Cardiotoxicity from anti-leukemic therapies remains a major concern in pediatric hemato-oncology - often subclinical in the short term but potentially life-threatening in the long term. In children, who are exposed to cardiotoxic treatments at an early age and have long life expectancies, a proactive strategy for prevention, early detection, and management is essential. Anthracyclines remain a cornerstone of pediatric acute leukemia treatment but are associated with a risk of heart failure in approximately 10% of cases, particularly at cumulative doses exceeding 300mg/m2 of doxorubicin-equivalent. Dexrazoxane, once controversial, is now supported by robust data demonstrating both safety and cardioprotective efficacy. Its use is recommended alongside anthracyclines in patients receiving a cumulative dose≥300mg/m2 of doxorubicin-equivalent. Other agents - including tyrosine kinase inhibitors, immunotherapies, and CAR-T cells - also carry cardiotoxic potential, warranting tailored monitoring strategies. These multidisciplinary SFCE-endorsed recommendations emphasize the need for early and repeated assessment of cardiovascular risk factors throughout treatment. A dedicated heart team, involving pediatric cardiologists and pediatric hematologists, should coordinate active surveillance, including management of modifiable cardiovascular risk factors and systematic imaging with global longitudinal strain, which is more sensitive than ejection fraction in detecting subclinical dysfunction. Prospective pediatric studies are needed to define age-appropriate imaging thresholds, validate the role of cardiac biomarkers, and assess liposomal anthracycline formulations. If confirmed to be both safe and effective, such agents should be integrated into future treatment protocols to enhance long-term cardioprotection without compromising anti-leukemic efficacy.
The combination of antiangiogenic therapy with immune checkpoint blockade has demonstrated significant clinical benefits in various cancers, however, the precise mechanisms of action on the immune system are not fully understood. In particular, the early intratumoral immune responses induced by angiogenesis inhibition remain unclear. Using preclinical models of colorectal cancer, we examined the immune changes elicited by combined vascular endothelial growth factor receptor-2 (VEGFR-2) and programmed cell death protein-1 (PD-1) blockade. Our findings reveal that CD8 T cells respond directly and early to VEGFR-2 inhibition, preceding the acquisition of overt cytotoxic function. Shortly after treatment, intratumoral CD8 T cells expanded and produced interleukin-10 (IL-10). Unexpectedly, this CD8 T cell-derived IL-10 promoted the recruitment of natural killer (NK) cells into tumors. Recruited NK cells subsequently gained effector activity and produced granulocyte-macrophage colony-stimulating factor, which supported macrophage maturation and the induction of CXCL11. This sequence of events enhanced secondary CD8 T-cell infiltration and sustained antitumor immune activity. Disruption of IL-10 signaling or NK-cell function eliminated the therapeutic benefit of combined VEGFR-2 and PD-1 blockade, whereas regulatory T-cell depletion further improved tumor control. Together, these findings identify an unanticipated role for CD8 T cell-derived IL-10 in coordinating early innate and adaptive immune responses following angiogenesis inhibition and define an immune program initiated by VEGFR-2 blockade that is required for therapeutic efficacy in two preclinical colorectal cancer models.
Hughes-Stovin syndrome (HSS) is a rare and aggressive type of systemic vasculitis which is characterized by peripheral venous thrombosis and pulmonary artery aneurysms (PAAs) at the onset of the disease, as well as the absence of recent or previous attacks of uveitis. The onset of HSS and its dominant clinical disease presentations differ in many aspects from those observed in Behçet's disease (BD). The absence of uveitis is a mandatory exclusion criterion in the preliminary diagnostic criteria proposed by the HSS International Study Group (HSSISG), to avoid misclassification between HSS and BD. The presence of PAAs is an obligatory "entry criterion" for diagnosis, while vascular thrombotic events are a "major criterion" after excluding other causes of coagulopathy-induced thrombosis. The HSSISG regards HSS and BD as one disease, yet exhibiting distinct patterns of disease expression, particularly at disease onset. Differentiating HSS from BD is especially important for early diagnosis and optimal management. While the presence of HLA-B51 is the strongest genetic risk factor for BD, it is not used as a criterion to confirm a diagnosis because it lacks sufficient specificity. The prevalence of HLA-B51 in HSS is relatively low, suggesting that different genetic drivers might exist or that HSS is a unique entity with overlapping features with BD. In HSS, both HLA-B51 positive and negative cases have been described; thus, it cannot be a hallmark of the syndrome, and it does not play a role in the diagnostic criteria.
