Persistent Disease Research Articles

Molecular analysis of persistent and recurrent Barrett's esophagus in the setting of endoscopic therapy.

Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. While effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre- and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (p=0.01), amplifications of oncogenes (p=0.01), and deletions of tumor suppressor genes (p=0.02). These associations were no longer significant after adjusting for patient age and BE length. Over half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre- and post-treatment samples that shared at least 50% of their driver mutations. Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. While it was expected to find shared driver mutations in pre- and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Long-term outcomes of childhood-onset systemic lupus erythematosus.

Data on the long-term outcome of patients with childhood-onset Systemic Lupus Erythematosus (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity. We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, histological and treatment data were collected from medical records during follow-up. A total of 138 patients with cSLE, diagnosed between 1971 and 2015, were included. With a median follow-up of 15.4 [9.6-22.4] years, 51% of patients had a SLICC-Damage Index score ≥ 1 at last follow-up with the musculoskeletal, cutaneous, renal, neurological, and cardiovascular damage being the most common manifestations. The proportion of patients with a SLICC-DI score ≥ 1 increased significantly with the duration of the follow-up (p< 0.001). On multivariate analysis, duration of follow-up was associated with increased risk of cumulative damage (OR 1.08, 95% CI 1.01, 1.15, p= 0.035). At the last visit, 34% of patients still had active disease with a SLEDAI score of ≥ 6. On multivariate analysis, Sub-Saharan African ethnicity was associated with 7-fold increased odds of having active disease at the last visit compared with Caucasians (OR 7.44, 95% CI 2.24, 24.74, p= 0.0002). The prevalence of damage remains high in patients with cSLE even when the diagnosis of c-SLE has been made in the recent decades.

Dual Role of microRNA-146a in Experimental Inflammation in Human Pulmonary Epithelial and Immune Cells and Expression in Inflammatory Lung Diseases

microRNA (miR)-146a emerges as a promising post-transcriptional regulator in various inflammatory diseases with different roles for the two isoforms miR-146a-5p and miR-146a-3p. The present study aimed to examine the dual role of miR-146a-5p and miR-146a 3p in the modulation of inflammation in human pulmonary epithelial and immune cells in vitro as well as their expression in patients with inflammatory lung diseases. Experimental inflammation in human A549, HL60, and THP1 via the NF-kB pathway resulted in the major upregulation of miR-146a-5p and miR-146a-3p expression, which was partly cell-specific. Modulation by transfection with miRNA mimics and inhibitors demonstrated an anti-inflammatory effect of miR-146a-5p and a pro-inflammatory effect of miR-146a-3p, respectively. A mutual interference between miR-146a-5p and miR-146a-3p was observed, with miR-146a-5p exerting a predominant influence. In vivo NGS analyses revealed an upregulation of miR-146a-3p in the blood of patients with cystic fibrosis and bronchiolitis obliterans, while miR-146a-5p levels were downregulated or unchanged compared to controls. The reverse pattern was observed in patients with SARS-CoV-2 infection. In conclusion, miR-146a-5p and miR-146a-3p are two distinct but interconnected miRNA isoforms with opposing functions in inflammation regulation. Understanding their interaction provides important insights into the progression and persistence of inflammatory lung diseases and might provide potential therapeutic options.

Comparison of 8th and 7th editions of TNM staging in terms of mortality, persistent disease, and response to treatment in patients with differentiated thyroid cancer.

