The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Ostracism Predicting Suicidal Behavior and Risk of Relapse in Substance Use Disorders.

INTRODUCTION: The present study investigated the predictive relationship between ostracism and suicidal behaviors in individuals with substance use disorders. It also attempts to highlight the mediating role of the risk of relapse between ostracism and suicidal behavior. METHODS: The study was based on a cross-sectional survey design. The sample comprised 100 men aged between 30 to 45 years (M = 35.25, SD = 3.06) from Karachi. The purposive sampling technique was employed. The study employed demographic forms and three self-reporting measures: the Ostracism Experience Scale (OES-A), the Advance Warning of Relapse Questionnaire 3.0 (AWARE), and the Suicide Behaviors Questionnaire-Revised (SBQ-R). RESULTS: Ostracism significantly predicted relapse risk and suicidal behavior. Risk of relapse positively predicted both dimensions of ostracism (ignored: r = 0.33, p < 0.01; excluded: r = 0.43, p < 0.01) and suicidal behavior (r = 0.35, p < 0.01). Additionally, the risk of relapse strongly correlated with overall ostracism score (r = 0.43, p < 0.01). However, no significant mediating effect of ostracism on suicidal behavior was found. The effect was mediated through the risk of relapse (B indirect = 0.12, 95% CI = 0.04, 0.23). These findings suggest that ostracism increases the likelihood of recurrence, which in turn is associated with suicidal behavior. The mediation model explained 17% of the variation in suicidal behavior. CONCLUSION: The findings propose the importance of addressing ostracism as a risk factor for suicidal behavior and relapse in substance use disorders. The results suggest that reducing the adverse effects of ostracism and improving social support for individuals can have a significant impact on their mental health.

Patterns of disease-modifying therapy utilization before, during, and after pregnancy and postpartum relapses in women with multiple sclerosis.

BACKGROUND: Pregnancy is a common consideration for people with multiple sclerosis (pwMS); MS onset is typically between 20 and 45 years of age, during potential child-bearing years. Pregnancy and postpartum care are a significant factor influencing disease-modifying therapy (DMT) selection for many pwMS. To date, few DMTs are considered safe to continue during pregnancy and real-world treatment patterns before, during, and after pregnancy remain uncharacterized. Evolving guidance is needed regarding how to optimize management of the pregnancy and postpartum periods considering the changing DMT landscape. This analysis in two large claims databases describes DMT utilization for the treatment of MS before, during, and after pregnancy and relapse patterns during pregnancy and postpartum. METHODS: In this retrospective, observational study, the US MarketScan Commercial and Medicaid claims database was assessed for female patients aged 18-55 years with ≥1 insurance claim submitted under the diagnosis code of MS from 01 January 2016-30 April 2021 and continuous enrollment eligibility from ≥6 months prior to pregnancy date (preconception) through 6 months of follow-up following delivery (postpartum period). Comorbid conditions were examined preconception and postpartum, including anxiety and depression. Moderate/severe relapse was defined as MS-related hospitalization, or an outpatient visit and one claim within 7 days of the visit with steroids or total plasma exchange. RESULTS: A total of 944 patients (mean [standard deviation] age, 32.4 [5.0] years) were eligible; 688 (73%) were commercially insured and 256 (27%) received Medicaid. Compared with commercially-insured patients, use of DMTs was lower among Medicaid patients at 6 months preconception (25.4% vs 40.4%; p < 0.001), with similar patterns observed both during pregnancy and postpartum. Overall, prevalence of DMT use declined sharply during pregnancy, from 36.3% of patients in the 6 months preconception to 17.9%, 5.3%, and 5.8% in trimesters 1, 2 and 3, respectively. Postpartum DMT utilization increased to 20.9% at 0-3 months and 24.4% at 4-6 months. Of all patients in the preconception period, the most frequently used DMTs were glatiramer acetate (14.3%), dimethyl fumarate (6.0%), interferon (5.2%), and natalizumab (4.9%). Due to small sample size, information was limited for anti-CD20s and alemtuzumab. The proportion of patients with any moderate/severe relapse declined over pregnancy (preconception, n = 82 [8.7%]; pregnancy, n = 25 [2.6%]), but increased postpartum (n = 94 [10.0%]). Of the 889 patients who stopped DMT during pregnancy, the risk of postpartum relapses was lower in the patients who resumed DMT postpartum (10/192) than in patients who did not (76/697) (5.2% vs 10.9%; odds ratio, 0.455 [95% confidence interval 0.216-0.860], p = 0.018). Cases of postpartum depression and anxiety were significantly lower in commercially-insured patients vs Medicaid patients (postpartum depression, 13.7% vs 27.0%, p < 0.01; postpartum anxiety, 16.3% vs 30.5%, p < 0.01). CONCLUSION: DMT utilization declined sharply during pregnancy; it gradually increased postpartum but remained below pre-pregnancy use. The proportion of pwMS experiencing a moderate/severe relapse and number of relapses declined over pregnancy but increased postpartum. Reinitiation of DMT during the postpartum period was associated with lower risk of relapses, supporting a role for early reinitiation of DMT postpartum. STUDY SUPPORTED BY: Biogen.

