Spectrum Of Disease Research Articles

Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation.

Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

Spectrum of non-diabetic kidney diseases in patients with type 2 DM who underwent kidney biopsy in Egypt.

Diabetic kidney disease (DKD) affects 30-40% of diabetic patients. The prevalence of non-diabetic kidney disease (NDKD) in patients with type 2 DM (T2D) in Egypt is unknown. This study aimed to assess the prevalence of NDKD in patients with T2D in Egypt. In this cross-sectional study, we searched the data of patients with T2D who underwent a native kidney biopsy between January 2010 and December 2020 in a kidney pathology laboratory in Egypt. Of 12,006 patients who underwent kidney biopsy, 677 patients had T2D. NDKD was found in 285 patients (42.7%), DKD in 220 patients (33%), and mixed DKD and NDKD in 162 patients (24.3%). The total prevalence of NDKD was 67% in patients with T2D in our study group. Membranous nephropathy (MN) was the most common histopathological disease in patients with NDKD (20.6%) followed by acute tubular injury (ATI) (19.2%) and focal segmental glomerulosclerosis (FSGS) (15.2%). The presence of ATI in kidney biopsy was associated with a significantly higher mean serum creatine level (P<0.001). Minimal change disease was associated with significantly higher proteinuria level (P>0.001). In multivariate analysis, the duration of diabetes was a significant predictor of NDKD, with longer duration decreasing the likelihood of the 'NDKD' outcome. NDKD is prevalent among patients with T2D. Kidney biopsy remains the gold standard for diagnosing NDKD in patients with T2D.

Reversibility of Endoplasmic Reticulum Stress Markers During Long-Term Glucose Starvation in Astrocytes

Previous studies have demonstrated a brain volume decrease linked to long-term starvation in patients with anorexia nervosa (AN). Food intake is critically diminished in this disorder, leading to one of the highest mortality rates within the psychiatric disease spectrum. As reported in animal models, astrocytes seem to be the most affected cell type in AN. In a recently established primary cell culture model, an elevated unfolded protein response (UPR) was observed in long-term glucose semi-starved astrocytes. A well-functioning protein machinery is essential for every cell, and prolonged UPR will lead to cell death. As a nucleic acid stress-sensing pathway with the activator located in the endoplasmic reticulum, the regulation of the cGAS-STING pathway (cyclic GMP-AMP synthase/stimulator of interferon genes) was additionally investigated in the starvation context. In the current study, a glucose semi-starvation protocol of 15 days, during which cells were supplied with 2 mM glucose in the medium, was prolonged with an additional 6-day long recovery period. Our findings showed that increased UPR mRNA expression was reversible after re-establishing the standard glucose concentration of 25 mM. Furthermore, we were able to verify the presence of cGAS and STING in astrocytes with a characteristic presence of cGAS in the astrocyte nucleus during starvation. A correlation between STING and the glial fibrillary acidic protein (GFAP) could be established, hinting at a conditional presence of STING with a specific astrocyte phenotype.Graphical

Variable Phenotypes in the Same Patient with PRRT2-Associated Disorders

AbstractMutations in the PRRT2 gene lead to a spectrum of diseases with a common pathophysiology including self-limited (familial) infantile epilepsy and paroxysmal kinesigenic dyskinesia as well as other paroxysmal diseases involving movement and headache disorders. Atypical phenotypes, associated with episodic ataxia, epilepsy, hemiplegic migraine, developmental delay, and intellectual disability, have been reported in approximately 5% of the patients, which is probably an underestimation. Here, we present three patients with variable PRRT2 phenotypes in each patient. In the first two patients, the manifestations were characterized by episodes of nonepileptic paroxysms and focal seizures starting in the first years of life with good response to carbamazepine. One of them had no family history either of epilepsy or nonepileptic motor manifestations. The other patient simultaneously developed epileptic spasms. Neurodevelopment was normal in both. The third patient presented with early-onset focal epilepsy that was resistant to antiseizure medications and evolved to spike-wave activation in sleep associated with cognitive impairment and ataxia. In this patient, in addition to the mutation in the PRRT2 gene, a novel pathogenic SCN1A variant was identified. The distinct clinical presentations in the same patient observed in our cases confirm the broad spectrum of PRRT2-associated diseases.