To compare the eighth and seventh editions of TNM staging (TNM-8 and TNM-7) on disease-related mortality, persistent disease, and response to treatment in patients with differentiated thyroid cancer (DTC). We studied 400 patients (79% female) with DTC with a mean age of 40.93±14.11 years. TNM staging was recorded according to the 7th and 8th editions and patients were followed for at least 1 year and response to therapy was recorded according to ATA response categorization. The mean follow up time was 42.5±15.24 months. Overall, 108 patients (27%) were down-staged using the TNM-8, mainly due to the changes in the age cut-off (14.5%), N (9.25%), and T categorization (3.25%). All patients in stage III and 82.8% in stage IV were down-staged. The mean Tg levels were significantly higher in stages III and IV in TNM-8 compared to TNM-7. Four disease-related death were recorded during follow up, all in stage IV according to TNM-7, while one was in stage II according to TNM-8. One year after treatment, persistent disease was detected in 12% and 77% of patients in stage III according to the 7th and 8th editions, respectively (P= 0.04). Similarly, biochemical incomplete response one year after treatment was seen in 7.3% and 87% in stage III disease using 7th and 8th editions (P = 0.006) that fell to 2.4% and 22% in the last visit respectively (P = 0.04). Persistent disease and incomplete response to therapy were more common in stages III and IV in TNM-8 compared to TNM-7. The eighth edition was a better predictor of persistent disease in stages III and IV disease.

Persistent albuminuria and chronic kidney disease in adults with sickle cell anaemia: Results from a multicenter natural history study.

Clinical and laboratory correlates of chronic kidney disease (CKD) in sickle cell anaemia remain incompletely defined. In a multicenter cohort study, we evaluated the prevalence of persistent albuminuria (PA) and characteristics associated with PA, albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) using logistic, linear and multinomial regression models, respectively. Of 269 participants (median age: 30 years; 57.2% females), the prevalence of PA was 35.7%. Using baseline ACR values of <100 and ≥100 mg/g, the probabilities of PA were 30.0% and 94.6%, respectively. In multivariable logistic regression analyses, male sex (β = 0.80 [SE = 0.36], p = 0.024) and ACE inhibitors/ARBs use (β = 1.54 [SE = 0.43], p < 0.001) were associated with higher likelihoods of PA, while higher haemoglobin (β = -0.33 [SE = 0.13], p = 0.009) and HbF (β = -0.04 [SE = 0.02], p = 0.041) were associated with lower likelihoods of PA. In multivariable multinomial regression analyses, older age (β = 0.06 [SE = 0.02], p = 0.004) and higher alkaline phosphatase (β = 0.01 [SE = 0.00], p = 0.004) were associated with higher odds of having eGFR 60-90 versus eGFR>90 mL/min/1.73 m2 using the cystatin C-based CKD-EPI-2012 equation. Additionally, higher systolic blood pressure (β = 0.11 [SE = 0.03], p = 0.001) and blood urea nitrogen (β = 0.45 [SE = 0.12], p < 0.001) were associated with higher odds, while higher haemoglobin (β = -1.22 [SE = 0.43], p = 0.004) was associated with lower odds of having eGFR<60 versus eGFR>90 mL/min/1.73 m2. PA and decreased eGFR are associated with measures of disease severity and comorbid conditions (Clinicaltrials.gov Identifier: NCT03277547).

Serum phosphate levels at diagnosis predict long-term risk for hypopituitarism in patients with acromegaly.

Excess growth hormone (GH) secretion in acromegaly has a major impact on mineral balance and serum phosphate levels. However, the clinical utilization of serum phosphate levels as a marker for long-term disease outcomes in acromegaly has not been evaluated. This is a retrospective study of patients with acromegaly who were followed in a tertiary center. Data were retrieved on patient characteristics, endocrine and biochemical evaluation, and tumor parameters. Comparisons were performed by measuring baseline phosphate levels and conductingcorrelation analysis and multivariable logistic regression. Sixty-one patients were followed for 4.5years (range 1-21). Patients with hyperphosphatemia (> 4.5mg/dl) at baseline had larger adenomas (15.0mm [8.0, 47.0] vs. 10.0mm [3.0, 24.0], p = 0.001), a rate chance of invasive adenoma (16 [80.0%] vs. 14 [46.7%], p = 0.02), and lower serum cortisol levels (226.0nmol/l [27.6, 516.0] vs. 294.0nmol/l [32.0, 610.0], p = 0.02). Baseline serum phosphate levels positively correlated with IGF-1 levels (r = 0.43, p = 0.003) and negatively correlated with morning plasma cortisol levels (r = -0.46, p = 0.002). Regarding long-term impact, baseline phosphate levels correlated with the number of pituitary axes involved 6months after diagnosis (r-0.34, p = 0.01). In multivariable analysis, baseline plasma phosphate levels were independently associated with risk for disease progression/recurrence (odds ratio [OR] 9.66, 95% confidence interval [CI] 1.5, 105.9, p = 0.03) and for invasive adenoma (OR 6.21, 95% CI 1.6, 28.7, p = 0.01). Elevated pretreatment serum phosphate levels are associated with a greater risk of disease persistence and recurrence and with altered pituitary function in patients with acromegaly.