PRIORITI: Phase 4 study of triptorelin or active surveillance in high-risk prostate cancer.

AIM: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes. METHODS: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed. RESULTS: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile. CONCLUSION: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant.

Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Methods: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

A Descriptive Review and Meta-Regression Study of Demographic and Study Context Factors in US Clinical Trials of Cognitive Behavioral Interventions for Alcohol or Other Drug Use.

Objectives. Cognitive-Behaviorally Based Interventions (CBIs) are evidence-based treatments for alcohol and other drug (AOD) use with potential variable effectiveness by population sub-groups. This study used evidence synthesis to examine treatment effect by demographic and study context factors in clinical trials of CBI for AOD. Methods. Studies were systematically identified, and their characteristics and outcome data were extracted and summarized. Standardized mean differences were calculated for within- and between-condition effects on substance use outcomes. Demographic and study context moderators were identified during data acquisition and several sensitivity analyses were conducted. Results. The sample included K = 29 trials and a total of 15 study-level moderators were examined. Information on participants' age, biological sex, and race were reported in at least 26 trials, but information on gender identity, sexual orientation, and ethnicity were reported infrequently or in non-inclusive ways. The mean between-condition effect size was small and moderately heterogenous (d = 0.158, 95% CI = 0.079, 0.238, I2 = 46%) and the mean within-condition effect size was large and showed high heterogeneity (dz = 1.147, 95% CI = 0.811, 1.482, - I2 = 96%). The specific drug targeted in the study and whether biological assay-based outcomes were used moderated between-condition CBI efficacy and the inclusion of co-occurring mental health conditions and study publication date moderated within-condition CBI effects. Conclusions. Results provide preliminary data on study context factors associated with effect estimates in United States based clinical trials of CBI for AOD.

Management strategy for children with ovarian immature teratoma: results from a tertiary pediatric oncology center.

