Late Treatment Research Articles

Early versus late caffeine and/or non-steroidal anti-inflammatory drugs (NSAIDS) for prevention of intermittent hypoxia-induced neuroinflammation in the neonatal rat.

Preterm infants often experience frequent intermittent hypoxia (IH) episodes which are associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non-steroidal inflammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH-induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hyperoxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) daily caffeine (Caff) citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5mg/kg from P1-P14); 2) ketorolac (Keto) topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Ibu, Neoprofen, 10mg/kg loading dose on P0 followed by 5mg/kg/day on P1 and P2); 4) Caff+Keto co-treatment; 5) Caff+Ibu co-treatment; or 6) equivalent volume saline (Sal). On P14, animals were placed in room air (RA) with no further treatment until P21. For late treatment, pups were exposed from P0 to P14, then placed in RA during which they received similar treatments from P15-P21 (Sal, Caff, and/or Keto), or P15-P17 (Ibu). RA controls were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, myelination, and biomarkers of inflammation. IH caused significant brain injury and hemorrhage, inflammation, reduced myelination, and apoptosis. Early treatment with Caff alone or in combination with NSAIDs conferred better neuroprotection against IH-induced damage than late treatment. Early postnatal treatment during a critical time of brain development, may be preferable for the prevention of IH-induced brain injury in preterm infants.

Dihydroartemisinin-piperaquine treatment failure of uncomplicated Plasmodium falciparum malaria infection in a traveller.

We report a late dihydroartemisinin–piperaquine treatment failure of uncomplicated Plasmodium falciparum malaria infection in a traveller without evidence of drug resistance. The correct treatment intake was confirmed, isolates drugs susceptibility was confirmed by RSA-PSA and chemosusceptibility. No molecular markers associated with resistance to artemisinin derivatives or piperaquine were identified.

Acute kidney injury requiring dialysis in children: a multicentric, emerging country perspective.

Acute kidney injury (AKI) is a life-threatening condition, especially in extreme age groups and when kidney replacement therapy (KRT) is necessary. Studies worldwide report mortality rates of 10-63% in pediatric patients undergoing KRT. Over 13years, this multicenter study analyzed data from 693 patients with AKI, all receiving KRT, across 74 hospitals and medical facilities in Rio de Janeiro, Brazil. The majority were male (59.5%), under one year old (55.6%), and treated in private hospitals (76.5%). Sixty-six percent had comorbidities. Pneumonia and congenital heart disease were the most common admission diagnoses (21.5% and 20.2%, respectively). The mortality rate was 65.2%, with lower rates in patients over 12years (50%). Older age was protective (HR: 2.35, IQR [1.52-3.62] for neonates), and primary kidney disease had a three-fold lower mortality rate. ICU team experience (HR: 0.74, IQR [0.60-0.91]) correlated with lower mortality, particularly in hospitals treating 20 or more patients. Among the deceased, 40% died within 48h of KRT initiation, suggesting possible late referral or treatment futility. This study confirms the high mortality in pediatric dialytic AKI in middle-income countries, underlining early mortality and offering critical insights for improving outcomes.

Effects of Blood-Derived Products on Cellular Senescence and Inflammatory Response: A Study on Skin Rejuvenation.

Blood-derived products, such as citrate platelet-rich plasma (CPRP) and hyperacute serum (HAS), are recognized for their rich growth factor content. When human dermal fibroblast (HDF) cells are exposed to combined mitogenic and DNA-damaging stimuli, it can lead to an increased burden of senescent cells and a modified senescence-associated secretory phenotype. In this study, the senescent state was comprehensively assessed through various methods, including phosphorylated histone H2AX (γH2AX) staining, p21 and p16 q-PCR, p21-western blot, growth curves, and senescence-associated ß-galactosidase staining. Two primary treatments with blood products were administered, one early (immediately after etoposide) and the other late (11 days after etoposide treatment). The effects of the blood product treatment were evaluated by measuring interleukin 6 and 8 (IL-6 and IL-8) levels, as well as collagen 1 (COL1) and p21 mRNA expression. Additionally, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays, cell size measurements, viability assays, and cell number calculations were conducted. The results revealed that cells treated with hyperacute serum in the early treatment phase exhibited the lowest observed IL-6 and IL-8 levels. In contrast, a clear inflammatory response for IL-8 was observed in cells treated with hyperacute serum and citrate platelet-rich plasma during the late treatment. Furthermore, an upregulation of COL1 expression was observed in the early treatment, while cells in the late treatment group remained unaffected. Notably, citrate platelet-rich plasma-treated cells showed a decrease in COL1 expression. Overall, the treatment with blood products appears to have slightly positive effects on skin rejuvenation.