Unveiling the spectrum of cardiac disease complicating pregnancy: A comprehensive exploration of maternal and fetal outcomes

Cardiac diseases pose a significant non-obstetrical threat to maternal well-being during pregnancy, contributing to nearly 10% of maternal mortality. The intersection of pregnancy and cardiac disease presents a complex scenario, affecting approximately 1-3% of pregnancies. Rheumatic heart disease (RHD) remains a prevalent issue in developing countries, while advancements in pediatric cardiology have increased survival rates for congenital heart disease. This exploration aims to comprehensively understand the impact of cardiac diseases on maternal and fetal outcomes during pregnancy.A prospective observational study conducted over 1 year and 6 months included 40 pregnant women with cardiovascular disease. Antenatal investigations, electrocardiogram, and echocardiography were performed. Maternal and fetal outcomes were assessed, and data were presented as descriptive statistics. The study revealed a 2.07% prevalence of cardiac disease in 1926 deliveries, with a mean age of 24±4 years. Cesarean section was the predominant mode of delivery (70%). Most cases had NYHA grade I disease (80%). Maternal outcomes were uneventful in 88%, and only 12% had ICU admission. Complications due to cardiac disease were observed in 17.5% of participants. Neonatal outcomes included NICU admission (25%), low birth weight (22.5%), and preterm birth (20%).Cardiovascular complications in pregnancy affect up to 4% of cases. The prevalence in this study aligns with existing literature. Rheumatic heart disease and congenital heart disease were predominant, consistent with global trends. Maternal and perinatal outcomes were favorable in NYHA grades I and II, emphasizing the importance of early intervention and healthcare accessibility.Cardiac disease is a substantial risk factor for maternal mortality during pregnancy. The study highlights the dual risk of balancing maternal well-being and fetal development. Prevalence, complications, and outcomes underscore the significance of pre-pregnancy counseling, early detection, and multidisciplinary management for optimal pregnancy outcomes.

Persistence and Variation of the Indirect Effects of COVID-19 Restrictions on the Spectrum of Notifiable Infectious Diseases in China: Analysis of National Surveillance Among Children and Adolescents From 2018 to 2021.

Beyond the direct effect of COVID-19 infection on young people, the wider impact of the pandemic on other infectious diseases remains unknown. This study aims to assess changes in the incidence and mortality of 42 notifiable infectious diseases during the pandemic among children and adolescents in China, compared with prepandemic levels. The Notifiable Infectious Disease Surveillance System of China was used to detect new cases and fatalities among individuals aged 5-22 years across 42 notifiable infectious diseases spanning from 2018 to 2021. These infectious diseases were categorized into 5 groups: respiratory, gastrointestinal and enterovirus, sexually transmitted and blood-borne, zoonotic, and vector-borne diseases. Each year (2018-2021) was segmented into 4 phases: phase 1 (January 1-22), phase 2 (January 23-April 7), phase 3 (April 8-August 31), and phase 4 (September 1-December 31) according to the varying intensities of pandemic restrictive measures in 2020. Generalized linear models were applied to assess the change in the incidence and mortality within each disease category, using 2018 and 2019 as the reference. A total of 4,898,260 incident cases and 3701 deaths were included. The overall incidence of notifiable infectious diseases decreased sharply during the first year of the COVID-19 pandemic (2020) compared with prepandemic levels (2018 and 2019), and then rebounded in 2021, particularly in South China. Across the past 4 years, the number of deaths steadily decreased. The incidence of diseases rebounded differentially by the pandemic phase. For instance, although seasonal influenza dominated respiratory diseases in 2019, it showed a substantial decline during the pandemic (percent change in phase 2 2020: 0.21, 95% CI 0.09-0.50), which persisted until 2021 (percent change in phase 4 2021: 1.02, 95% CI 0.74-1.41). The incidence of gastrointestinal and enterovirus diseases decreased by 33.6% during 2020 but rebounded by 56.9% in 2021, mainly driven by hand, foot, and mouth disease (percent change in phase 3 2021: 1.28, 95% CI 1.17-1.41) and infectious diarrhea (percent change in phase 3 2020: 1.22, 95% CI 1.17-1.28). Sexually transmitted and blood-borne diseases were restrained during the first year of 2021 but rebounded quickly in 2021, mainly driven by syphilis (percent change in phase 3 2020: 1.31, 95% CI 1.23-1.40) and gonorrhea (percent change in phase 3 2020: 1.10, 95% CI 1.05-1.16). Zoonotic diseases were not dampened by the pandemic but continued to increase across the study period, mainly due to brucellosis (percent change in phase 2 2020: 0.94, 95% CI 0.75-1.16). Vector-borne diseases showed a continuous decline during 2020, dominated by hemorrhagic fever (percent change in phase 2 2020: 0.68, 95% CI 0.53-0.87), but rebounded in 2021. The COVID-19 pandemic was associated with a marked decline in notifiable infectious diseases in Chinese children and adolescents. These effects were not sustained, with evidence of a rebound to prepandemic levels by late 2021. To effectively address the postpandemic resurgence of infectious diseases in children and adolescents, it will be essential to maintain disease surveillance and strengthen the implementation of various initiatives. These include extending immunization programs, prioritizing the management of sexually transmitted infections, continuing feasible nonpharmaceutical intervention projects, and effectively managing imported infections.