OBJECTIVES: We present an Egyptian study on pediatric ovarian immature teratomas (ITs), aiming to clarify our treatment strategy selection. METHODS: A retrospective review of all children with pure ovarian ITs who were treated at our institution between 2008 and 2023. The analysis included clinical characteristics, tumor staging according to Children's Oncology Group (COG), grading based on the Norris system, management, and outcomes. RESULTS: Thirty-two patients were included, with a median age of 9 years. All patients underwent primary surgery. Unilateral salpingo-oophorectomy was performed in 31 patients. Surgical staging was completed in all patients. Based on COG staging, there were 28 patients (87.5%) stage I, 1 (3%) stage II, and 3 (9.5%) stage III. According to Norris classification, 16 patients (50%) were classified as grade I, 9 (28%) grade II, and 7 (22%) grade III. All patients in stage I were treated using surgery-alone approach, whereas the remaining four (12.5%) received adjuvant chemotherapy. Five patients in stage I had gliomatosis peritonei (GP), and none of them underwent extensive surgery. At a median follow-up of 86 months, two patients had events. The first patient (stage III/grade I) developed IT relapse on the operative bed, and the second (stage I/grade I) had a metachronous IT on the contralateral ovary. Both patients were successfully managed with surgery followed by second-line chemotherapy. Five-year overall survival and event-free survival for all patients were 100% and 93.4%, respectively. CONCLUSIONS: Surgery-alone strategy with close follow-up achieves excellent outcomes for localized ovarian ITs in children, irrespective of the Norris grading or the presence of GP. However, adjuvant chemotherapy is questionable for patients with incompletely resected or locally advanced tumors, and its role requires further evaluation through prospective multicentric studies with a larger sample size.

First-line immunosuppressive therapies for acquired hemophilia A: A 25-year cohort experience and network meta-analysis.

Acquired hemophilia A (AHA) presents a significant bleeding risk. Management involves bleeding control and immunosuppressive therapy (IST) to eliminate inhibitors. This study, encompassing a retrospective cohort of 76 newly diagnosed AHA patients (1997-2022), evaluated IST outcomes such as complete remission (CR), relapse, and mortality rates, alongside influencing factors. Supplementing these findings, a systematic review and network meta-analysis compared CR and relapse rates across ISTs, sourcing from Embase, Scopus, and ScienceDirect up to November 2023. In our cohort, demarcated by a 20 Bethesda-unit titer threshold, cyclophosphamide plus prednisolone (CP; n = 64) was the predominant initial IST. Lower inhibitor levels significantly correlated with higher CR rates (86.8 % vs 62.2 %; P = .014) and showed an odds ratio of 0.26 for CR (P = .021). Median relapse-free survival (RFS) extended to 37.13 months, significantly enhanced by CP (hazard ratio, 0.24; 95 % confidence interval, 0.10-0.60; P = .002). Our network meta-analysis, including 1476 CR and 636 relapse patients, indicated CP and rituximab-based ISTs significantly outperformed steroid monotherapy in terms of CR and lower relapse rates (risk differences of 0.15 and -0.13/-0.15, respectively; P < .05), without significant differences between CP and rituximab. Moreover, adding rituximab to the front-line treatment did not produce superior outcomes compared to the CP regimen alone, positioning CP as a viable first-line choice, particularly where rituximab is less accessible. The consideration of IST toxicity remains critical in treatment decisions.

Multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes after autologous haematopoietic stem cell transplantation for acute myeloid leukaemia.

This retrospective study analysed 106 acute myeloid leukaemia (AML) patients undergoing autologous haematopoietic stem cell transplantation (ASCT) to assess the impact of multiple small-dose infusions of granulocyte-colony-stimulating factor (G-CSF)-mobilized haploidentical lymphocytes as post-ASCT maintenance therapy. Among them, 50 patients received lymphocyte maintenance therapy, 21 received alternative maintenance therapy, and 35 received no maintenance therapy. Patients receiving lymphocyte maintenance therapy demonstrated significantly higher overall survival (OS) and disease-free survival (DFS) compared to those without maintenance therapy, with 4-year OS and DFS rates notably elevated. While there were no significant differences in recurrence rates among the three groups, lymphocyte maintenance therapy showcased particular benefits for intermediate-risk AML patients, yielding significantly higher OS and DFS rates and lower relapse rates compared to alternative maintenance therapy and no maintenance therapy. The study suggests that multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes may offer promising outcomes for AML patients after ASCT, particularly for those classified as intermediate-risk. These findings underscore the potential efficacy of lymphocyte maintenance therapy in reducing disease relapse and improving long-term prognosis in this patient population.

Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia-A single centre retrospective analysis.

