Large Cohort Of Patients Research Articles

Microbiome characterization of patients with Crohn disease and the use of fecal microbiota transplantation: A review.

Inflammatory bowel disease is a chronic inflammatory condition predominantly affecting the intestines, encompassing both ulcerative colitis and Crohn disease (CD). As one of the most common gastrointestinal disorders, CD's pathogenesis is closely linked with the intestinal microbiota. Recently, fecal microbiota transplantation (FMT) has gained attention as a potential treatment for CD, with the effective reestablishment of intestinal microecology considered a crucial mechanism of FMT therapy. This article synthesizes the findings of population-based cohort studies to enhance our understanding of gut microbial characteristics in patients with CD. It delves into the roles of "beneficial" and "pathogenic" bacteria in CD's development. This article systematically reviews and compares data on clinical response rates, remission rates, adverse events, and shifts in bacterial microbiota. Among these studies, gut microbiome analysis was conducted in only 7, and a single study examined the metabolome. Overall, FMT has demonstrated a partial restoration of typical CD-associated microbiological alterations, leading to increased α-diversity in responders and a moderate shift in patient microbiota toward the donor profile. Several factors, including donor selection, delivery route, microbial state (fresh or frozen), and recipient condition, are identified as pivotal in influencing FMT's effectiveness. Future prospective clinical studies with larger patient cohorts and improved methodologies are imperative. In addition, standardization of FMT procedures, coupled with advanced genomic techniques such as macroproteomics and culture genomics, is necessary. These advancements will further clarify the bacterial microbiota alterations that significantly contribute to FMT's therapeutic effects in CD treatment, as well as elucidate the underlying mechanisms of action.

Intrapatient 16α-[18F]Fluoro-17β-Estradiol PET Heterogeneity as a Prognostic Factor for Endocrine Therapy Response and Survival in Patients with Estrogen Receptor-Positive Metastatic Breast Cancer.

Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[18F]fluoro-17β-estradiol ([18F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [18F]FES PET heterogeneity score (i.e., percentage of [18F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [18F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [18F]FES and [18F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [18F]FES-positive lesions) and ER heterogeneous (both [18F]FES-positive and [18F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [18F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [18F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [18F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [18F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [18F]FES PET heterogeneity score in all lesions.

Automated scoring to assess RAD51-mediated homologous recombination in ovarian patient-derived tumor organoids.

PARP inhibitors (PARPi) have been shown to improve progression-free survival, particularly in homologous recombination deficient (HRD) ovarian cancers. Identifying patients eligible to PARPi is currently based on next-generation sequencing (NGS), but the persistence of genomic scars in tumors after restoration of HR or epigenetic changes can be a limitation. Functional assays could thus be used to improve this profiling and faithfully identify HRD tumors. The RECAP test assesses the formation of RAD51 foci in proliferating cells after irradiation and can be used on tumors as well as on patient-derived tumor organoids (PDTO). However, RAD51 foci scoring is often performed manually without standardization. The purpose of this translational study was to develop an automated tool for scoring RAD51-mediated HR based on whole slide imaging of ovarian PDTO. To that end, we quantified Cyclin A2 and RAD51 immunofluorescence on 9 PDTO models derived from 8 ovarian cancer patients and next compared RECAP test results to genome instability score (GIScar) and to the patient clinical response. We therefore developed a standardized and automatized quantitative histo-imaging tool allowing a comparative RAD51 foci evaluation and thus to define the HR status in PDTO. Our RECAP-based classification was correlated to the GIScar score, offering a new opportunity for standardization of HR assessment in PDTO. This new automated tool to score HR status, that remains to be validated on a large cohort of patients, may thus be used as a complement to NGS-based tests in order to improve the identification of the number of patients eligible to PARPi.