Therapeutic plasma exchange in critically ill children: A single center experience.

Therapeutic plasma exchange (TPE) is used in a wide spectrum of diseases in critically ill pediatric patients. We aim to review the indications, complications, safety, and outcomes of critically ill children who received TPE. All of the TPE procedures performed in a pediatric intensive care unit providing tertiary care during 19 years (January 2013-January 2023) were evaluated retrospectively. A total of 154 patients underwent 486 TPE sessions. Median age was 6 years (2-12.5) and 35 children had a body weight of <10 kg (22.7%). Number of organ failure was 4 (2-6). Liver diseases were the most common indication for TPE (31.2%) followed by sepsis with multiorgan dysfunction syndrome (27.3%). Overall survival rate was 72.7%. The highest mortality was observed in hemophagocytic lymphohistiocytosis group. Non-survivors had significantly higher number of organ failure (p < 0.001), higher PRISM score (p < 0.001), and higher PELOD score on admission (p < 0.001). Adverse events were observed in 68 (13.9%) sessions. Hypotension (7.8%) and hypocalcemia (5.1%) were the most frequent adverse events. TPE is safe for critically ill pediatric patients with experienced staff. Survival rate may vary depending on the underlying disease. Survival decreases with the increase in the number of failed organs.

Unveiling metabolic similarities of entheses in psoriasis and psoriatic arthritis patients using non-invasive in vivo imaging - results from the MAPSA study.

To assess and compare molecular tissue changes at the entheses in patients with psoriasis (PsO), psoriatic arthritis (PsA), and healthy controls (HC) in vivo using multispectral optoacoustic tomography (MSOT) and to describe their relationship with clinical and ultrasound findings of enthesitis. A cross-sectional study (MAPSA) in bDMARD-naïve PsA and PsO patients and HC was performed. Participants underwent clinical, ultrasonographic and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, Achilles tendon attachment). MSOT-measured haemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified and mean differences between groups were calculated using linear mixed-effects models. MSOT-measured analytes were compared between entheses with and without clinical and ultrasound anomalies. Ninety participants were included (30 PsO, 30 PsA, 30 HC), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Both PsA and PsO patients showed increased oxygenated Hb (PsA: p=0.003; PsO: p=0.054) and SO2 (PsA: p<0.001; Pso: p=0.001) levels and decreased collagen signals (PsA: p<0.001; PsO: <0.001) compared to HC, with more pronounced changes in PsA. Significantly lower collagen levels (p=0.01) and increased lipids (p=0.03) were recorded in tender entheses compared to non-tender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (p=0.014) and lipid signals (p=0.020), respectively. PsA and PsO patients exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immuno-metabolic tissue changes.

Visual Functions Are Associated with Biomarker Changes in Alzheimer's Disease.

While various biomarkers of Alzheimer's disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Data from participants (N = 1,460) in the Alzheimer's Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination (MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1-42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition.

Key aspects of papillomavirus infection influence the host cervicovaginal microbiome in a preclinical murine papillomavirus (MmuPV1) infection model.

Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States and are a major etiological agent of cancers in the anogenital tract and oral cavity. Growing evidence suggests changes in the host microbiome are associated with the natural history and ultimate outcome of HPV infection. We sought to define changes in the host cervicovaginal microbiome during papillomavirus infection, persistence, and pathogenesis using the murine papillomavirus (MmuPV1) cervicovaginal infection model. Cervicovaginal lavages were performed over a time course of MmuPV1 infection in immunocompetent female FVB/N mice and extracted DNA was analyzed by qPCR to track MmuPV1 viral copy number. 16S ribosomal RNA (rRNA) gene sequencing was used to determine the composition and diversity of microbial communities throughout this time course. We also sought to determine whether specific microbial communities exist across the spectrum of MmuPV1-induced neoplastic disease. We, therefore, performed laser-capture microdissection to isolate regions of disease representing all stages of neoplastic disease progression (normal, low- and high-grade dysplasia, and cancer) from female reproductive tract tissue sections from MmuPV1-infected mice and performed 16S rRNA sequencing. Consistent with other studies, we found that the natural murine cervicovaginal microbiome is highly variable across different experiments. Despite these differences in initial microbiome composition between experiments, we observed that MmuPV1 persistence, viral load, and severity of disease influenced the composition of the cervicovaginal microbiome. These studies demonstrate that papillomavirus infection can alter the cervicovaginal microbiome.IMPORTANCEHuman papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States. A subset of HPVs that infect the anogenital tract (cervix, vagina, anus) and oral cavity cause at least 5% of cancers worldwide. Recent evidence indicates that the community of microbial organisms present in the human cervix and vagina, known as the cervicovaginal microbiome, plays a role in HPV-induced cervical cancer. However, the mechanisms underlying this interplay are not well-defined. In this study, we infected the female reproductive tract of mice with a murine papillomavirus (MmuPV1) and found that key aspects of papillomavirus infection and disease influence the host cervicovaginal microbiome. This is the first study to define changes in the host microbiome associated with MmuPV1 infection in a preclinical animal model of HPV-induced cervical cancer. These results pave the way for using MmuPV1 infection models to further investigate the interactions between papillomaviruses and the host microbiome.

A Systematic Review and Meta-analysis of Selective Cyclooxygenase-2 Inhibitors and Non-selective Non-steroidal Anti-inflammatory Drugs for Acute Gout

Background:The term “gout” refers to a broad clinical spectrum of diseases, including common and complex forms of arthritis, that affect multiple joints in a patient due to an elevated serum urate concentration. Purpose: The study aims to compare the efficacy and safety of selective cyclooxygenase-2 (COX-2) inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of acute gout, as well as to conduct a meta-analysis on safety. Methods: As of December 2021, the literature search was conducted using authorised electronic databases such as PubMed, Embase, Web of Science, and the Cochrane Library. Results: There were seven investigations included in this study’s findings. Three COX-2 inhibitors, etoricoxib, celecoxib, and meloxicam, were reportedly compared to indomethacin or diclofenac. Four hours after the initial dose, 120 mg of etoricoxib reduces pain and inflammation by diminishing erythema. At higher dosages, celecoxib is more effective than at lower doses. Meloxicam has the same efficacy as NSAIDs. The subgroup analysis revealed that the risk of adverse events was 8.0% lower in the COX-2 inhibitors group than in the non-selective NSAIDs group (risk ratio = 0.92, 95% confidence interval = 0.60 to 0.40, p-value = 0.5). Conclusion: Etoricoxib, a COX-2 inhibitor, has a more potent effect and may be more effective than nonselective NSAIDs. COX-2 inhibitors are more well tolerated and reduce the risk of adverse gastrointestinal events more effectively than nonselective NSAIDs. In the treatment of gout, nonselective NSAIDs may be a suitable alternative to COX-2 inhibitors.

Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort.

Keratinopathic ichthyoses are a group of hereditary skin disorders caused by pathogenic variants in keratin genes such as KRT1, KRT2 and KRT10, resulting in conditions such as epidermolytic ichthyosis (EI), autosomal-recessive EI, superficial EI and epidermal nevus. Case reports highlight the diversity of clinical manifestations, but only limited information exists regarding the quality of life and burden of disease. The objective of this study was to assess the clinical spectrum, genotype-phenotype correlations and burden of disease in patients with epidermolytic ichthyosis in Germany. We conducted an observational study involving 48 patients diagnosed with EI. Evaluations included the severity of skin involvement using the Investigator's Global Assessment (IGA), the modified Ichthyosis Area Severity Index (mIASI) and complications. The burden of disease was evaluated using the Dermatology Life Quality Index (DLQI) or the Children's Dermatology Life Quality Index (cDLQI). Based on clinical features, mIASI and IGA, EI can be categorized into localized, intermediate and severe forms. Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations. The study highlights that around half of the patients with EI experienced itch and severe pain. Quality of life was affected, with daily life restrictions of 78% due to care and therapies. Reimbursement for moisturizing ointments by health insurance was insufficient for one-quarter of cases. The results emphasize the need for targeted interventions and comprehensive care strategies to enhance the quality of life for affected individuals.

Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Chronic Nonbacterial Osteomyelitis, Hidradenitis Suppurativa, and SAPHO Syndrome

Introduction: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome may represent one side of a spectrum of disease that also includes chronic nonbacterial osteomyelitis. Case: A 23-year-old male with bone pain in the anterior chest, shoulder, clavicles, left elbow, and left ankle presented to rheumatology clinic after multiple evaluations for infectious osteomyelitis. Imaging and deep bone biopsies of affected areas were consistent with chronic osteomyelitis, with labs notable for elevated erythrocyte sedimentation rate, C-reactive protein, and positivity for HLA-B27. A full skin exam was consistent with hidradenitis suppurativa, and he was started on infliximab and methotrexate with improvement in both his osteoarticular and skin symptoms. Conclusions: Patients presenting with features of follicular occlusion or neutrophilic dermatoses in conjunction with bone pain should be evaluated for SAPHO/CNO. In patients with SAPHO/CNO with vertebral involvement, bisphosphonates in addition to anti-inflammatory medications (such as methotrexate and TNF-inhibitors) can be effective.

Criteria for granting access by an EU member state to a severely ill patient to an unauthorized medicine

The article focuses attention on the fact that a structural element of everyone's subjective legal right to medical care is the right to access to a medicinal product. It is emphasized that the Covid-19 pandemic, the increase in the spectrum of incurable diseases and the number of patients suffering from them, Russia's aggression against Ukraine, the consequences of which are an increase in the number of military personnel and civilians who need the use of medicinal products created using the latest technologies, but which (medicines) are still not allowed in the state, the integration of Ukraine with the EU became the factors that actualized the discussion of scientists and practitioners on the issue of the conditions that must be observed by the EU member state in order to apply the provisions of Article 1. 5 of Directive 2001/83/EC of the European Parliament and of the Council on the Community Code regarding medicinal products intended for human use, the exception is to provide an EU member state with access to a patient to a medicinal product not authorized by the competent authorities of such a member state and thereby fulfill its obligation to provide everyone's constitutional right to medical care. The conditions that must be observed by the EU member state in order to apply the provisions of Article 1. 5 of the Exclusion Directives - for an EU member state to provide a patient with access to a medicinal product that is not authorized by the competent authorities of such a member state: 1) the presence of a norm of national law that allows the supply of a medicinal product for which a permit was not granted; 2) the goal is to meet the special needs of a specific seriously ill patient (private interest) and ensure the protection of public health (public interest); 3) be due to the absence on the national market of any authorized medicinal product - the equivalent of an unauthorized medicinal product; 4) delivery is made in response to a bona fide order on one's own initiative; 5) supply is carried out according to the prescription in accordance with the specifications of the authorized medical worker; 6) an unauthorized medicinal product is prescribed for use by a specific patient under his direct personal responsibility. The signs of the patient's special needs are highlighted: 1) the specific situation of the patient's state of health and the course of his illness; 2) medical reasoning, which is justified; 3) the patient's need for a certain medicinal product. The grounds for an unregistered medicinal product to be prescribed by a doctor are: the doctor's therapeutic considerations; results of research, analyzes of the patient. In a situation where there are authorized medicinal products on the market of an EU member state - analogues of prohibited medicinal products - the import of unauthorized medicinal products can be qualified as an act of non-fulfillment by the EU member state of its obligations, provided for in Article 1. 6 Directives.

Study on preparation technology of Qi Yu constitution Yangsheng granules.

Understanding how pharmaceutical formulas target specific illnesses is crucial for developing effective treatments. Enriching ion channel data is a critical first step in comprehending a formula's mechanism of action. This study aims to explore the effective disease spectrum of the Qi Yu granule formula through network pharmacology analysis and backtracking, and analyze its potential curative effects on liver and spleen system diseases, particularly depression and breast cancer. Using pharmacological tools and database analysis, the ion channel data of the formula's components were investigated. The effective disease spectrum was determined, and diseases related to liver and gallbladder, liver depression, and spleen deficiency were identified. Network pharmacology analysis was conducted to backtrack diseases, target gene proteins, and drug compositions. The extraction technology of volatile oil from medicinal herbs was experimentally studied to optimize the preparation process. The effective disease spectrum analysis identified potential curative effects of the Qi Yu granule formula on various diseases, including breast cancer. Backtracking revealed relationships between diseases, target gene proteins, and drug compositions. Experimental studies on volatile oil extraction provided insights into optimizing the preparation process. The study underscores the potential therapeutic benefits of the Qi Yu granule formula for liver and spleen system diseases. By integrating network pharmacology analysis and experimental research, this study offers valuable insights into the formulation and efficacy of the Qi Yu granules, paving the way for further exploration and optimization of TCM formulations.