Management of immune thrombocytopenia (ITP) beyond initial glucocorticoid therapy is challenging. In this retrospective single-centre cohort study, we compared all ITP patients relapsed or non-responsive to glucocorticoid therapy treated with either continuous TPO-RAs (n = 35) or rituximab induction (n = 20) between 2015 and 2022. While both groups showed high initial complete response rates (CR, 68.6 vs. 80.0%, ns), the overall rate of progression to the next therapy was higher after time-limited rituximab (75.0 vs. 42.9%), resulting in a lower relapse-free survival (median 16.6 vs. 25.8 months, log-rank; p < 0.05). We conclude that both treatments show similar initial efficacy and their ideal duration of therapy warrants further investigation.

Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

The methods and baseline characteristics of a multi-site randomized controlled trial evaluating mindfulness-based relapse prevention in conjunction with peer support to improve adherence to medications for opioid use disorders.

Introduction: Medications for opioid use disorders (MOUD) remain the gold standard for treating OUD, but treatment initiation and adherence remain challenging. Exclusive utilization of pharmacotherapy as a treatment modality for OUD is sub-optimal, and a combination of psychotherapies and pharmacotherapies is recommended. General trends indicate the benefits of peer mentoring and MBRP separately. Therefore, we hypothesize that the combined effect of MBRP and Peer mentoring will produce synergistic improvements in MOUD adherence compared to an enhanced twelve-step facilitation (TSF). Methods: This paper describes the methods and baseline characteristics of a multi-site randomized controlled trial evaluating the effectiveness of a combination of MBRP and peer support (MiMP) compared to an enhanced TSF in improving adherence to MOUD. Both MiMP and TSF are 12-week manualized protocols that utilize licensed therapists. The interventions are delivered in weekly group sessions that last about 75-90 minutes per session. The primary outcome is MOUD adherence. Secondary and exploratory outcomes include relapse, cravings, depression, anxiety, stress, quality of life, and pain catastrophizing. Results: The participants' ages ranged from 21 years to 77 years, with a mean age of 44.5 (SD ± 11.5 years). There was an almost equal distribution of gender and place of residence. Overall, 51.9% (n=54) of participants identified as female and 48.1% (n=50) were male. Similarly, 51.9% (n=54) of participants resided in urban areas, while 48.1% (n=50) resided in rural areas. Participants identified as either black or white, with over three-quarters identifying as white (77.9%, n= 81) and 22.1% (n= 23) as black. Most participants randomized to the 12-step facilitation group were white (93.1%). Relationships and employment status were well distributed between categories. Over half of the participants reported some college or higher education. Over 90% of the participants made less than $75,000 per year. Some participants indicated that they had both public and private health insurance. Discussion and conclusion: This study is innovative in several ways including combining MBRP and peer support, addressing comorbid mental health issues among individuals with OUD, utilizing manualized protocols, and evaluating of both physiological and self-reported measures in assessing cortisol reactivity as a predictor of relapse and treatment outcomes.

[Efficacy and safety of gilteritinib-based combination therapy bridging allo-HSCT in relapsed or refractory acute myeloid leukemia patients with positive FLT3-ITD mutation].