Utility of Novel Radiohybrid PSMA Ligands in PET Imaging of Biochemical Recurrence of Prostate Cancer-A Systematic Review and Meta-analysis.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a novel class of radiopharmaceuticals developed for potential theranostic application in prostate cancer (PCa). We aimed to consolidate existing evidence on utility of 18F-rhPSMA-7/7.3 for PET imaging in PCa in the setting of biochemical recurrence (BCR). A comprehensive literature search was performed using relevant keywords in PubMed, Scopus, and EMBASE. Articles evaluating utility of 18F-rhPSMA-7/7.3 PET in PCa BCR, published through September 30, 2024, were included. rhPSMA PET detection rate (DR) in BCR was calculated on a per-patient basis, with pooled proportion and 95% confidence interval. Furthermore, pooled DRs using different cutoff values of serum prostate-specific antigen (PSA) were obtained. Five studies with 1513 patients (overall) were included. The pooled DR of 18F-rhPSMA-7/7.3 PET in BCR was 81.7% (95% confidence interval: 76.3%-86.5%). The pooled DRs stratified by serum PSA levels were 60.7% for PSA <0.5 ng/mL, 80.1% for PSA between 0.5 and <1.0 ng/mL, 85.9% for PSA between 1.0 and <2.0 ng/mL, and 95.1% for PSA ≥2.0 ng/mL, respectively. Our results suggest that novel radiotracers 18F-rhPSMA-7/7.3 have excellent diagnostic utility as PET imaging agents in BCR of PCa. Further prospective multicenter studies are required to validate these novel tracers in diverse clinical settings with larger patient cohorts and assess their diagnostic accuracy in comparison to the PSMA ligands in current clinical practice.

Bone Marrow Aspiration Concentrate in the Treatment of Osteoarthritis: A Review of its Current Clinical Application.

Bone marrow aspiration concentrate (BMAC) has gained acceptance as a safe orthobiologic for treating osteoarthritis (OA), despite lacking robust supporting evidence. Although several publications have documented the use of BMAC in OA, evidence confirming its unequivocal efficacy remains limited. This review aims to summarize the current clinical evidence regarding BMAC as a therapeutic for OA, while also presenting the author's perspective. Sixteen studies were reviewed, including ten randomized clinical trials (RCTs) and six cohort studies. From the review of existing literature, BMAC injections do not appear to significantly improve pain and function compared to conventional therapies such as hyaluronic acid and corticosteroids, although some studies report a longer duration of effectiveness. Furthermore, the evidence for structural improvement, which was the original rationale for cell therapy, is seldom reported. In light of these findings, it is suggested that high-quality data from a large patient cohort is needed to determine the role of BMAC injections in OA treatment and address reimbursement issues. From the author's perspective, the introduction of a national registry system that provides valuable information on the cost-effectiveness of various orthopedic procedures may offer a solution.

Baseline PSMA PET/CT parameters predict overall survival and treatment response in metastatic castration-resistant prostate cancer patients.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response. Sixty mCRPC patients underwent [18F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3-4 months of treatment. Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17-1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16-1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07-1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68-0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49-0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06-0.83]) and SUVmean (OR = 1.72 per doubling [1.08-2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not. Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts. Question mCRPC is a highly heterogeneous disease, requiring good prognostic markers. Findings PSMA-TV was the best independent prognostic marker for OS; maximum distance between lesions (DmaxVox) can be used as a simpler alternative. Clinical relevance Baseline PSMA PET/CT parameters representing tumour burden were independently associated with OS in mCRPC patients, providing prognosticinsights for clinical decision-making. Although PSMA-TV was the best prognostic marker, DmaxVox can serve as an easier to obtain alternative.

Evaluation of the recombinant protein Sh-TSP-2 for the serological diagnosis of imported urogenital schistosomiasis and comparison with commercially available tests.

Different agencies have emphasized the need to evaluate current serological methods for screening patients with suspected urogenital schistosomiasis. However, there is still a lack of evidence regarding the most appropriate methods for this purpose. Here we assessed the diagnostic efficacy of a newly developed serological technique that utilizes the recombinant protein Sh-TSP-2, applied to the urine and serum of migrants suspected of having urogenital schistosomiasis. The sensitivity, specificity, positive and negative predictive values of an in-house enzyme-linked immunosorbent assay (ELISA) using the recombinant protein Sh-TSP-2 were analysed and compared with other commercial serological methods. Due to the limitations of microscopy as a perfect reference method, a latent class analysis (LCA) and composite reference standard (CRS) approach was used to determine the sensitivity and specificity of each test. According to the LCA model, the commercial tests NovaLisa® and immunochromatography test (ICT) immunoglobulin G–immunoglobulin M (IgG–IgM) presented the highest sensitivity (100%), whereas the Sh-TSP-2 serum ELISA test had 79.2%. The Sh-TSP-2 urine and serum ELISA tests had the highest specificities among the serological methods (87.5 and 75%, respectively). CRS modelling showed that the ICT IgG–IgM, NovaLisa® and Sh-TSP-2 serum tests led in sensitivity at 97.1, 88.6 and 71.4%, respectively, with all tests except that the ICT IgG–IgM test having a specificity >90%. Sh-TSP-2 has been validated as a screening tool for patients suspected of having urogenital schistosomiasis. Although commercial serological tests have shown higher sensitivities, Sh-TSP-2 could be valuable for confirming results from tests with lower specificity. Nevertheless, further studies with larger patient cohorts are necessary to fully verify its potential.