Dysregulated proteasome activity and steroid hormone biosynthesis are associated with mortality among patients with acute COVID-19

The persistence of coronavirus disease 2019 (COVID-19)-related hospitalization severely threatens medical systems worldwide and has increased the need for reliable detection of acute status and prediction of mortality. We applied a systems biology approach to discover acute-stage biomarkers that could predict mortality. A total 247 plasma samples were collected from 103 COVID-19 (52 surviving COVID-19 patients and 51 COVID-19 patients with mortality), 51 patients with other infectious diseases (IDCs) and 41 healthy controls (HCs). Paired plasma samples were obtained from survival COVID-19 patients within 1 day after hospital admission and 1–3 days before discharge. There were clear differences between COVID-19 patients and controls, as well as substantial differences between the acute and recovery phases of COVID-19. Samples from patients in the acute phase showed suppressed immunity and decreased steroid hormone biosynthesis, as well as elevated inflammation and proteasome activation. These findings were validated by enzyme-linked immunosorbent assays and metabolomic analyses in a larger cohort. Moreover, excessive proteasome activity was a prominent signature in the acute phase among patients with mortality, indicating that it may be a key cause of poor prognosis. Based on these features, we constructed a machine learning panel, including four proteins [C-reactive protein (CRP), proteasome subunit alpha type (PSMA)1, PSMA7, and proteasome subunit beta type (PSMB)1)] and one metabolite (urocortisone), to predict mortality among COVID-19 patients (area under the receiver operating characteristic curve: 0.976) on the first day of hospitalization. Our systematic analysis provides a novel method for the early prediction of mortality in hospitalized COVID-19 patients.

P-291 In women with endometriosis, effective treatment of chronic endometritis with antibiotics lowers serum CA-125 levels