Objective: This study aims to evaluate the safety and effectiveness of gilteritinib (Gilt) -based combination therapy bridging allo-HSCT for FLT3-ITD(+) R/R AML. Additionally, it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT. Methods: The clinical data of 26 patients with FLT3-ITD(+) R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed. The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS) time, disease-free survival (DFS) time, and adverse events experienced by all enrolled patients. Results: A total of 26 patients with FLT3-ITD(+) R/R AML were enrolled, including 14 men and 12 women with a median age of 38 (18-65) years. A total of 18 cases were refractory, and eight cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 26.9% (7/26), the CR with hematology incomplete recovery was 57.7% (15/26), and the partial response (PR) rate was 7.7% (2/26). The CRc was 84.6% (22/26), and the minimal residual disease (MRD) negativity rate was 65.4%. The 12 month cumulative OS rate for all patients was 79.0%, and the 24 month cumulative OS rate was 72.0%. The median OS time was not determined. The median follow-up time was 16.0 months. Among the patients who responded to treatment, the 12 month cumulative DFS rate was 78.0%, and the 24 month cumulative DFS rate was 71.0%. The median DFS time was not determined. Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT (3.3 months, 95%CI 2.2-4.3 months, P=0.005). The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined, but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment (P=0.019). The FLT3-ITD mutation clearance rate in this study was 38.5%, and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (15.0 months; P=0.018). The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia (76.9%), neutropenia (76.9%), febrile neutropenia (61.5%), thrombocytopenia (69.2%), and anemia (57.7%). One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment, but his condition improved after treatment. Conclusion: The Gilt-based combination therapy is highly effective in treating FLT3-ITD(+) R/R AML. It demonstrates a high CRc, MRD negativity rate, and rapid onset, leading to a significant improvement in patients' survival. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients' survival. Closely monitoring and managing any adverse event that may occur during treatment are crucial.

Antimicrobial Resistance in Uropathogenic Escherichia coli Strains Isolated from Relapses from Recurrent Urinary Tract Infections.

Little is known about the characteristics of uropathogenic Escherichia coli (UPEC) associated with recurrent urinary tract infections (RUTIs). The present study aimed to analyze the phenotypic antimicrobial resistance of recurrent UPEC isolates attributable to either relapse or reinfection. A total of 140 E. coli strains were isolated from 70 outpatients with RUTIs. All isolates were analyzed by random amplified polymorphic DNA-polymerase chain reaction to evaluate genetic similarity between the first and second isolates. We found that 64.2% (45/70) of outpatients had a relapse with the primary infecting E. coli strain and 35.7% (25/70) had reinfection with a new E. coli strain. Compared with reinfecting strains, relapse UPEC isolates exhibited much higher antimicrobial resistance; 89% of these isolates were multidrug-resistant and 46.6% were extended-spectrum ß-lactamase producers. Our study provides evidence that RUTIs are mainly driven by the persistence of the original strain in the host (relapses) despite appropriate antibiotic treatments, and only RUTIs attributed to relapses seem to favor multidrug resistance in UPEC isolates.

Targeting cancer stem cells in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy of bone marrow (BM) plasma cells with excessive clonal expansion and is associated with the overproduction of light-chain or monoclonal immunoglobulins (Igs). MM remains incurable, with high rates of relapses and refractory disease after first-line treatment. Cancer stem cells (CSCs) have been implicated in drug resistance in MM; however, the evidence for CSCs in MM is not adequate, partly due to a lack of uniformity in the definitions of multiple myeloma stem cells (MMSCs). We review advances in understanding MMSCs and their role in drug resistance to MM therapies. We also discuss novel therapeutic strategies to overcome MMSC-mediated relapses and drug resistance.

Successful treatment of fulminant and recurrent lymphocytic myocarditis with calcineurin inhibitors.

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

Architectural dysplasia in surgical margins and the risk of local relapse in oral cancer.