Socioeconomic Disparities in Anal Cancer: Effect on Treatment Delay and Survival.

Socioeconomic inequities have implications for access to health care and may be associated with disparities in treatment and survival. To investigate the impact of socioeconomic inequities on time to treatment and survival of anal squamous-cell carcinoma. This is a retrospective study using a nationwide data set. The patients were selected from the National Cancer Database and enrolled from 2004 to 2016. We identified patients with stage I to III squamous-cell carcinoma of the anus who were treated with chemoradiation therapy. Socioeconomic factors, including race, insurance status, median household income, and percentage of the population with no high school degrees, were included. The association of these factors with treatment delay and overall survival was investigated. A total of 24,143 patients who underwent treatment for grade I to III squamous-cell carcinoma of the anus were identified. The median age was 60 years, and 70% of patients were women. The median time to initiation of treatment was 33 days. Patients from zip codes with lower median income, patients with a higher percentage of no high school degree, and patients with other government insurance followed by Medicaid insurance had treatment initiated after 60 days from diagnosis. Kaplan-Meier survival analysis showed that the late-treatment group had worse overall survival compared to the early treatment group (98 vs 125 months; p < 0.001). No detailed information is available about the chemoradiotherapy regimen, completion of treatment, recurrence, disease-free survival, and individual-level socioeconomic condition and risk factors. Patients from communities with lower median income, level of education, and enrolled in public insurance had longer time to treatment. Lower socioeconomic status was also associated with poorer overall survival. These results warrant further analysis and measures to improve access to care to address this disparity. See Video Abstract . ANTECEDENTES:Las desigualdades socio-económicas tienen implicaciones en el acceso a la atención médica y pueden estar asociadas con disparidades en el tratamiento y la sobrevida.OBJETIVO:Indagar el impacto de las desigualdades socio-económicas sobre el tiempo de retraso en el tratamiento y la sobrevida en casos de carcinoma a células escamosas del ano (CCEA).DISEÑO:Estudio retrospectivo utilizando un conjunto de datos a nivel nacional.AJUSTES:Todos aquellos pacientes inscritos entre 2004 a 2016 y que fueron seleccionados de la Base Nacional de Datos sobre el Cáncer.PACIENTES:Identificamos pacientes con CCEA en estadíos I-III y que fueron tratados con radio-quimioterápia.PRINCIPALES MEDIDAS DE RESULTADOS:Se incluyeron factores socio-económicos tales como la raza, el tipo de seguro de salud, el ingreso familiar medio y el porcentaje de personas sin bachillerato de secundaria (SBS). Se investigó la asociación entre estos factores con el retraso en iniciar el tratamiento y la sobrevida global.RESULTADOS:Se identificaron un total de 24.143 pacientes que recibieron tratamiento para CCEA estadíos I-III. La mediana de edad fue de 60 años donde 70% eran de sexo femenino. La mediana del tiempo transcurrido desde el diagnóstico hasta el inicio del tratamiento fue de 33 días. Los pacientes residentes en zonas de código postal con ingresos medios más bajos, con un mayor porcentaje de individuos SBS y los pacientes con otro tipo de seguro gubernamental de salud, seguidos del seguro tipo Medicaid iniciaron el tratamiento solamente después de 60 días al diagnóstico inicial de CCEA. El análisis de Kaplan-Meier de la sobrevida mostró que el grupo de tratamiento tardío tuvo una peor supervivencia general comparada con el grupo de tratamiento precoz o temprano (98 frente a 125 meses; p <0,001).LIMITACIONES:No se dispone de información detallada sobre el tipo de radio-quimioterapia utilizada, ni sobre la finalización del tratamiento o la recurrencia, tampoco acerca de la sobrevida libre de enfermedad ni sobre las condiciones socio-económicas o aquellos factores de riesgo a nivel individual.CONCLUSIÓN:Los pacientes de comunidades con ingresos medios más bajos, con un nivel de educación limitado e inscritos en un seguro público tardaron mucho más tiempo en recibir el tratamiento prescrito. El nivel socio-económico más bajo también se asoció con una sobrevida global más baja. Los presentes resultados justifican mayor análisis y medidas mas importantes para mejorar el acceso a la atención en salud y poder afrontar esta disparidad. (Traducción-Dr. Xavier Delgadillo ).