Abstract Study question To evaluate the effect of chronic endometritis treatment on serum CA-125 levels in women with endometriosis. Summary answer Cure of chronic endometritis leads to a reduction in serum Ca-125 levels in women with endometriosis. What is known already Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is hypothesized that the disease exerts direct inflammatory effects on the ovaries, fallopian tubes, and the eutopic endometrium. In endometriosis, CA-125 levels are often elevated. Literature reports a frequent coexistence of endometriosis and chronic endometritis (CE) in women undergoing hysterectomy for benign indications. CE, characterized by macroscopic and histological alterations of the endometrium, was present in 38.5%-42.3% of women with endometriosis, compared to lower prevalence rates in controls infertile patients without endometriosis, supporting a potential etiopathogenic link between endometriosis and CE. Study design, size, duration This retrospective case-control study was conducted at the Department of Obstetrics and Gynecology, University of Bari. The study included 51 patients suffering of both ovarian endometriosis and CE. The primary objective was to investigate whether CE cure modifies serum CA-125 levels among women with ovarian endometriosis. The secondary objective was to assess any modifications in the size of endometriotic cysts following the cure of CE. Recruitment period was from September 2021 to February 2023. Participants/materials, setting, methods All patients received antibiotic therapy (100 mg of doxycycline, twice daily for ten days) and, the following month, hysteroscopy with control biopsy. Of these, 36 women were cured of chronic endometritis (Group A), while 15 women showed persistent disease (Group B). Endometriosis was diagnosed by transvaginal ultrasound and chronic endometritis through hysteroscopy, histology, and immunohistochemistry for CD138. Serum CA-125 levels were measured before antibiotic therapy and approximately 3 months later. Main results and the role of chance The primary outcome was to compare the change in CA-125 values between women cured of chronic endometritis and women with persistent disease. There were no statistically significant differences in baseline characteristics between the groups (p=ns). The majority of patients in both groups had a single ovarian endometrioma and the micropolypoid endometrial appearance was the predominant finding of chronic endometritis observed during hysteroscopy in both Groups. In Group A, the mean CA-125 value significantly decreased after antibiotic therapy from 58.56 U/mL (± 32.45) to 38.25 U/mL (± 17.31) (p &amp;lt; 0.001). No significant changes in CA-125 values were observed in Group B before and after antibiotic therapy (69.70 ± 27.42 versus 67.47 ± 24.52 U/mL, p=ns). The absolute change in CA-125 values was significantly greater in terms of reduction in Group A compared to Group B (-20.31 ± 27.09 versus -2.13 ± 12.51 U/mL; p = 0.02). Adjustment for confounders in a multivariable regression model revealed that the cure of chronic endometritis was independently associated with a significant decrease in absolute serum CA-125 levels (p = 0.006). Cyst size did not significantly change after antibiotic therapy in both groups (p=ns). Limitations, reasons for caution The main weakness of our study is that CA-125 was only measured once before and once after treatment of CE with a course of antibiotics. Moreover, our study does not allow for inferences regarding the impact of the observed reduction in serum CA-125 on the subjective symptoms related to endometriosis. Wider implications of the findings Our study constitutes the first demonstration that effective treatment of CE results in a significant decrease in a non-invasive marker of endometriosis, CA-125 supporting the emerging concept that the endometriosis might have an infectious origin. Trial registration number not applicable

The Learning Curve for Robotic Lateral Pelvic Lymph Node Dissection for Rectal Cancer: A View from the West.

Lateral pelvic lymph-node dissection is performed for selected patients with rectal cancer with persistent lateral nodal disease after neoadjuvant therapy. This technique has been slow to be adopted in the West due to concerns regarding technical difficulty. This is the first report on the learning curve for lateral pelvic lymph node dissection in the US or Europe. The aim of this study was to analyze the learning curve associated with robotic lateral pelvic lymph node dissection. Retrospective observational cohort. Tertiary academic cancer center. Consecutive patients from 2012 to 2021. All patients underwent robotic lateral pelvic lymph node dissection. The primary endpoints were the learning curves for maximum number of nodes retrieved and urinary retention which was evaluated with simple cumulative-sum and two-sided Bernoulli cumulative-sum charts. Fifty-four procedures were included. A single-surgeon (n = 35) and an institutional learning curve are presented in the analysis. In the single-surgeon learning curve, a turning point marking the end of a learning phase was detected at the 12th procedure for the number of retrieved nodes and at the 20th for urinary retention. In the institutional learning curve analysis, two turning points were identified at the 13th and 26th procedures indicating progressive improvements for the number of retrieved nodes and at the 27th for urinary retention. No sustained alarm signals were detected at any time point. The retrospective nature, small sample size and the referral center nature of the reporting institution that may limit generalizability. In a setting of institutional experience with robotic colorectal surgery including beyond TME resections, the learning curve for robotic lateral pelvic lymph node dissection is acceptably short. Our results demonstrate feasibility of acquisition of this technique in a controlled setting, with sufficient case volume and proctoring can optimize the learning curve. See Video Abstract.

