Results: Putamen volume decreased as migraine duration increased, and subcortical gray matter, left cerebellar cortex, and bilateral thalamus volumes were lower in the chronic and episodic group compared to the control group, bilateral putamen and right cerebellar cortex volumes were lower in patients with chronic migraine compared to patients in episodic migraine and control groups. Upon neuropsychological examination, delayed memory was affected as the duration of migraine increased, and there was impairment in patients with chronic migraine upon fluency tests and mental control tests. Conclusions: Changes in subcortical volume and cognitive effects in patients with migraine raise questions about whether migraine qualifies as a benign disease. Structural changes and cognitive impairment may contribute to migraine-associated disability, and therefore, these causalities should be investigated by future studies. Silent infarcts, white matter damage, and cortical spreading depression, which occur in migraine cases, may be associated with subcortical volume changes and thus, cognitive effects. In the context, studies with larger samples to achieve a better understanding are needed.

Dark Tea Wine Protects Against Metabolic Dysfunction-Associated Steatotic Liver Disease In Vivo Through Activating the Nrf2/HO-1 Antioxidant Signaling Pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and multifactorial disease. Dark tea exhibits great potential for various bioactivities for metabolic health. In this study, we aimed to evaluate therapeutic effects and the underlying mechanisms of dark tea wine (DTW) on MASLD with obesity. A rat model of MASLD was established by high-fat diet and administered with different doses of DTW as an intervention. The biomarkers of lipid metabolism and oxidative stress in rats were tested. The weight of organs and adipose tissues and the expressions of nuclear factor erythroid 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) were investigated based on the pathology and western blot analysis. We found that DTW enhanced antioxidant capacity via activating the Nrf2/HO-1 signaling pathway, further markedly triggering inhibition of weight gain, reduction of lipid dysfunction, and improvement of pathological characteristics to ameliorate MASLD induced by high-fat diet. These results suggest that DTW is a promising functional supplement for prevention and treatment of MASLD and obesity.

Non-genetic heterogeneity and immune subtyping in breast cancer: Implications for immunotherapy and targeted therapeutics

Breast cancer (BC) is a complex and multifactorial disease, driven by genetic alterations that promote tumor growth and progression. However, recent research has highlighted the importance of non-genetic factors in shaping cancer evolution and influencing therapeutic outcomes. Non-genetic heterogeneity refers to diverse subpopulations of cancer cells within breast tumors, exhibiting distinct phenotypic and functional properties. These subpopulations can arise through various mechanisms, including clonal evolution, genetic changes, epigenetic changes, and reversible phenotypic transitions. Although genetic and epigenetic changes are important points of the pathology of breast cancer yet, the immune system also plays a crucial role in its progression. In clinical management, histologic and molecular classification of BC are used. Immunological subtyping of BC has gained attention in recent years as compared to traditional techniques. Intratumoral heterogeneity revealed by immunological microenvironment (IME) has opened novel opportunities for immunotherapy research. This systematic review is focused on non-genetic variability to identify and interlink immunological subgroups in breast cancer. This review provides a deep understanding of adaptive methods adopted by tumor cells to withstand changes in the tumor microenvironment and selective pressure imposed by medications. These adaptive methods include alterations in drug targets, immune system evasion, activation of survival pathways, and alterations in metabolism. Understanding non-genetic heterogeneity is essential for the development of targeted therapies.

Successful treatment of cicatricial stenosis of the main, intermediate and upper lobe bronchi of the right lung complicated by total lung atelectasis in an infant: a clinical case

BACKGROUND: The authors present a rare clinical case of stenosis of the main, intermediate and upper lobe bronchi of the right lung complicated by total lung atelectasis in an infant. They discuss issues of complex disease diagnostics, analyze X-ray and bronchological images, assess outcomes after multidisciplinary approach in the treatment of a premature baby as well as analyze data of catamnestic observation. CLINICAL CASE DESCRIPTION: Girl T., one of monochorionic diamniotic twins, was born at 27 week gestation in 2021 with weight at birth 825 grams, Apgar score 4/5. Since her birth, she had artificial lung ventilation due to her deep immaturity and developed severe respiratory distress syndrome. At the age of 19 days, total atelectasis of the right lung was diagnosed in the child as a result of stenosis formation in the main, intermediate and upper lobe bronchi which was confirmed by clinical and radiological findings. A probable etiology of acquired stenosis is consequences of prolonged intubation under insufficiently formed cartilaginous framework. Chlamydial infection, detected in the child, could also support inflammatory process in the bronchi. The child was examined with the following instruments: radiography, multispiral computed tomography-angiography of the thoracic cavity, bronchofibroscopy, echocardiography. Laboratory tests: polymerase chain reaction of blood and sputum for herpes viruses type 1–6, mycoplasma, ureaplasma, Chlamydia pneumonia; blood enzyme immunoassays — antibodies to viruses of Herpesviridae type 1–6, Chlamydia trachomatis. Conservative therapy provided only temporal improvement; atelectasis was relapsing. At the age of 5 months and 20 days, the child underwent bronchoplasty with resection of damaged areas of the bronchi. Further, age-related diameter of the bronchial lumen was maintained by the staged bougienage. Catamnestic observation lasted for 3 years. Late timing of surgical intervention is explained by severe problems in a deeply premature and immature child that required immediate treatment (intraventricular hemorrhages, hydrocephalus, retinopathy, etc.). Effective surgical treatment (bronchoplasty), active growth of lung tissue at the first year of life as well as reasonable rehabilitation allowed to obtain good long-term outcomes. By the age of 1 year 2 months, normalization of right lung airiness was achieved. Currently, there is a slight reduction in right lung volume. Multispiral computed tomography-angiography revealed a few cylindrical bronchoectases in the segmental and subsegmental bronchi of the upper and middle lobes of the right lung which do not have clinical equivalents yet. The child is under pulmonologist's observation and management. CONCLUSION: A multidisciplinary approach to the treatment of complicated patient's state and high compensatory capabilities of neonatal and infantile periods have promoted the restoration of normal lung aeration and functioning after long-lasting lung atelectasis