Delay in seeking treatment and associated factors among pulmonary tuberculosis patients attending public health facilities in the Metekel zone, Benishangul Gumuz region, Western Ethiopia.

Tuberculosis is a major global public health problem and a leading cause of morbidity and mortality in Ethiopia. TB prevention and control in low-income countries, such as Ethiopia, face significant challenges, including late detection and treatment initiation. A delay in the initiation of tuberculosis treatment increases the morbidity and mortality of patients and community transmission. Therefore, this study aimed to assess patient delay and associated factors among pulmonary tuberculosis patients attending public health facilities in the Metekel Zone, Benishangul Gumuz Region, Western Ethiopia. An institution-based cross-sectional study was conducted from March to August 2020 among newly diagnosed pulmonary tuberculosis patients. All pulmonary tuberculosis patients (416) who came to all public health facilities of the Metekel zone for treatment during the period were included. Data were collected through face-to-face interviews using a structured and pretested questionnaire. A multivariable logistic regression was fitted to identify independent factors for delay in seeking treatment among PTB patients. Adjusted odds ratios with 95% CIs were determined, and variables with p values <0.05 were considered statistically significant. Nearly three-fourths 302 (72.6, 95% CI: 68.5, 76.7) of the patients were delayed in seeking medical advice, with a median patient delay of 27 days (IQR: 21-31). Age of the patients [above 54 years (AOR = 2.65, 95% CI: 1.30, 5.40), 36-54 years (AOR = 1.86, 95% CI: 1.14,3.02)], family size of 5 members and above (AOR = 1.62, 95% CI: 1.10-3.14), travel time above 60 min (AOR = 3.65, 95% CI: 1.55, 8.60), history of visits to informal care providers (AOR = 1.74, 95% CI: 1.11, 3.14), and poor knowledge about PTB (AOR = 1.64, 95% CI: 1.04-2.44) were statistically significant factors associated with delays in seeking treatment among PTB patients. Most pulmonary tuberculosis patients delay seeking medical advice for their illnesses. Delays in seeking treatment were associated with older age, large household size, longer travel time to reach the nearby health facility, visiting informal care providers, and poor knowledge about pulmonary tuberculosis. Hence, it is crucial to consider community screening programs, enhance public awareness, and ensure the accessibility of TB diagnostic and treatment services.

Cost-Effectiveness of Late Endovascular Thrombectomy vs. Best Medical Management in a Clinical Trial Setting and Real-World Setting.

To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a "real-world" setting. Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a "real-world" setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY. Two-hundred and forty-nine patients were included (ESCAPE-LATE:n = 200, ESCAPE EVT-arm:n = 29, ESCAPE control-arm:n = 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%-99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%-61.6%), but not the "real-world" setting (acceptability:32.9%-42.6%). EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and "real-world" setting, although this was largely related to baseline patient differences favoring the "real-world" EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.

The failed adult traumatic brachial plexus reconstruction.

Traumatic adult brachial plexus injuries typically cause immediate loss of upper limb function. Timely multidisciplinary treatment in specialized centres often results in a useful helper arm. Both the patient and the surgical team can benefit from an open discussion to set realistic expectations. Surgical reconstruction is customized for each patient, considering their injury factors and functional objectives. Optimizing pain control, adherence to procedure indications and using meticulous surgical techniques help minimize the risk of failing to meet the patient's goals. The need for potential alternative treatment(s) if the desired result is not achieved should be detailed before the initial reconstruction. This review discusses late treatment options, including tendon transfers, joint fusions, free functioning muscle transfers and prosthetics, for managing the failed primary reconstruction of the traumatic adult brachial plexus.