Exploration of the Shared Gene Signatures and Molecular Mechanisms between Chronic Bronchitis and Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis: Evidence from Transcriptome Data

Background: Chronic Bronchitis (CB) is a recurrent and persistent pulmonary inflammation disease. Growing evidence suggests an association between CB and Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis (ANCA-GN). However, the precise mechanisms underlying their association remain unclear. Aims: The purpose of this study was to further explore the molecular mechanism of the occurrence of chronic bronchitis (CB) associated with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA- GN). Objective: Our study aimed to investigate the potential shared pathogenesis of CB-associated ANCA-GN. Methods: Datasets of ANCA (GSE108113 and GSE104948) and CB (GSE151052 and GSE162635) were obtained from the Gene Expression Omnibus (GEO) datasets. Firstly, GSE108113 and GSE151052 were analyzed to identify common differentially expressed genes (DEGs) by Limma package. Based on common DEGs, protein-protein interaction (PPI) network and functional enrichment analyses, including GO, KEGG, and GSEA, were performed. Then, hub genes were identified by degree algorithm and validated in GSE104948 and GSE162635. Further PPI network and functional enrichment analyses were performed on hub genes. Additionally, a competitive ceRNA network was constructed through miRanda and spongeScan. Transcription factors (TFs) were predicted and verified using the TRRUST database. Furthermore, the CIBERSORT algorithm was employed to explore immune cell infiltration. The Drug Gene Interaction Database (DGIDB) was utilized to predict small-molecular compounds of CB and ANCA-GN. Result: A total of 963 DEGs were identified in the integrated CB dataset, and 610 DEGs were identified in the integrated ANCA-GN dataset. Totally, we identified 22 common DEGs, of which 10 hub genes (LYZ, IRF1, PIK3CG, IL2RG, NT5E, ARG2, HBEGF, NFATC2, ALPL, and FKBP5) were primarily involved in inflammation and immune responses. Focusing on hub genes, we constructed a ceRNA network composed of 323 miRNAs and 348 lncRNAs. Additionally, five TFs (SP1, RELA, NFKB1, HIF1A, and SP3) were identified to regulate the hub genes. Furthermore, immune cell infiltration results revealed immunoregulation in CB and ANCA-GN. Finally, some small-molecular compounds (Daclizumab, Aldesleukin, and NT5E) were predicted to predominantly regulate inflammation and immunity, especially IL-2. Conclusion: Our study explores the inflammatory-immune pathways underlying CB-associated ANCA-GN and emphasizes the importance of NETs and lymphocyte differentiation, providing novel insights into the shared pathogenesis and therapeutic targets.

INCIDENTALLY VS. NON-INCIDENTALLY DIAGNOSED PAPILLARY THYROID CARCINOMA: ARE THERE DIFFERENCES?

Compare incidental vs. non-incidental TC (ITC vs. NITC) regarding demographic, clinical, histological data and 5-year clinical outcomes. Retrospective analysis of 225 papillary TC (PTC) cases that completed a 5-year follow-up. Created 2 groups: ITC (including the incidentalomas) and NITC (cases of palpable or visible nodules or with thyroid compressive complaints). Included 225 PTC (122 were ITC). There were 95 women in ITC and 78 in NITC. ITC patients were significantly older (53.3±14.8 vs 47.2±17.7, p=0.006). Groups had no differences in family history of TC. ITC mean tumour size was smaller (19.1±9.2 vs 28.6±16.2, p<0.01). Tumours >20mm comprised 36.1% of ITC and 58.2% of NITC. We found no differences in tumour multifocality, histological thyroiditis, aggressive PTC subtypes, capsule or lymph-vascular invasion and gross extrathyroidal extension. There were no differences regarding the number of patients submitted to RAI or in RAI activity. pTMN staging showed higher prevalence of T3a and T4 cases (p<0.01), and M1 status (p=0.025) in NITC. There were no differences in the rates of persistence of disease. Logistic regression showed that the diagnostic modality had no impact on the 5-year clinical outcome. ITC patients were older and had smaller tumours. NITC showed no worst histological features or 5-year clinical outcome. Approximately, one third of ITC had diameters >20mm. As even large tumours can be ITC, overdiagnosis can be the most likely cause for the TC increasing incidence.