Exploring sex differences in Alzheimer’s disease: a comprehensive analysis of a large patient cohort from a memory unit

BackgroundAlzheimer’s disease (AD) stands as the leading cause of dementia worldwide, and projections estimate over 150 million patients by 2050. AD prevalence is notably higher in women, nearly twice that of men, with discernible sex differences in certain risk factors. To enhance our understanding of how sex influences the characteristics of AD patients and its potential impact on the disease trajectory, we conducted a comprehensive analysis of demographic, clinical, cognitive, and genetic data from a sizable and well-characterized cohort of AD dementia patients at a memory clinic in Barcelona, Spain.MethodsThe study cohort comprised individuals with probable and possible AD dementia with a Clinical Dementia Rating (CDR) score between 1 and 3 diagnosed at the Memory Unit from Ace Alzheimer Center Barcelona, Spain, between 2008 and 2018. We obtained cognitive baseline data and follow up scores for the Mini-Mental State Examination (MMSE), the CDR scale, and the neuropsychological battery used in our center (NBACE). We employed various statistical techniques to assess the impact of sex on cognitive evolution in these dementia patients, accounting for other sex-related risk factors identified through Machine Learning methods.ResultsThe study cohort comprised a total of 6108 individuals diagnosed with AD dementia during the study period (28.4% males and 71.6% females). MMSE scores exhibited an average decline of approximately two units per year, unaffected by sex. Similarly, the decline in most neuropsychological functions assessed by NBACE did not exhibit significant differences between males and females. However, we observed that women diagnosed with mild AD dementia progressed more rapidly based on their CDR score (HR = 2.57, 95%CI:2.33–2.84) than men (HR = 2.03, 95%CI: 1.71–2.41) (p-interaction = 0.01).ConclusionsOur findings do not strongly support the notion that sex significantly modifies the clinical progression of AD dementia based on cognitive data. Further research is essential to validate whether women with mild AD dementia indeed progress more rapidly than men at a similar stage and to delve into the potential underlying reasons for this finding.

Prevalence and endoscopic features of colorectal non-polypoid lesions: a single-center retrospective study from a large cohort of FIT-positive screening patients in Northern Italy.

Colorectal non-polypoid lesions (NPLs) are flat, hard-to-detect and mainly right-sided lesions. We aimed to assess the prevalence and endoscopic features of NPLs lesions in a large cohort of screening patients in Northern Italy. FIT-positive subjects between 50 and 69 years old who had undergone at least a screening colonoscopy from March 2005 to December 2017 at the Endoscopy Unit of Ferrara were included. We selected only non-diminutive (>5 mm) and neoplastic polyps (i.e.: adenomas, serrated adenomas and carcinomas). Patients' demographics and polyps' endoscopic-histopathological data were collected. Categorical variables were compared using the Pearson's χ2 test and Fisher's Exact Test, while odd Ratios and confidence intervals were estimated with univariate analysis. 6,676 FIT-positive subjects underwent 7,616 colonoscopies during the study period. Total lesions were 3,231, of which 133 were NPLs and among these 123 were neoplastic. Prevalence of NPLs among total lesions was 4.1% while prevalence of neoplastic NPLs among total neoplastic lesions was 4.6%. Prevalence of NPLs and neoplastic NPLs among total colonoscopies was 1.7% and 1.6%, respectively. Neoplastic NPLs were more frequent between 60 and 64 years old (p=0.03) and associated with other colonic polyps in subjects older than 60 years (p=0.016). Cancerized NPLs were more likely in younger patients (50-59 years old, p=0.04). Prevalence of NPLs is low among screening population, but NPLs are frequently associated with other colonic polyps in patients older than 60 years and carry a higher risk of cancer in patients younger than 60 years old.

Phenotypic Heterogeneity of ADTKD-MUC1 Diagnosed Using VNtyper, a Novel Genetic Technique.