The impact of large core and late treatment trials: An update on the modelled annual thrombectomy eligibility of UK stroke patients.

To support decisions about thrombectomy provision, we have previously estimated the annual UK population eligible for treatment as ∼10% of stroke admissions. Since then, eight further randomised trials that could alter the eligibility rate have reported in 2021-23. We updated our estimates of the eligible population from these trials and other recent studies. An updated decision tree describing the EVT eligible population for UK stroke admissions was produced. Decision criteria were derived from the highest level of evidence available. For nodes where no specific RCT data existed, evidence was obtained from the latest systematic review(s) or the highest quality observational data. We estimate that 15,420 (approximately 15%) of admitted UK stroke patients are now eligible for thrombectomy, or 14,930 if advanced brain imaging using MRI/CT perfusion or collateral assessment were used in all patients. This is a 54% increase in our previous estimate in 2021. Over 50% of LAO strokes are now potentially eligible for thrombectomy. The increase in eligibility is principally due to a much larger cohort of later presenting and/or larger ischaemic core patients. Most previously independent LAO stroke patients presenting within 24 h, even in the presence of a large ischaemic core on initial non-contrast CT, should be considered for thrombectomy with use of advanced brain imaging in those presenting beyond 12 h to identify salvageable penumbral brain tissue. Treatment in most patients remains critically time-dependent and our estimates should be interpreted with this in mind.

Canine Fossa Abscess In Pediatric: Case Report

Odontogenic infections are a major reason for consultation in dental practice especially in pediatric population. It comprises various clinical conditions, whose importance varies depending on their potential severity. Pediatric patients with active infections pose additional challenges and difficult to manage. Insufficiency or late treatment may lead to serious and possibly life-threatening complications. This case report is to discuss the management of treatment in canine fossa abscess in pediatric patient. A-3 years-old male patient referred to the Oral and Maxillofacial Surgery Clinic with complaints of swelling in his left cheek since 3 days ago. Physical examination showed fluctuant swelling in left infraorbital region. The patient was diagnosed with canine fossa abscess. The treatment was given are intravenous antibiotics, multiple tooth extraction and drainage incision under general anesthesia. Early identification, proper intravenous antibiotics and elimination of source of infection are the keys to the treatment.

Психологические предикторы несвоевременного обращения больных раком предстательной железы за онкологическим лечением

&lt;p&gt;Among oncological diseases, prostate cancer ranks third after lung and stomach cancer. A timely (early) application of patients for medical help, early diagnosis and early treatment are the factors of a favourable course and survival rate. The purpose of the study is to identify a set of psychological predictors associated with untimely primary care-seeking in men with prostate cancer. 81 men diagnosed with prostate cancer took part in the study, aged from 53 to 85 years old (mean age &amp;mdash; 64.4, standard deviation &amp;mdash; 8.8), 42 men at early stages of the disease (I, II), 39 men at late stages (III, IV), who first sought professional medical help in the Chelyabinsk Regional Clinical Centre of Oncology and Nuclear Medicine, Chelyabinsk, Russia. Seeking medical help at the early stages of the disease (I, II stages) is timely, or an early application, while treatment at later stages (III, IV) is late treatment. The study used survey methods, in particular, psychodiagnostic techniques: the World Assumptions Scale (R. Janoff-Bulman; adapted by M.A. Padun, A.V. Kotelnikova), the Level of Subjective Control method (E.F. Bazhin, E.A. Golynkina, L.M. Etkind), the Life Orientation Test (M.F. Scheier, C.S. Carpenter, adapted by D.A. Tsiring, K.Y. Evnina), the S. Maddi test of resilience, adapted by D.A. Leontiev, E.I. Rasskazova, the SF-36 &amp;ldquo;Quality of Life Assessment&amp;rdquo; questionnaire (the translation into Russian and the approbation of the methodology was carried out by the Institute of Clinical and Pharmacological Research, St. Petersburg). The study found that men who do not seek medical help in a timely manner experience intense pain that interferes with their daily activity, they are also internalized in the field of industrial relations, showing more personal responsibility for successes and failures in the professional sphere. Also, men with prostate cancer who seek help in the late stages of the disease are close to a pessimistic expectation of the future.&lt;/p&gt;