Dupilumab Safety and Efficacy up to 1 Year in Children Aged 6 Months to 5 Years with Atopic Dermatitis: Results from a Phase 3 Open-Label Extension Study.

Pediatric patients with moderate-to-severe atopic dermatitis (AD) often experience a high disease burden and have a high risk of persistent disease. Standard-of-care immunosuppressive systemic treatments have been used off-label for AD in pediatric patients despite concerns for suboptimal safety with continuous use and risk of relapse upon discontinuation. The biologic agent dupilumab is the first systemic treatment approved for moderate-to-severe AD in children as young as 6 months. Long-term safety and efficacy data in this patient population are needed to inform continuous AD management. The purpose of this work was to determine the long-term safety and efficacy of dupilumab treatment up to 1 year in an open-label extension (OLE) study [LIBERTY AD PED-OLE (NCT02612454)] in children aged 6 months to 5 years with moderate-to-severe AD who previously participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434 part B; parent study) and were subsequently enrolled in PED-OLE. In PED-OLE, patients received dupilumab every 4 weeks according to a weight-tiered regimen (body weight ≥ 5 kg to < 15 kg: 200 mg; ≥ 15 kg to < 30 kg: 300 mg). Data for 142 patients were analyzed, 60 of whom had completed the 52-week visit at time of database lock. Mean age at baseline was 4.1 y [SD, 1.13; range, 1.0-5.9 years]. A majority (78.2%) of patients reported ≥ 1 treatment-emergent adverse event (TEAE), most of which were mild or moderate and transient. The most frequently reported TEAEs were nasopharyngitis (19.7%), cough (15.5%), and pyrexia (14.1%). One TEAE led to treatment discontinuation (severe urticaria, which resolved in 1 day). By week 52, 36.2% of patients had achieved an Investigator's Global Assessment score of 0/1 (clear/almost clear skin), and 96.6%, 79.3%, and 58.6% had at least 50%, 75%, or 90% improvement, respectively, in Eczema Area and Severity Index scores. Consistent with results seen in adults, adolescents, and older children (aged 6-11 years), treatment with dupilumab for up to 1 year in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD demonstrated an acceptable long-term safety profile and sustained efficacy. These results support the long-term continuous use of dupilumab in this patient population. ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B).

A mean field analysis of the role of indirect transmission in emergent infection events

We developed a mathematical model to investigate the role of indirect transmission in the spread of infectious diseases, using the illustrative example of sarcoptic mange as a case study. This disease can be transmitted through direct contact between an infected host and a susceptible one, or indirectly when potential hosts encounter infectious mites and larvae deposited in the environment, commonly referred to as fomites. Our focus is on exploring the potential of these infectious reservoirs as triggers for emerging infection events and as stable reservoirs of the disease. To achieve this, our mean field compartmental model incorporates the epidemiological dynamics driven by indirect transmission via fomites. We identify different types of dynamics that the system can go into, controlled by different levels of direct and indirect transmission. Among these, we find a new regime where the disease can emerge and persist over time solely through fomites, without the necessity for direct transmission. This possibility of the system reveals an evolutionary pathway that could enable the parasite to enhance its fitness beyond host co-evolution. We also define a new threshold based on an effective reproductive number, that enables us to predict the conditions for disease persistence. Our model allows us to assess the potential effectiveness of various disease intervention measures by incorporating a feature observed in real systems. We hope this contributes to a better understanding of infectious disease outbreaks.

Longterm-outcomes in patients with Cushing’s disease vs. non-functioning pituitary adenoma after pituitary surgery: An active-comparator cohort study

Abstract Objective There is increasing evidence that multisystem morbidity in patients with Cushing's disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with non-functioning pituitary adenoma (NFPA) after pituitary surgery. Design Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021. Methods Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (i.e., myocardial infarction, unstable angina, heart failure, cardiac arrest, ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence. Results After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. CD presence was associated with a higher incidence rate of the primary endpoint (40.6 vs. 15.7 events per 1,000 person-years, HR 2.75; 95% CI, 1.54 to 4.90). CD patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59 to 6.71) and a trend for sepsis (HR 3.15; 95% CI, 0.95 to 10.40). Conclusions Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis.