Molecular diagnosis of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to variants in the MUC1 gene has long been challenging since variants lie in a large Variable Number of Tandem Repeat (VNTR) region, making identification impossible using standard short read techniques. Previously, we addressed this diagnostic limitation by developing a computational pipeline, named VNtyper, for easier reliable detection of MUC1 VNTR pathogenic variants from short read sequences. This led to unexpected diagnoses of ADTKD-MUC1 among patients with kidney disease referred for genetic testing, which we report here. Cross-sectional observational study. 4,040 patients referred to Necker Enfants-Malades Hospital from 2017 to 2023 for genetic testing for (1) glomerular disease, (2) ciliopathy, (3) congenital anomalies of the kidneys and urinary tracts (CAKUT), (4) ADTKD, or (5) chronic kidney disease (CKD) of unknown origin, in whom MUC1 had not been previously tested by SNaPshot mini-sequencing. Clinical suspicion of ADTKD. ADTKD-MUC1 diagnosed using VNtyper. Data were collected from patients in whom ADTKD-MUC1 was newly diagnosed and patients in whom ADTKD was clinically suspected were compared to those in whom ADTKD was not. We identified 40 patients with MUC1 variants by VNtyper, including 33 new index patients and 7 relatives. Of the 33 index cases, 20 had been suspected of having ADTKD based on clinical features, and in the other 13, ADTKD had not been considered. In patients in whom ADTKD had not been considered clinically, the detection rate was 0.05% (1/1895) among patients with glomerular disease, 1.2% (4/329) among patients with ciliopathy, 0.09% (1/1099) among patients with CAKUT and 2.5% (7/285) among patients with CKD of unknown origin. In six patients, there was no family history of kidney disease, and we confirmed de novo presentation in two patients by segregation studies. Observational study and selected referral population (may not represent the prevalence or phenotypes in the general kidney disease population). With VNtyper, we were able to diagnose new cases of ADTKD-MUC1 in a large cohort of patients with various phenotypes. Some patients had atypical phenotypes due to a variant in another gene, and some had no family history of kidney disease, suggesting de novo disease which was confirmed in two patients.

Retrospective multicenter analysis of the Trenza Embolization Device for endovascular therapy of intracranial aneurysms: initial results and short-term follow-up

BackgroundIntrasaccular devices are increasingly used in endovascular therapy of intracranial aneurysms, in particular wide-necked and ruptured aneurysms. The Trenza Embolization Device (TED) is an innovative intrasaccular device for medium- to...

Clinical consequence of hypophosphatemia during antiviral therapy for chronic hepatitis B.

Antiviral therapy is an essential treatment for chronic hepatitis B (CHB) infection. Although hypophosphatemia is an important adverse effect of antiviral agents, its clinical significance remains unclear. We investigated the incidence and clinical consequences of hypophosphatemia in a large cohort of CHB patients. This retrospective cohort study included CHB patients who started antiviral therapy between 2005 and 2015 and continued it for at least 1 year. Patients with decompensated liver cirrhosis, diabetes mellitus, hypertension, concomitant diuretic administration, and end-stage renal disease were excluded. The primary outcome was a change in renal function. Secondary outcomes included the incidence of infection and changes in serum potassium, uric acid, and total carbon dioxide (tCO2). Among the 4,335 patients, hypophosphatemia developed in 75 (1.7%). During the median 2-year follow-up period, patients with hypophosphatemia showed a lower estimated glomerular filtration rate than those in the control group. The incidence of infection and changes in serum potassium, uric acid, and tCO2 were similar between groups. Hypophosphatemia was associated with a renal function decline in patients with CHB receiving antiviral therapy.

Titanium clips and ligamentum flavum-epidural fat patch graft for midline lumbar durotomy closure in pediatric neurosurgery.