Congenital bladder diverticula are rare in children and result from a developmental defect of the detrusor muscle, allowing mucosal outpouching through the bladder wall. Hutch diverticulum is an uncommon congenital paraureteral diverticulum frequently associated with vesicoureteral reflux. We report the case of a 7-year-old boy born to second-degree consanguineous parents who presented with an intermittent right inguinal mass and decreased urine output. Imaging revealed a giant Hutch diverticulum with grade II reflux. Surgical treatment consisting of diverticulectomy and intravesical ureteral reimplantation using the Politano-Leadbetter technique led to a favorable outcome.
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The COVID-19 pandemic negatively affected residents of long-term care facilities (LTCFs). This situation highlighted the necessity to translate evidence-based policies and practices into this setting. However, implementing innovations represents a challenge for LTCFs. This study aims to identify the facilitators and barriers to the implementation of innovations in Canadian LTCFs. We conducted a longitudinal correlational study involving different LTCFs participants and the use of the Organizational Readiness for Knowledge Translation (OR4KT) measurement tool before and after the implementation of an innovation. Only data collected at T1 were considered in the analysis due to the low response rate obtained at T2. A mixed-model effect with a random effect for LTCFs was used to account for within organization dependency on responses. In total, 256 respondents from 55 (60.4%) LTCFs participated in the study of which 107 participants were high and middle-level managers, and 149 were non-managerial staff. Variations in OR4KT scores were explained by some organizational factors. The province of location of the LTCF emerged as a significant factor for five subscales of the OR4KT as well as for the total score. The presence of a medical director and belonging to a chain (an organization with multiple LTCFs) seemed to be associated with higher OR4KT scores. Successful LTCF innovation implementation may rely on the geographical administration of healthcare (e.g., the province), the presence of a medical director and the organizational contextual factors between the different actors of LTCFs and the health system.
Extracorporeal life support provides temporary cardiorespiratory support for patients with severe, potentially reversible cardiac and/or respiratory failure refractory to conventional measures. Its application has broadened across a wide spectrum of critical illness, yet the mechanistic basis of its physiological benefit remains incompletely defined.This review explores the mechanisms through which extracorporeal life support may confer benefit in respiratory and cardiac failure. These include restoration of gas exchange, optimization of circulatory dynamics, and mitigation of secondary organ injuries, creating conditions that facilitate tissue repair, enable adjunctive therapies, and in selected cases, provide a bridge to transplantation. In isolated respiratory failure, respiratory extracorporeal life support stabilizes gas exchange and modulates respiratory drive, enabling lung-protective ventilation and potentially attenuating ventilator- and patient self-inflicted lung injury. In cardiogenic shock, cardiac extracorporeal life support restores systemic perfusion and may reduce myocardial oxygen demand, while during cardiac arrest it may confer neuro-protective effects. In combined cardiorespiratory failure, advanced extracorporeal support modalities may augment both systemic and pulmonary circulation, supporting gas exchange and maintaining end-organ perfusion. Mechanistically, these interventions interrupt the cascade of hypoxemia- and/or hypercapnia- induced pulmonary vasoconstriction, right ventricular overload, and systemic hypoperfusion, facilitating multi-organ recovery. Optimizing patient selection, timing for extracorporeal life support initiation, and use of adjunctive therapies require a nuanced understanding of the interplay between these physiological pathways alongside careful considerations of key limitations including device-related complications, hematologic and inflammatory perturbations, and physiological trade-offs. This concise clinical review synthesizes the current literature on the mechanistic basis of extracorporeal life support in adults.
Exercise-based heavy lifting has been suggested to challenge pelvic organ support, yet no study has investigated this in women at risk of pelvic organ prolapse. This study aimed to investigate the immediate impact of heavy weightlifting on pelvic floor morphometry in premenopausal, vaginally parous women trained in exercise-based heavy lifting. Participants without symptoms of vaginal bulge attended a heavy weightlifting session (heavy barbell back squats [5 × 5 repetitions at 80% one repetition maximum]). Pelvic floor morphometry was measured before and immediately after the session. Bladder neck and rectal ampulla positions, anorectal and levator plate angles, levator anteroposterior distance, and levator hiatal area were assessed using transperineal ultrasound at rest, during bearing down, and during pelvic floor muscle contraction, in supine and standing positions. The maximal vaginal descent was assessed using the Pelvic Organ Prolapse Quantification in supine. Thirty-seven women participated in the study. Compared to pre-lifting, immediately after lifting the anorectal angle at rest was larger in supine and standing (p ≤ 0.05); during pelvic floor muscle contraction the bladder neck was more caudal in supine (p < 0.001) and the levator hiatal area was larger in standing (p = 0.02); during bearing down the levator plate angle was smaller in standing (p = 0.002) and the levator hiatal area was larger in supine (p = 0.01). No other significant pre-post changes were found. In asymptomatic, trained, premenopausal, vaginally parous women, a single heavy lifting session may induce small immediate pelvic floor morphometric changes, with minor impact on organ support, as shown by stable bladder neck, rectal ampulla, and vaginal wall measures.