A mean field analysis of the role of indirect transmission in emergent infection events

We developed a mathematical model to investigate the role of indirect transmission in the spread of infectious diseases, using the illustrative example of sarcoptic mange as a case study. This disease can be transmitted through direct contact between an infected host and a susceptible one, or indirectly when potential hosts encounter infectious mites and larvae deposited in the environment, commonly referred to as fomites. Our focus is on exploring the potential of these infectious reservoirs as triggers for emerging infection events and as stable reservoirs of the disease. To achieve this, our mean field compartmental model incorporates the epidemiological dynamics driven by indirect transmission via fomites. We identify different types of dynamics that the system can go into, controlled by different levels of direct and indirect transmission. Among these, we find a new regime where the disease can emerge and persist over time solely through fomites, without the necessity for direct transmission. This possibility of the system reveals an evolutionary pathway that could enable the parasite to enhance its fitness beyond host co-evolution. We also define a new threshold based on an effective reproductive number, that enables us to predict the conditions for disease persistence. Our model allows us to assess the potential effectiveness of various disease intervention measures by incorporating a feature observed in real systems. We hope this contributes to a better understanding of infectious disease outbreaks.

First Trimester Hemorrhage Revealing A Partial Molar Pregnancy: About A Case

Partial molar pregnancy is a triploid conception with a chromosomal lot of paternal origin. Progression to persistent trophoblastic disease, invasive mole or choriocarcinoma remains exceptional. We report the case of a 45-year-old woman who presented with heavy bleeding of genital origin and a partial molar pregnancy on ultrasound with no visible embryonic structure. Careful ultrasound-guided aspiration was performed under antibiotic and uterotonic cover, and the aspirate was sent for histological examination. The patient underwent monthly b-hCG monitoring for 6 months, with a final negativation.

Effective and Successful Quantification of Leukemia-Specific Immune Cells in AML Patients' Blood or Culture, Focusing on Intracellular Cytokine and Degranulation Assays.

Novel (immune) therapies are needed to stabilize remissions or the disease in AML. Leukemia derived dendritic cells (DCleu) can be generated ex vivo from AML patients' blasts in whole blood using approved drugs (GM-CSF and PGE-1 (Kit M)). After T cell enriched, mixed lymphocyte culture (MLC) with Kit M pretreated (vs. untreated WB), anti-leukemically directed immune cells of the adaptive and innate immune systems were already shown to be significantly increased. We evaluated (1) the use of leukemia-specific assays [intracellular cytokine production of INFy, TNFa (INCYT), and degranulation detected by CD107a (DEG)] for a detailed quantification of leukemia-specific cells and (2), in addition, the correlation with functional cytotoxicity and patients' clinical data in Kit M-treated vs. not pretreated settings. We collected whole blood (WB) samples from 26 AML patients at first diagnosis, during persisting disease, or at relapse after allogeneic stem cell transplantation (SCT), and from 18 healthy volunteers. WB samples were treated with or without Kit M to generate DC/DCleu. After MLC with Kit M-treated vs. untreated WB antigen-specific/anti-leukemic effects were assessed through INCYT, DEG, and a cytotoxicity fluorolysis assay. The quantification of cell subtypes was performed via flow cytometry. Our study showed: (1) low frequencies of leukemia-specific cells (subtypes) detectable in AML patients' blood. (2) Significantly higher frequencies of (mature) DCleu generable without induction of blast proliferation in Kit M-treated vs. untreated samples. (3) Significant increase in frequencies of immunoreactive cells (e.g., non-naive T cells, Tprol) as well as in INCYT/DEG ASSAYS leukemia-specific adaptive-(e.g., B, T(memory)) or innate immune cells (e.g., NK, CIK) after MLC with Kit M-treated vs. untreated WB. The results of the intracellular production of INFy and TNFa were comparable. The cytotoxicity fluorolysis assay revealed significantly enhanced blast lysis in Kit M-treated vs. untreated WB. Significant correlations could be shown between induced leukemia-specific cells from several lines and improved blast lysis. We successfully detected and quantified immunoreactive cells at a single-cell level using the functional assays (DEG, INCYT, and CTX). We could quantify leukemia-specific subtypes in uncultured WB as well as after MLC and evaluate the impact of Kit M pretreated (DC/DCleu-containing) WB on the provision of leukemia-specific immune cells. Kit M pretreatment (vs. no pretreatment) was shown to significantly increase leukemia-specific IFNy and TNFa producing, degranulating cells and to improve blast-cytotoxicity after MLC. In vivo treatment of AML patients with Kit M may lead to anti-leukemic effects and contribute to stabilizing the disease or remissions. INCYT and DEG assays qualify to quantify potentially leukemia-specific cells on a single cell level and to predict the clinical course of patients under treatment.