CSF leaks are a significant source of patient morbidity following intradural spine surgeries. Watertight dural closure is crucial during these procedures to minimize the risk of a CSF leak. This study reports postoperative outcomes and changes in patient management after switching to penetrating titanium clips for dural closure in a large cohort of pediatric patients receiving a tethered cord release (TCR) or a selective dorsal rhizotomy (SDR). An IRB-approved retrospective review was conducted of the medical charts of all patients who underwent thoracolumbar dorsal midline dural closure with the AnastoClip GC Closure System during the 7 years between May 22, 2017, and May 21, 2024. Selected data such as evidence of a CSF leak and postoperative length of stay were collected. A total of 290 patients were treated with AnastoClips GC for dural closure. Of these patients, 232 (80.0%) underwent a TCR only, 52 (17.9%) received an SDR, and 6 (2.1%) underwent a complex TCR. The mean duration between surgery and last follow-up was 7.96 months (range 0.27-54.57 months). One patient, who received a simple TCR, experienced a transient pseudomeningocele without headache, emesis, or visible leak that resolved without surgical intervention within 8 weeks. Three (1%) patients had positional headaches without other evidence of a CSF leak, all limited to the initial 2 weeks of postoperative care. Six (2%) patients had delayed wound healing, 2 of whom underwent operative wound revisions. As of January 1, 2021, patients no longer had to lie flat postoperatively. While 60.6% of TCR patients were discharged from the hospital on POD 1 (none on POD 0) prior to this date, 87.5% of patients were discharged from the hospital on either POD 0 (3.1%) or POD 1 (84.4%) afterward. Similarly, 50% of SDR patients were discharged on POD 2 or 3 after the need for lying flat postoperatively was removed versus 21% before the protocol change. AnastoClip GC Closure System titanium clips are safe and effective for dural closure in both TCR and SDR, with rare complications. Their efficacy has prompted us to remove flat bed rest requirements for postoperative patients, significantly reducing the length of stay, and has opened the door to making simple TCRs a same-day surgery.

Updates on the molecular spectrum of MEFV variants in lebanese patients with Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder, particularly present in the Mediterranean populations, and associated with pathogenic variants in the MEFV gene. This study aims to investigate the distribution of MEFV variants in a large cohort of Lebanese patients, and to explore the genotype-phenotype correlation among affected individuals. A retrospective analysis was conducted on 3,167 patients referred for MEFV sequencing at the Medical Genetics and Genomics Center(CGGM) at Saint-Joseph University of Beirut-Lebanon, from 2006 to 2023. Sanger sequencing was used to detect MEFV variants, focusing initially on hot-spot exons. Among the 3,167 patients, 46.73% (N = 1,480) carried at least one MEFV variant. The most common variants detected were M694V and V726A, both found in 28.98% of cases, followed by E148Q(27.83%) and M694I(13.98%). Moreover, Shiites and Sunni Muslims, and individuals from South and North Lebanon exhibited the highest frequency of variants. Interestingly, family history was found to be significantly higher in patients having two MEFV variants than those with one variant (p = 0.0026). The most commonly reported symptoms were fever(78%), abdominal pain(88%), joint pain(65%), and thoracic pain(46%). The genotype-phenotype correlation analysis revealed a more severe phenotype in patients carrying the M694V or V726A mutations compared to those with the homozygous E148Q genotype. This study, the largest in Lebanon, highlights the high prevalence of MEFV variants, particularly M694V and V726A, in FMF patients. Our data provide valuable insights into the genetic landscape of FMF in Lebanon and emphasize the importance of early genetic screening for a better disease management and genetic counselling.

Genotype-Phenotype Correlation in Progressive External Ophthalmoplegia: Insights From a Retrospective Analysis.

Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated. We analysed the clinical, pathological and genetic characteristics of a large cohort of patients with PEO, based on the type of their mtDNA variations. Eighty-two PEO patients were enrolled and grouped into three categories: mtDNA single large-scale deletions (SLDs), multiple deletions (MulDs) and the m.3243A > G point variant. Patients in the SLD category were further divided into 'common deletion' and 'noncommon deletion' groups based on the presence or absence of a 4977-bp deletion. The mutational load of deleted mtDNA of these patients was comprehensively detected by real-time polymerase chain reaction (RT-PCR). SLD Patients showed the highest proportion of cytochrome C oxidase-negative (COX-n) fibres on muscle biopsy. The mutational load of deleted mtDNA exhibited an inverse relationship with deletion length and a direct relationship with the COX-n fibre ratio. Compared with patients having noncommon deletions, those with common deletions tend to have other muscle involvement, lower body mass index (BMI) scores (17 ± 3 vs. 22 ± 4 kg/m2), higher mutational load in muscle (63% ± 22% vs. 46% ± 24%), more COX-n fibres (26% vs. 9%, interquartile range [IQR]: 15%-32% vs. 6%-26%) and higher growth and differentiation factor 15 (GDF15) levels (2583 vs. 1472, IQR: 1746-4081 vs. 924-2155 pg/mL). MulDs patients displayed milder symptoms, especially compared to patients with m.3243A > G variant, as indicated by their later age of onset (31 vs. 13, IQR: 27-49 vs. 6-29 years), higher BMI scores (24.0 ± 4 vs. 16.5 ± 3.4 kg/m2), lower lactate (1.6 ± 1.1 vs. 6.3 ± 6.0 mmol/L) levels and lower proportion of ragged-blue fibres (RBFs) (3 vs. 16, IQR: 1%-9% vs. 7%-27%). The m.3243A > G variant group exhibits more severe symptoms compared to other subgroups, particularly MulDs patients. In the SLD group, those with common deletions experience more severe clinical and pathological manifestations. These findings enhance our understanding of PEO, facilitating its diagnosis, prognosis and genetic counselling.