These guidelines address acute community-acquired urinary tract infections (UTIs) in adult men. The following situations are not covered: pediatric UTIs, UTIs in immunocompromised patients, catheter-associated UTIs (vesical, ureteral, or nephrostomy), neurogenic bladder, nosocomial UTIs, chronic and recurrent UTIs. This update defines nosological entities, including confirmation of the existence of cystitis in men. Definitions are provided in the first chapter. Epidemiological and bacterial resistance data specific to male UTIs-previously scarce and fragmented-are presented in the second chapter. Pharmacokinetic and pharmacodynamic data for antibiotics used in male UTIs are comprehensively reviewed and summarized in the third section. Treatment recommendations for each entity are detailed in the fourth chapter. The final chapter outlines investigations to be considered after UTI in men and situations requiring urological referral. This document presents a concise text, and brief supporting arguments regarding key points have been added. Four clinical vignettes summarizing the diagnosis and management of cystitis, pyelonephritis, and epididymo-orchitis are presented at the end of this recommendation (Figs. 1, 2, 3 and 4).
This study aimed to describe urodynamic voiding patterns in patients with MS (PwMS) using standardized assessments, and to compare the performance of the available nomograms and indices for obstruction and bladder contractility. PwMS and lower urinary tract symptoms underwent cystometry and pressure flow studies. Fluoroscopy findings were collected when available. Bladder contractility was assessed using the following parameters: bladder voiding efficiency (BVE), bladder contractility index (BCI), Watts factor (WF) for men, Projected Isovolumetric Pressure 1 (PIP1), the Valentini-Besson-Nelson (VBN) parameter k, and the urodynamic cut-off proposed by Gammie et al. for women. Obstruction was assessed using the bladder outlet obstruction index (BOOI) in men, and BOOIf in women. Agreement between the diagnosis of detrusor underactivity (DUA) and obstruction according to each parameter was assessed with weight kappa. Ninety-seven PwMS were included (mean age 48.4 ± 10.5, 58 [60%] women, mean EDSS 3.9 ± 1.8). Sphincter dysfunction was observed in 68 patients (70%), most frequently detrusor sphincter dyssynergia (DSD) in 32 (33%), followed by non-relaxing urethral sphincter in 29 (30%), and delayed relaxation of the urethral sphincter in 7 (7%) PwMS. DUA was found in 22 PwMS (23%). All indices demonstrated low to moderate agreement with the diagnosis of DUA and obstruction in this cohort. Abnormal voiding patterns are common in PwMS, especially sphincter dysfunction. None of the developed indices for obstruction and DUA appear highly relevant in this specific neurogenic population.
Somatostatin analogues reduce liver and kidney cyst volume in autosomal dominant polycystic kidney disease (ADPKD), but randomized trials have not demonstrated a consistent benefit on kidney function decline. We tested whether the analogue lanreotide slows glomerular filtration rate (GFR) decline over three years in adults with ADPKD stages 2/3. In this randomized, double-blind, placebo-controlled trial, we enrolled adults with ADPKD and measured GFR (mGFR) 30-89 mL/min/1.73 m2. Patients were randomized to receive monthly injections of lanreotide 120 mg or 0.9% sodium chloride placebo for three years. The primary endpoint was mGFR slope (iohexol clearance) assessed at baseline, weeks 72 and 144 and analyzed with a linear mixed-effects model (LMM). Secondary endpoints included annual estimated GFR decline (creatinine-based, assessed at 11 scheduled visits), kidney events, quality of life, and safety. Due to slow enrollment, recruitment stopped after 144 of 180 planned participants. All randomized participants were included in the analysis (intention-to-treat). The primary endpoint was not met: the model-derived annualized between-arm difference in mGFR trajectory was -0.3 ml/min/1.73 m2 per year (95% confidence interval -3.4 to 2.8). The time × lanreotide coefficient from the pre-specified creatinine-eGFR LMM was significant +1.2 ml/min/1.73 m2 per year (0.27 to 2.15); however, this signal was not replicated by cystatin C-eGFR nor urinary creatinine clearance, consistent with a non-GFR effect on creatinine physiology. Rates of kidney events and quality-of-life scores were similar between arms. Gastrointestinal adverse events were more frequent with lanreotide. Hypoglycemia occurred in 11.1% of lanreotide-treated versus 1.4% of placebo-treated participants. Lanreotide did not slow mGFR decline in adults with stage 2/3 ADPKD. The creatinine-eGFR signal is exploratory, not supported by muscle-mass-independent markers, and should be interpreted in the context of a negative primary endpoint. An unexpected hypoglycemia signal warrants proactive monitoring when considering lanreotide in this population.