PROFILE OF DEATHS OF PEDIATRIC PATIENTS WITH DILATED CARDIOMYOPATHY IN BRAZIL, FROM 2018 TO 2020

Introduction: Dilated cardiomyopathy (DCM) is a pathology that affects the left ventricle resulting in high morbidity and mortality. It is the most common clinical form of cardiomyopathy in the pediatric population, although it is difficult to diagnose due to late treatment. Objective: To identify the death profile of pediatric patients with IDCD in Brazil. Method: This is an epidemiological, observational, analytical, cross-sectional study with data from the Hospital Admission System (SIH-DATASUS) from 2018 to 2020. The study population consisted of 678 children, aged 0 to 19 years , with the variables used: sex, age group, nationality, ethnicity, type of hospitalization, place of hospitalization, legal nature, management, ICU stay, specialty, diagnosis and treatment. A bivariate analysis was performed using the Mantel-Haenszel chi-square method, considering the relative risk of death and its respective 95% confidence interval as a measure of association. in search. Results: The prevalence was female, over 5 years old, Brazilian, of brown ethnicity and had no comorbidities. We highlight the higher mortality rate in the specialty of pediatrics, in children younger than 5 years old, with comorbidities and who needed to be admitted to the ICU. Conclusion: Children under 5 years old, especially those with comorbidities, especially heart failure, should be analyzed with greater caution and that health service professionals can monitor them rigorously and intervene early, in order to avoid possible negative outcomes such as to evolve unfavorably and/or to death.

Effectiveness of Early Intervention with Palatal Expansion Versus Late Orthodontic Treatment for Correcting Maxillary Crowding

ABSTRACT Background: Maxillary crowding is a common orthodontic issue that can impact a patient’s oral health and overall well-being. The timing of orthodontic treatment plays a crucial role in achieving optimal results. Materials and Methods: Thirty patients who received early intervention with palatal expansion (Group A) and 30 patients who underwent late orthodontic treatment (Group B) were included in this study. The age range for Group A was 8–10 years, while Group B had an age range of 16–18 years. Pretreatment and posttreatment records, including dental models and cephalometric radiographs, were analyzed to assess the effectiveness of the respective treatments. Results: In Group A, the mean duration of treatment was 12 months, and the maxillary crowding was corrected by an average of 4.5 mm. In Group B, the mean treatment duration was 24 months, and maxillary crowding was corrected by an average of 3.2 mm. The early intervention group (Group A) exhibited a statistically significant reduction in treatment duration and greater correction of maxillary crowding compared to the late orthodontic treatment group (Group B) (P &lt; 0.05). Conclusion: Early intervention with palatal expansion is an effective approach for correcting maxillary crowding, leading to shorter treatment duration and greater improvement compared to late orthodontic treatment.

Abstract WP58: Intermittent Theta-Burst Stimulation Attenuates Oligodendrocytes Dysfunction and Alleviates Depression-Like Behaviors in Hypoxia-Ischemia Rats

Rationale: Perinatal hypoxic-ischemic (HI) brain injury is a significant cause of mortality and morbidity among newborns. Children who survive newborn hypoxic-ischemic encephalopathy (HIE) are at an increased risk of developing mood disturbances, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS) is considered a promising therapeutic tool for treating neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. Methods: Postnatal day 10 Sprague-Dawley male and female rats were subjected to hypoxic (6% O 2 ) conditions for 2 h after ligating the right common carotid artery. Transcranial application of iTBS (15 Gauss) was administered daily for seven consecutive days, starting either one day after HI insult (early iTBS) or 18 days after HI insult (late iTBS). Depression-like behaviors were examined 5 weeks after HI. The levels of oligodendrocyte progenitor cells (OPCs) proliferation, differentiation, and apoptosis, as well as the myelinating of oligodendrocytes (OLs) were measured and analyzed using immunofluorescence staining and automated western blot. Results: The male and female rats exposed to HI exhibited apparent OLs dysfunction, including a decrease in OPCs proliferation, a reduction in OPCs differentiation, diminished survival of OLs, and hindered myelination in the corpus callosum (CC) area. These alternations were concomitant with depression-like behaviors. Crucially, early iTBS treatment significantly alleviated HI-caused myelination damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment could not significantly impact these behavioral deficits. Conclusion: Our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms are suggested to be associated with the promoted the differentiation of OPCs and the alleviated myelination damage following iTBS administration.