Refining the clinical and therapeutic spectrum of granulomatous myositis from a large cohort of patients.

Granulomatous myositis (GM) is a rare entity whose precise clinical features and therapeutic outcomes have not yet been well defined. Given the limited evidence, data from a large cohort of patients is needed to aid in the recognition and management of this condition. We retrospectively analyzed our institutional databases to identify patients who had myositis and non-caseating granuloma on muscle biopsy (GM). We collected data on clinical and diagnostic features, management, and outcomes of these cases and compared them with inclusion body myositis (IBM) controls. 22 GM patients were identified and subdivided into 3 main groups:13 patients with GM and sarcoidosis (6 of whom subsequently developed suspected or confirmed IBM), 7 patients with idiopathic isolated GM (2 of whom subsequently developed confirmed IBM), 2 patients with GM and Crohn's disease. Patients with GM and sarcoidosis without IBM, as well as patients with isolated GM, exhibited variable clinical presentation ranging from myalgia to mostly symmetrical proximo-distal weakness, with most showing complete or at least partial response to therapies. Patients with GM associated with Crohn's disease had only mild clinical impairment and good therapeutic outcomes. Conversely, patients with GM and IBM presented more severe asymmetric proximo-distal muscle weakness, increased occurrence of dysphagia and poor treatment response, similar to IBM controls. A frequent association of GM with IBM and/or sarcoidosis was demonstrated in our cohort. When associated with IBM, GM led to treatment refractoriness and more severe clinical impairment, unlike the other GM groups which showed satisfactory outcomes in most cases.

Unexpected Clinically Relevant Findings Detected via Computed Tomography in Patients with Severe Aortic Stenosis Who Are Candidates for Transcatheter Aortic Valve Replacement.

Background: The detection of unexpected findings (UF) during CT scans of patients undergoing TAVR is frequent; however, it is unclear whether such findings have a clinical impact on the TAVR pathway. Methods: We conducted a retrospective, single-center observational study enrolling patients who were candidates for TAVR. All enrolled patients underwent a CT scan before valve implantation. The primary outcome of this study was all-cause mortality, while the secondary outcome was to determine whether the diagnosis of clinically relevant UF on CT scans results in a significant delay in the TAVR procedure. Results: A total of 284 patients were enrolled. Clinically relevant UF were identified in 15% of the patients, with the most common types being pulmonary masses or nodules. During the follow-up period, 83 patients (29.2%) died. The prognosis was worsened by chronic kidney disease (HR 1.76, p = 0.03) and left ventricular dilatation (HR 1.74, p = 0.04), while the diagnosis of clinically relevant UF did not impact all-cause mortality (p = 0.38). No statistically significant differences were found in the delay from the diagnosis of severe aortic stenosis to TAVR between patients with and without clinically relevant UF (p = 0.07), although patients with clinically relevant UF experienced a median delay of approximately 37 days in the TAVR procedure. Conclusions: The presence of clinically relevant UF on preoperative CT scans does not affect all-cause mortality but shows a trend toward increasing the time from diagnosis to the procedure in patients with severe aortic stenosis undergoing TAVR. Further studies are required to confirm these findings in larger patient cohorts.

Triglyceride-glucose index: carotid intima-media thickness and cardiovascular risk in a European population