BACKGROUND: A major challenge in the clinical management of oral cavity squamous cell carcinoma is local relapse. Even when surgical margins are tumor-free, local relapses occur frequently, and relapse prediction by histology remains suboptimal. In leukoplakia, an oral potentially malignant disorder, the presence of architectural dysplasia is a critical risk factor for malignant transformation. This study aimed to investigate whether the presence of architectural dysplasia in oral cavity squamous cell carcinoma surgical margins is a risk factor for local relapse. METHODS: Hematoxylin and eosin-stained slides of resection margins from a consecutive cohort of surgically treated patients diagnosed with stage I-IV oral cavity squamous cell carcinoma between 2008 and 2014 were assessed for the presence of architectural dysplasia (N = 311). Five-year local relapse-free survival rates of oral cavity squamous cell carcinoma with architectural dysplasia were compared to those of oral cavity squamous cell carcinoma without architectural dysplasia. RESULTS: In total, 92 of 311 (29.6%) of oral cavity squamous cell carcinoma displayed architectural dysplasia in the margins. The presence of architectural dysplasia was associated with higher patient age, female sex, less pack years, lower cT-stage, and a cohesive tumor growth pattern. In oral cavity squamous cell carcinomas with architectural dysplasia, postoperative (chemo)radiotherapy was less often indicated compared with oral cavity squamous cell carcinoma without architectural dysplasia (19.5% vs. 36.1%, p = 0.009). Five-year local relapse-free survival was significantly lower in oral cavity squamous cell carcinoma with architectural dysplasia than in oral cavity squamous cell carcinoma without architectural dysplasia (83.1% vs. 94.9%, p = 0.017). CONCLUSIONS: Oral cavity squamous cell carcinoma arising in the background of architectural dysplasia displays relatively favorable clinical and histopathological characteristics. Nonetheless, the presence of architectural dysplasia in oral cavity squamous cell carcinoma surgical margins is associated with a higher risk of local relapse, indicating its clinical relevance.

Exploring miRNAs' Based Modeling Approach for Predicting PIRA in Multiple Sclerosis: A Comprehensive Analysis.

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.

The Complex Intracellular Lifecycle of Staphylococcus aureus Contributes to Reduced Antibiotic Efficacy and Persistent Bacteremia.

Staphylococcus aureus bacteremia continues to be associated with significant morbidity and mortality, despite improvements in diagnostics and management. Persistent infections pose a major challenge to clinicians and have been consistently shown to increase the risk of mortality and other infectious complications. S. aureus, while typically not considered an intracellular pathogen, has been proven to utilize an intracellular niche, through several phenotypes including small colony variants, as a means for survival that has been linked to chronic, persistent, and recurrent infections. This intracellular persistence allows for protection from the host immune system and leads to reduced antibiotic efficacy through a variety of mechanisms. These include antimicrobial resistance, tolerance, and/or persistence in S. aureus that contribute to persistent bacteremia. This review will discuss the challenges associated with treating these complicated infections and the various methods that S. aureus uses to persist within the intracellular space.

Psychometric evaluation of the Chinese version of alcohol relapse risk scale (C-ARRS) in patients with alcohol use disorder.

Alcohol use disorder (AUD) is recognized as a chronic relapsing disorder. Alcohol Relapse Risk Scale (ARRS), a multidimensionally self-rating scale, was developed initially by the Japanese to assess the risk of alcohol reuse. The study aimed to validate the reliability and factor structure of the Chinese version of the ARRS (C-ARRS) for patients with AUD. A total of 218 patients diagnosed with AUD according to DSM-5 were recruited for self-administering C-ARRS. We assessed the internal consistency of C-ARRS using Cronbach's α coefficients and examined the factor structure through confirmatory factor analysis (CFA). Additionally, we investigated the concurrent validity by correlating C-ARRS with the Visual Analog Scale of Alcohol Craving (VAS), Penn Alcohol Craving Score (PACS), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) scores. CFA demonstrated inadequate data fit for the original 32-item C-ARRS, prompting the development of a revised 27-item version consisting of 6 subscales with satisfactory model fit estimates. The 27-item C-ARRS exhibited favorable internal consistency, with Cronbach's α ranging from 0.611 to 0.798, along with adequate factor loadings. The 27-item C-ARRS scores displayed significant correlations with the scores of VAS, PACS, BDI and BAI (p < .001). Our results indicated favorable reliability and factor structure of the 27-item C-ARRS. The significant correlation between the 27-item C-ARRS and clinical measures (such as depression, anxiety, and craving) demonstrates satisfactory concurrent validity. These observations collectively support the feasibility of using 27-item C-ARRS to assess the risk of alcohol relapse in patients with AUD.