Efficacy of Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) Monotherapy Can Be Improved after Treatment with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer: Long-Term Follow-Up and Updated Analysis of Two Previous Prospective Clinical Studies

Introduction: Recent studies have suggested enhanced therapeutic effects of subsequent chemotherapy after immune checkpoint inhibitor (ICI) treatment, highlighting the importance of subsequent treatment selection. Nanoparticle albumin-bound paclitaxel (nab-PTX) is commonly used in subsequent chemotherapies; however, its efficacy as a subsequent treatment after ICI treatment has not been reported. Methods: We retrospectively evaluated the efficacy and safety of nab-PTX using two prospective studies that we previously reported. The first study evaluated the efficacy and safety of nab-PTX as a second-line treatment after the failure of the first-line cytotoxic chemotherapy, excluding ICI (study 1; n = 32), and the other as a subsequent treatment after failure of ICI treatment, regardless of treatment line (study 2; n = 29). Results: The objective response rate was significantly higher in study 2 {55.2% (95% confidence interval [CI]: 28.1–79.6)} than in study 1 (28.1% [95% CI: 13.7–46.7]) (p = 0.04). Although the disease control rate was slightly higher in study 2 (86.2% [95% CI: 65.9–97.0]) than in study 1 (71.9% [95% CI: 53.3–86.3]), there was no significant difference (p = 0.2). The median progression-free survival was significantly longer in study 2 than in study 1 (3.9 months [95% CI: 2.0–5.5] in study 1 vs. 5.6 months [95% CI: 3.0–12.8] in study 2; hazard ratio [HR]: 0.46 [95% CI: 0.27–0.81], p = 0.006). The median overall survival was slightly longer in study 2 despite the greater number of patients who received nab-PTX in late treatment line, but there was no significant difference between study 1 and study 2 (10.9 months [95% CI: 5.1–16.8] in study 1 vs. 11.9 months [95% CI: 7.6–24.8] in study 2; HR: 0.77 [95% CI: 0.46–1.31], p = 0.34). Safety profiles did not differ between the patients in studies 1 and 2. Conclusion: Nab-PTX monotherapy may be an effective subsequent treatment option after ICI treatment.

New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo

Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers.

Characteristics of children and adolescents with gender dysphoria for their health care: scoping review

Objective: To identify the demographic and psychosocial characteristics of children and adolescents with gender dysphoria and of the health professionals involved in their care. Methods: Scoping review according to PRISMA-ScR with the databases Web of Science, Science Direct, Scopus, Virtual Health Library and Pubmed, using the descriptors: children, adolescents, gender dysphoria, pediatrics and health professionals. Inclusion criteria: primary and secondary research on gender dysphoria and sexual diversity in health care, with students or health professionals. Exclusion criteria: adult population, other context of health care, treatments, comorbidities and gray publication. Fifteen articles were included. Results: Children present with dysphoria around 6 years of age, with late diagnosis and treatment. They have a greater tendency toward mental health problems such as anxiety, depression and eating disorders, and family support is crucial. Health professionals have low undergraduate training, scarce continuous training and multidisciplinary work. Conclusion: It is necessary to incorporate subjects on diversity, gender identity and dysphoria into the training of health professionals, as well as continuous training with tools that allow a comprehensive approach, increasing confidence and security in the provider-patient relationship, in order to improve the well-being of children.

A practical guide to the diagnosis and management of osteoporosis in childhood and adolescence.