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Human papillomavirus (HPV) vaccine coverage (VC) remains suboptimal in many countries. The PrevHPV national research programme aimed to codevelop and evaluate a three-component intervention including: 'education and motivation' of adolescents, 'at-school vaccination', 'general practitioners (GPs)' training'. We assessed its impact on VC at one year through a cluster randomized trial (July 2021-April 2022) conducted in French municipalities (clusters) receiving 0, 1, 2, or 3 components. The outcomes (≥ 1-dose and full HPV VC at one year among 11-14-year-olds) were estimated using data from the national health reimbursement database and data collected during the trial. We performed intention-to-treat and post-hoc analysis adjusted for the dose of intervention using cluster-level linear models. Ninety-one municipalities were included. 'At-school vaccination' significantly increased ≥ 1-dose VC, in both intention-to-treat (+ 2.85 percentage points (pp), 95%CI = 0.62 to 5.09) and post-hoc analysis (+ 4.60 pp, 95%CI = 1.79 to 7.41). No significant effects were found for the other components. Results were similar for full VC. 'At-school vaccination' significantly increased VC only in municipalities with the lowest access to GPs. School-based vaccination was effective in increasing HPV VC in the medium term and may reduce VC healthcare access-driven territorial disparities. Challenges remain in parental engagement and consent for vaccination at school.Trial registration: Clinicaltrials.gov, NCT04945655. Registered 30 June 2021.
General practitioners (GPs) frequently serve as the first or only point of contact for patients with mental health disorders, playing crucial roles in detection, prevention, and management. Despite this, many GPs feel poorly prepared to address mental health issues, often citing the barriers of limited time, heavy workloads, and insufficient training. The present study's main objective was to make an in-depth exploration of the potential difficulties encountered by GPs as they manage and follow up with patients with mental health problems. Our qualitative approach involved semi-structured individual interviews with 17 GPs from French-speaking Switzerland. Interviews were transcribed and analysed using reflexive thematic analysis within an inductive theoretical framework. Once the most important themes and subthemes had emerged, we externally and internally validated them. Four principal themes emerged. GPs reported that: (i) they enjoyed caring for patients with mental health issues, valuing their unique position in providing comprehensive, long-term support; (ii) they faced significant systemic barriers, including frustration with limitations related to Switzerland's health assurance scheme; (iii) collaboration with psychiatrists was lacking and resources were insufficient; and (iv) they required help and new ideas to improve the quality of their care. GPs' experiences revealed a mixed reality: their dedication to patient care existed alongside their frustration with systemic constraints, highlighting the complexity of mental health management in primary care. Sustainable improvements would require addressing gaps in caregivers' training, greater interprofessional collaboration, and more public health initiatives to mainstream mental health care into society.
This study assessed the feasibility of remote halitosis diagnosis by evaluating VSC stability over 7 days and their association with periodontal parameters. One hundred adult patients attending a periodontal examination were included. Oral gas samples were collected using plastic syringes and analyzed by gas chromatography (OralChroma) at baseline (D0) and after 7 days of storage at room temperature (D7). Hydrogen sulfide (H2S), methyl mercaptan (CH3SH), and dimethyl sulfide ((CH3)2S) were quantified. Periodontal parameters were recorded. Correlations and agreement analyses were performed. At D0, 64% and 31% of patients were classified as having halitosis using thresholds of > 120 ppb and > 300 ppb, respectively. Mean VSC concentrations were 10.2 (33.1) ppb for H2S, 208.3 (443.2) ppb for CH3SH, and 79 (166) ppb for (CH3)2S, and increased after 7 days of storage for all compounds except H2S. Only (CH3)2S showed a significant correlation between D0 and D7 measurements. Agreement between halitosis diagnoses at D0 and D7 was poor for both thresholds (Cohen's kappa < 0.2). Associations between VSC levels and periodontal parameters were weak. Delayed analysis of oral gas samples significantly altered VSC measurements limiting their reliability for remote halitosis diagnosis. Periodontal parameters were not strongly associated with VSC levels.