A novel pathogenic mitochondrial DNA variant m.4344T>C in tRNAGln causes developmental delay.

Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. However, the genetic spectrum of this disease is not yet complete. In this study, we identified a novel variant m.4344T>C in mitochondrial tRNAGln from a patient with developmental delay. The mutant loads of m.4344T>C were 95% and 89% in the patient's blood and oral epithelial cells, respectively. Multialignment analysis showed high evolutionary conservation of this nucleotide. TrRosettaRNA predicted that m.4344T>C variant would introduce an additional hydrogen bond and alter the conformation of the T-loop. The transmitochondrial cybrid-based study demonstrated that m.4344T>C variant impaired the steady-state level of mitochondrial tRNAGln and decreased the contents of mitochondrial OXPHOS complexes I, III, and IV, resulting in defective mitochondrial respiration, elevated mitochondrial ROS production, reduced mitochondrial membrane potential and decreased mitochondrial ATP levels. Altogether, this is the first report in patient carrying the m.4344T>C variant. Our data uncover the pathogenesis of the m.4344T>C variant and expand the genetic mutation spectrum of mitochondrial diseases, thus contributing to the clinical diagnosis of mitochondrial tRNAGln gene variants-associated mitochondrial diseases.

Macrolide Resistance in the Aerococcus urinae Complex: Implications for Integrative and Conjugative Elements

The recognition of the Aerococcus urinae complex (AUC) as an emerging uropathogen has led to growing concerns due to a limited understanding of its disease spectrum and antibiotic resistance profiles. Here, we investigated the prevalence of macrolide resistance within urinary AUC isolates, shedding light on potential genetic mechanisms. Phenotypic testing revealed a high rate of macrolide resistance: 45%, among a total of 189 urinary AUC isolates. Genomic analysis identified integrative and conjugative elements (ICEs) as carriers of the macrolide resistance gene ermA, suggesting horizontal gene transfer as a mechanism of resistance. Furthermore, comparison with publicly available genomes of related pathogens revealed high ICE sequence homogeneity, highlighting the potential for cross-species dissemination of resistance determinants. Understanding mechanisms of resistance is crucial for developing effective surveillance strategies and improving antibiotic use. Furthermore, the findings underscore the importance of considering the broader ecological context of resistance dissemination, emphasizing the need for community-level surveillance to combat the spread of antibiotic resistance within the urinary microbiome.

Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models.

Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine-Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.

Actinobacteria: Smart Micro-Factories for The Health Sector.

Antibiotics are considered "wonder drugs" due to the fact that they are the most extensively utilised medication in the world. They are used to cure a broad spectrum of diseases and lethal infections. A variety of bacteria and fungi produce antibiotics as a result of secondary metabolism; however, their production is dominated by a special class of bacteria, namely Actinobacteria. Actinobacteria are gram-positive bacteria with high G+C content and unparalleled antibiotic-producing ability. They produce numerous polyenes, tetracyclines, β-lactams, macrolides, and peptides. Actinobacteria are ubiquitous in nature and are isolated from various sources, such as marine and terrestrial endophytes of plants and air. They are studied for their relative antibiotic-producing ability along with the mechanism that the antibiotics follow to annihilate the pathogenic agents that include bacteria, fungi, protozoans, helminths, etc. Actinobacteria isolated from endophytes of medicinal plants have amassed significant attention as they interfere with the metabolism of medicinal plants and acquire enormous benefits from it in the form of conspicuous novel antibiotic-producing ability. Actinobacteria is not only an antibiotic but also a rich source of anticancer compounds that are widely used owing to its remarkable tumorigenic potential. Today, amongst Actinobacteria, class Streptomyces subjugates the area of antibiotic production, producing 70% of all known antibiotics. The uniqueness of bioactive Actinobacteria has turned the attention of scientists worldwide in order to explore its potentiality as effective "micronanofactories". This study provides a brief overview of the production of antibiotics from Actinobacteria inhabiting diverse environments and the methods involved in the screening of antibiotics.