Osteoporosis in childhood distinguishes itself from adulthood in four important ways: 1) challenges in distinguishing otherwise healthy children who have experienced fractures due to non-accidental injury or misfortunate during sports and play from those with an underlying bone fragility condition; 2) a preponderance of monogenic "early onset" osteoporotic conditions that unveil themselves during the pediatric years; 3) the unique potential, in those with residual growth and transient bone health threats, to reclaim bone density, structure, and strength without bone-targeted therapy; and 4) the need to benchmark bone health metrics to constantly evolving "normal targets", given the changes in bone size, shape, and metabolism that take place from birth through late adolescence. On this background, the pediatric osteoporosis field has evolved considerably over the last few decades, giving rise to a deeper understanding of the discrete genes implicated in childhood-onset osteoporosis, the natural history of bone fragility in the chronic illness setting and associated risk factors, effective diagnostic and monitoring pathways in different disease contexts, the importance of timely identification of candidates for osteoporosis treatment, and the benefits of early (during growth) rather than late (post-epiphyseal fusion) treatment. While there has been considerable progress, a number of unmet needs remain, the most urgent of which is to move beyond the monotherapeutic anti-resorptive landscape to the study and application of anabolic agents that are anticipated to not only improve bone mineral density but also increase long bone cross-sectional diameter (periosteal circumference). The purpose of this review is to provide a practical guide to the diagnosis and management of osteoporosis in children presenting to the clinic with fragility fractures, one that serves as a step-by-step "how to" reference for clinicians in their routine clinical journey. The article also provides a sightline to the future, emphasizing the clinical scenarios with the most urgent need for an expanded toolbox of effective osteoporosis agents in childhood.

P564 Surgical treatment of jejuno-ileal Crohn’s disease. Results from the The JejUno Ileal Crohn's disEase (JUICE) international, multicentric, observational study

Abstract Background Crohn’s disease (CD) affecting the upper gastrointestinal (GI) tract is a rare condition, leading to a scarcity of information regarding its diagnosis, surgical treatment, and adjuvant therapy. The JUICE study aimed to conduct a surgical audit of duodeno-jejuno-ileal CD across 11 European IBD Referral Centres. Methods The study included all the consecutive, non-selected patients undergoing surgery for upper-GI CD between January 2010 and December 2022. Patients with synchronous ileal and colonic locations were included, while those with previous upper-GI CD surgery or multiple surgeries for ileo-colic CD were excluded. Univariate and multivariate analyses of 120 variables, covering pre-operative characteristics, intra-operative findings, and post-operative follow-up, were conducted. Results The study encompassed 279 patients, with a male/female ratio of 2.2. The average age at diagnosis was 30±14 years, and the disease duration was 11±10 years. The Montreal Classification revealed A1 15.4%, A2 61.3%, A3 23.3%; L1+L4 34.4%, L2+L4 4%, L3+L4 26.9%, isolated L4 34%; B1 1.8%, B2 67.4%, B3 30.8%; perianal location 19.4%. BMI averaged 21±3. Preoperative nutritional support was necessary in 50.5%. MRI-enterography was the predominant preoperative examination (86.7%). Comorbidities were present in 24.7%, with 61% having an ASA score &amp;gt;1. In the 30 days pre-surgery, 16.8% used steroids, 41.2% received biologicals, with 24.6% on combined (biologicals + steroids) therapy. Video-assisted approach was used in 70%, with a 5.1% conversion rate. Intraoperative staging revealed 1334 locations treated with 247 resections, 500 strictureplasties, 12 bypasses, and 53 concomitant colonic resections. Entero-enteric fistulas and intra-abdominal abscesses were present in 29% and 14%. Patients with thickened mesentery, wrapping fat, and lymph node enlargement were 50.8%, 38.7%, and 50.8%, respectively. Mortality was 1%, Clavien-Dindo grade 3 and 4 complication rate 11.1%. Hospital stay averaged 10±6 days; 90-day readmission was 3.2%. B3 behaviour, smoking, preoperative malnutrition, and preoperative biological therapy increased postoperative complication risk (p=0.01). 10-year Kaplan-Meier surgical recurrence rate was 23%, reduced to 11% with early and continuous post-op biologic treatment compared to late treatment or suspension (60% - Log-Rank p&amp;lt;0.0001). Conclusion This is by far the largest series of upper-GI CD ever studied, depicting a little known, complex, technically demanding sub-group of patients. Preoperative optimization, focusing on preoperative nutritional status and therapy, is crucial to reduce complication risk. Early-onset post-operative biological therapy seems to significantly reduce long-term surgical recurrence.

Induced pluripotent stem cell-derived exosomes attenuate vascular remodelling in pulmonary arterial hypertension by targeting HIF-1α and Runx2.

Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.