Urinary tract infections (UTIs) in men, though less frequent than in women, represent a significant clinical challenge due to their increasing incidence with age and distinct microbiological profiles. This expert review analyzed data of urine cultures in men with community-acquired UTIs, collected from emergency departments of 15 french hospitals, from the private laboratory group Atoutbio (21 sites in Meurthe-et-Moselle and the Vosges French departments, alongside primary care records from the AntibioClic tool and the PRIMO database, to characterize the bacterial epidemiology of community-acquired male UTIs in France. Escherichia coli (39-40%) dominated, followed by Enterococcus faecalis (13-15%), Klebsiella pneumoniae (6-8%), and Proteus mirabilis (5-6%). Resistance rates were as follows amoxicillin (47-53.5%), amoxicillin-clavulanate (24-35.7%), trimethoprim-sulfamethoxazole (25.4-31.5%), and fluoroquinolones (16.3-20.2%). Resistance to third-generation cephalosporins (6.6-9.3%) and mecillinam (6.8-8.9%) was lower, while fosfomycin (1.4-1.5%) and nitrofurantoin (0.4-0.7%) retained high susceptibility. Extended-spectrum β-lactamase (ESBL)-producing E. coli ranged from 2 to 8.4%, with carbapenemase producers remaining rare (0.1%). Resistance was higher in men >65 years, particularly in nursing homes, where 3GC resistance reached 15-18%. « Emerging uropathogens » (Aerococcus urinae 1-1.1%, Actinotignum schaalii 0.1-0.4%) were rare. This study highlights the greater microbial diversity in male UTIs compared to women and underscores the need for systematic urine culture, susceptibility testing, and empirical therapy tailored to resistance patterns, age, and risk factors.
The aim of this study was to estimate the bovine leukosis virus (BLV) herd-level and within-herd prevalence (WHP) in dairy herds and to assess the ability of three bulk tank milk (BTM) ELISA-Ab tests (SVANOVIR, Bovichek, and IDEXX) to predict the BLV WHP. A cross-sectional study was performed on a convenience sample of 93 dairy herds from Québec, Canada, where individual milk samples from all lactating cows and a BTM sample were collected. Individual milk ELISA-Ab results (n = 7612 cows) from a previously validated kit were incorporated into a two-stage hierarchical Bayesian latent class model to estimate BLV herd-level prevalence and WHP. To mitigate potential test saturation, we evaluated the three BTM ELISA-Ab tests with and without sample dilutions. Adjusted BTM ELISA-Ab optical density values were linked to the WHP estimates using a zero-inflated beta regression, and dilution-specific predictive models were compared. The herd-level BLV prevalence was estimated at 87% (95% Bayesian credible interval [BCI]: 78, 93), and BLV WHP ranged from 0% to 90%. The best predictive model-dilution combinations were SVANOVIR 1/10 (nonmonotonic curvilinear), Bovichek 1/5 (linear), and IDEXX 1/50 (nonmonotonic curvilinear). Across tests, optical density values increased with WHP, consistent with higher antibody concentrations in bulk milk. BLV remains highly prevalent at the herd level, with substantial variability in WHP among positive herds. These results indicate that BLV WHP can be reliably estimated from a single BTM sample, reducing the need for individual cow testing.
Citrus peels have traditionally been used for their anti-inflammatory properties. Their bioactive compounds can modulate neutrophil activation and reduce ROS production, both of which play key roles in the development of many chronic inflammatory diseases. The present study aimed to investigate the anti-inflammatory potential of an orange peel aqueous extract (OPE) and its major flavonoid, hesperidin (HSP), using integrated in vitro, in vivo, and in silico approaches. The anti-inflammatory activities of OPE and HSP were first assessed in isolated human neutrophils through degranulation and total ROS production assays. In vivo effects were evaluated in male Wistar rats using xylene-induced ear edema and λ-carrageenan-induced peritonitis models. In silico molecular docking analyses were performed to predict the interactions of hesperidin with key inflammatory targets. In vitro, OPE and HSP significantly inhibited ROS production in neutrophils stimulated with PMA and fMLF and markedly reduced neutrophil degranulation. In vivo, pretreatment with OPE or HSP resulted in a substantial decrease in ear edema and neutrophil infiltration in peritoneal exudates, with comparable effects to those of aspirin. Docking results showed strong predicted binding affinities of hesperidin for NADPH oxidase subunits, cyclooxygenases-1 and -2, p38 MAPK, and NF-κB. Collectively, these findings demonstrate that OPE and HSP exhibit potent anti-inflammatory effects via multiple complementary mechanisms, supporting the valorization of citrus by-products as nutritionally relevant functional ingredients with potential applications in the dietary management of inflammation-related disorders.