BackgroundThe triglyceride-glucose (TyG) index is now widely recognized as a marker of insulin resistance and has been linked to the development and prognosis of atherosclerotic cardiovascular diseases (ASCVD) in numerous populations, particularly in the Eastern world. Although there are fewer reports from the Western world, and they are sometimes contradictory, the absence of definitive data on the relationship between a raised TyG index and cardiovascular risk suggested the opportunity of testing this biochemical marker against a well-established vascular marker such as the carotid intima media thickness (c-IMT).MethodsPrimary prevention patients were selected from a cohort of individuals who underwent c-IMT measurement between 1984 and 2018 at the Dyslipidemia Center at the ASST Grande Ospedale Metropolitano Niguarda in Milan, Italy. The TyG index was calculated as the Ln [fasting TG (mg/dL)×fasting glucose (mg/dL)/2]. Carotid ultrasonography was performed using echographic measurements of the far walls of the left and right common, internal carotids, and bifurcations. Patients were followed for up to 20 years with periodic evaluation of biochemical parameters. ASCVD events were monitored through hospital records, where all patients were regularly examined.ResultsThe analysis included 3108 individuals with a mean age of 54.9 ± 13.1 years. Participants were generally non-obese, with an average BMI of 24.6 ± 3.5 Kg/m2. Among the women, 83.1% were postmenopausal. The mean TyG index was 8.65 ± 0.59. There was a significant association between the TyG index and all c-IMT measurements. Those in the highest TyG index quartiles had significantly higher IMTmean and IMTmax compared to those in the lower quartiles. These associations were consistent across all vascular sites examined and remained significant after adjusting for all potential confounders. Kaplan-Meier survival analysis revealed an increased incidence of ASCVD events in the two highest TyG index quartiles.ConclusionsTyG index is a sensitive marker of risk in a European population with moderate ASCVD risk, as assessed by c-IMT measurements, in a large cohort of Lipid Clinic patients.

Alopecia Areata and Vitamin D3 Deficiency: The Potential of Calcipotriol as a Treatment

Background: Alopecia areata is a non-scarring form of hair loss associated with the loss of the hair follicle immune privilege with a prevalence of 2% in the population. It results in an accumulation of lymphocytes around the lower part of the hair bulb ultimately leading to hair loss. Discussion: Vitamin D3 deficiency is significantly more prevalent in patients with alopecia areata than in healthy populations and correlates with disease severity. Screening patients with alopecia areata for vitamin D3 deficiency could be beneficial, potentially allowing for supplementation. The pathogenic involvement of vitamin D3 in alopecia areata is attributed to its regulatory impact on immune and epidermal cells’ function, particularly through modulation of the JAK/STAT pathway, T lymphocytes proliferation and hair follicle damage. Conclusion: The data on the effectiveness of vitamin D3 supplementation and topical calcipotriol in treating alopecia areata are inconsistent, and the evidence supporting their efficacy is primarily of low quality. This article underscores the need for randomized, placebo-controlled studies with large patient cohorts to evaluate the efficacy of calcipotriol in the treatment of alopecia areata.

Efficacy of alpelisib with rational use of metformin in HR+/HER2- advanced breast cancer patients with PIK3CA mutations (m): retrospective analysis in routine practice of several Russian centers

Background. Hyperglycemia (HG) is an on-target effect of ALP, and prophylactic with metformin was shown to decrease the rate and severity of HG. Here we present efficacy and safety of ALP in a large cohort of patients with rational approach to metformin usage based on risk factors of HG. Material and Methods. Patients (pts) with HR+/HeR2- PIK3CAmut ABC were treated with ALP 300 mg orally and FUL 500 mg IM until disease progression or intolerance. the primary endpoints were progression free survival (PFS) and rate of grade 3/4 HG in different risk groups. Pts were stratified to risk groups of HG based on the algorithm before starting ALP and received MET for prevention of HG. Results. a cohort comprised 139 pts. the median PFs (mPFS) on ALP – was 7.0 (CI 95 %: 5.0–8.9). the risk of HG was assessed in 138 pts: low (47), moderate (46), and high (42) risk, and 3 pts with type 2 diabetes mellitus. any grade HG was reported in 62 % pts, no cases HG G4 were detected. HG G3 was reported in 13 % pts; 10 % pts required ALP dose reduction to 250 mg due to HG G3; 3 pts (2 %) discontinued ALP due to HG. the mPFS in our analysis was longer than in BYlieve trial in cohort C: 7.0 vs 5.6 mo. We suggest that prophylactic of HG allowed maintenance of full dose of ALP in most patients and thus increased the efficacy of ALP. Furthermore, in contrast to the METALLICA trial we distinguished a low risk group (33 %) of pts who do not need the prophylactic use of MET. Conclusion. Rational use of MET in pts with moderate and high risk of HG reduces the frequency and severity of HG, decreases the rate of ALP dose reductions and as a result may increase the efficacy of ALP. Pts with low risk of HG don’t need MET for HG prevention.