Evaluation of heritability partitioning approaches in livestock populations

BackgroundHeritability partitioning approaches estimate the contribution of different functional classes, such as coding or regulatory variants, to the genetic variance. This information allows a better understanding of the genetic architecture of complex traits, including complex diseases, but can also help improve the accuracy of genomic selection in livestock species. However, methods have mainly been tested on human genomic data, whereas livestock populations have specific characteristics, such as high levels of relatedness, small effective population size or long-range levels of linkage disequilibrium.ResultsHere, we used data from 14,762 cows, imputed at the whole-genome sequence level for 11,537,240 variants, to simulate traits in a typical livestock population and evaluate the accuracy of two state-of-the-art heritability partitioning methods, GREML and a Bayesian mixture model. In simulations where a single functional class had increased contribution to heritability, we observed that the estimators were unbiased but had low precision. When causal variants were enriched in variants with low (< 0.05) or high (> 0.20) minor allele frequency or low (below 1st quartile) or high (above 3rd quartile) linkage disequilibrium scores, it was necessary to partition the genetic variance into multiple classes defined on the basis of allele frequencies or LD scores to obtain unbiased results. When multiple functional classes had variable contributions to heritability, estimators showed higher levels of variation and confounding between certain categories was observed. In addition, estimators from small categories were particularly imprecise. However, the estimates and their ranking were still informative about the contribution of the classes. We also demonstrated that using methods that estimate the contribution of a single category at a time, a commonly used approach, results in an overestimation. Finally, we applied the methods to phenotypes for muscular development and height and estimated that, on average, variants in open chromatin regions had a higher contribution to the genetic variance (> 45%), while variants in coding regions had the strongest individual effects (> 25-fold enrichment on average). Conversely, variants in intergenic or intronic regions showed lower levels of enrichment (0.2 and 0.6-fold on average, respectively).ConclusionsHeritability partitioning approaches should be used cautiously in livestock populations, in particular for small categories. Two-component approaches that fit only one functional category at a time lead to biased estimators and should not be used.

DMFVAE: miRNA-disease associations prediction based on deep matrix factorization method with variational autoencoder

MicroRNAs (miRNAs) are closely related to numerous complex human diseases, therefore, exploring miRNA-disease associations (MDAs) can help people gain a better understanding of complex disease mechanism. An increasing number of computational methods have been developed to predict MDAs. However, the sparsity of the MDAs may hinder the performance of many methods. In addition, many methods fail to capture the nonlinear relationships of miRNA-disease network and inadequately leverage the features of network and neighbor nodes. In this study, we propose a deep matrix factorization model with variational autoencoder (DMFVAE) to predict potential MDAs. DMFVAE first decomposes the original association matrix and the enhanced association matrix, in which the enhanced association matrix is enhanced by self-adjusting the nearest neighbor method, to obtain sparse vectors and dense vectors, respectively. Then, the variational encoder is employed to obtain the nonlinear latent vectors of miRNA and disease for the sparse vectors, and meanwhile, node2vec is used to obtain the network structure embedding vectors of miRNA and disease for the dense vectors. Finally, sample features are acquired by combining the latent vectors and network structure embedding vectors, and the final prediction is implemented by convolutional neural network with channel attention. To evaluate the performance of DMFVAE, we conduct five-fold cross validation on the HMDD v2.0 and HMDD v3.2 datasets and the results show that DMFVAE performs well. Furthermore, case studies on lung neoplasms, colon neoplasms, and esophageal neoplasms confirm the ability of DMFVAE in identifying potential miRNAs for human diseases.

Use of diabetes technology in children.

Children with type 1 diabetes and their caregivers face numerous challenges navigating the unpredictability of this complex disease. Although the burden of managing diabetes remains significant, new technology has eased some of the load and allowed children with type 1 diabetes to achieve tighter glycaemic management without fear of excess hypoglycaemia. Continuous glucose monitor use alone improves outcomes and is considered standard of care for paediatric type 1 diabetes management. Similarly, automated insulin delivery (AID) systems have proven to be safe and effective for children as young as 2 years of age. AID use improves not only blood glucose levels but also quality of life for children with type 1 diabetes and their caregivers and should be strongly considered for all youth with type 1 diabetes if available and affordable. Here, we review key data on the use of diabetes technology in the paediatric population and discuss management issues unique to children and adolescents.