Liquid chromatography-tandem mass spectrometry for determination of fingolimod and its active metabolite fingolimod phosphate in whole blood of patients with multiple sclerosis.

Fingolimod is an oral drug for the escalation of treatment of relapsing-remitting multiple sclerosis in patients with persistent disease activity on first-line drugs or in patients with rapidly progressive severe relapsing-remitting multiple sclerosis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method for determining the concentrations of fingolimod and its active metabolite fingolimod phosphate in whole blood has been developed and validated. The advantages of this method are the easy, fast and cheap sample preparation using protein precipitation from blood with a mixture of acetonitrile-methanol (40:60, v/v). Chromatographic separation was performed on a ultra-high performance liquid chromatography BEH C18 1.7 μm (100 × 2.1mm) column. Two modes of ionization, electrospray ionization and atmospheric pressure chemical ionization, were tested and compared. For validation, the electrospray ionization mode was chosen. As internal standard, isotopically labeled fingolimod-D4 was used to quantify the analytes. The method was validated according to the rules of the European Medicines Agency. The coefficients of variation for fingolimod were in the range of 1.13-11.88%, and the recovery was 98.80-106.00%. The coefficients of variation for fingolimod phosphate were in the range of 2.73-9.31%, and the recovery was 90.08-107.00%. The method is quite easy and fast and can be used for routine analysis.

Global research trends in precision-targeted therapies for systemic lupus erythematosus (2003–2023): A bibliographic study

BackgroundSystemic lupus erythematosus (SLE) is a persistent inflammatory disease caused by an autoimmune response that predominantly affects multiple organs and systems. Growing evidence highlights the critical role of precision-targeted therapies in the management of SLE. Surprisingly, only a handful of bibliometric studies have thoroughly assessed this area. This study attempts to assess the global landscape of literature output and research trends related to precision-targeted therapy for SLE. MethodPublications related to precision-targeted therapy for SLE from 2003 to 2023 were searched in the Web of Science Core Collection (WoSCC) database. VOSviewers, CiteSpace and the R package “bibliometrix” were used to perform this bibliometric analysis. ResultsA total of 3700 papers were retrieved, showing a steady annual increase in publications from 2003 to 2022. The United States led the field with the highest number of papers (36.1 %) and secured the top position in terms of citation frequency (59,889) and H-index (115). Anhui Medical University System claimed the top spot with an impressive output of 70 papers. Principal investigators Tsokos, George C. C., and Lu, Qianjin led the research effort. Among the journals, Frontiers in Immunology stood out, publishing the highest number of articles with 191. In particular, precision-targeted therapy for SLE has become a major research focus in recent years, covering aspects such as T cells, B cells, oxidative stress, remission, and PHASE-III. ConclusionThis bibliometric study of ours systematically analyses research trends in precision targeted therapy for systemic lupus erythematosus, and this information identifies the research frontiers and hot directions in recent years and will serve as a reference for scientists working on targeted therapies.

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.